The contributions of oxytocin and vasopressin pathway genes to human behavior

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Hormones and Behavior 61 (2012) 359–379

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Review

The contributions of oxytocin and vasopressin pathway genes to human behavior

Richard P. Ebstein a,b,⁎, Ariel Knafo b, David Mankuta c, Soo Hong Chew d, Poh San Lai e

a Department of Psychology, National University of Singapore, Singaporeb Department of Psychology, Hebrew University Jerusalem, Israelc Department of Obstetrics and Gynecology, Hadassah Medical Center, Hebrew University, Jerusalem, Israeld Department of Economics, National University of Singapore, Singaporee Department of Pediatrics, National University of Singapore, Singapore

⁎ Corresponding author at: Department of Psycholo66396945.

E-mail address: rpebstein@gmail.com (R.P. Ebstein).

a b s t r a c t

Article history:Received 11 October 2011Revised 20 December 2011Accepted 21 December 2011Available online 29 December 2011

Keywords:OxytocinVasopressinADP-ribosyl cyclase (CD38)Oxytocin receptor (OXTR)Arginine vasopressin 1a receptor (AVPR1a)Arginine receptor 1b receptor (AVPR1b)LNPEP (oxytocinase)Plasma oxytocinNeurophysinPolymorphism

Arginine vasopressin (AVP) and oxytocin (OXT) are social hormones and mediate affiliative behaviors inmammals and as recently demonstrated, also in humans. There is intense interest in how these simple non-apeptides mediate normal and abnormal behavior, especially regarding disorders of the social brain such asautism that are characterized by deficits in social communication and social skills. The current reviewexamines in detail the behavioral genetics of the first level of human AVP–OXT pathway genes includingarginine vasopressin 1a receptor (AVPR1a), oxytocin receptor (OXTR), AVP (AVP-neurophysin II [NPII]) andOXT (OXT neurophysin I [NPI]), oxytocinase/vasopressinase (LNPEP), ADP-ribosyl cyclase (CD38) and argininevasopressin 1b receptor (AVPR1b). Wherever possible we discuss evidence from a variety of research tracksincluding molecular genetics, imaging genomics, pharmacology and endocrinology that support theconclusions drawn from association studies of social phenotypes and detail how common polymorphismsin AVP–OXT pathway genes contribute to the behavioral hard wiring that enables individual Homo sapiensto interact successfully with conspecifics.This article is part of a Special Issue entitled Oxytocin, Vasopressin, and Social Behavior.

Contents

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 360Structural genes for OXT and AVP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 360

OXT–AVP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 360Genes for metabolism. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 361

Oxytocinase/vasopressinase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 361Overview of the AVP and OXT receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 361

OXTR gene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 362Autism and OXTR . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 362

Non-genetic evidence for a role of OT in autism. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 363Genetic studies in healthy subjects. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 363Neuroeconomics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 365Failure to replicate association studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 365Imaging genomics and OXTR . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 366CD38 and autism spectrum disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 366

CD38 expression in lymphoblastoid cells. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 366Retinoids (Vitamin A) and CD38 expression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 367Link between CD38 expression and clinical characteristics in the ASD sample . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 367

Plasma OXT levels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 368AVPR1a receptor gene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 370

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360 R.P. Ebstein et al. / Hormones and Behavior 61 (2012) 359–379

Autism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 371Neuroeconomics and the AVPR1a receptor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 371Affiliative behaviors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 372Eating, social behavior and AVPR1a . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 372Dance and music . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 373Microsatellite functionality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 373AVPR1a SNP polymorphisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 373

Substance abuse . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 373AVPR1b . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 373Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 374Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 374References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 374

Introduction

This review examines the genes encoding the proximate elementsof the OXT–AVP neural pathways including the receptors for oxytocin(OXTR) and arginine vasopressin (AVPR1a and 1b), CD38 – ADP-ribosyl cyclase recently found to mediate brain OT release (Jin et al.,2007) and oxytocinase (LNPEP) – the enzyme that metabolizes OXTand AVP but also likely is the receptor for angiotensin IV (Albistonet al., 2001; Albiston et al., 2003). There is now an extensive literatureon these polymorphic genes and their role in modulating the socialbrain in humans. Genes encoding synaptic elements of other impor-tant neurotransmitter systems that interact with the OT–AVP neuralpathways specifically gonadal sex hormone genes (Choleris et al.,2009; Rissman, 2008) and genes related to the HPA-axis and stress(Chen et al., 2011; Koolhaas et al., 2010; Szczepanska-Sadowska,2008) are not included due to space constraints and the reader is re-ferred to the many reviews on the extended OT–AVP pathway and itsinteractions (Carter et al., 2008). We discuss association studies be-tween OT–AVP gene pathway polymorphisms and social phenotypesand deepen our scrutiny of the literature by bringing into focus otherapproaches including imaging, pharmacology and endocrinology thathave been integrated along with genetics toward understanding howpeptides modulate the social brain in humans. Imaging genomics(Hariri and Weinberger, 2003; Thompson et al., 2010) and pharma-cology are powerful approaches and a number of informative investi-gations have been carried out in the magnet(Furman et al., 2011b;Inoue et al., 2010; Meyer-Lindenberg et al., 2009) as well as byleveraging the novel route of intranasal administration (Born et al.,2002; Fehm et al., 2000) of neuropeptides often combined with inno-vatice paradigms borrowed from behavioral economics (Kosfeld et al.,2005). We also have a full discussion of the relationship betweenplasma OXTmeasurements and social phenotypes including very pre-liminary results from a GWAS analysis carried out by our group.

The five genes that are examined in this review (OXTR, AVPR1aand 1b, CD38 and LNPEP) have been studied with various degrees ofthoroughness regarding social cognition. OXTR and AVPR1a have re-ceived the most attention (Ebstein et al., 2009) and a rich literaturehas evolved in the past decade generating evidence that polymor-phisms in these genes contribute to social and affiliative behaviorsnot only in normal subjects but also to psychopathology. Studies ofthe OXTR receptor have focused on single nucleotide polymorphisms(SNPs) along this gene region whereas resonating with the vole story(Insel, 2010), the promoter repeat regions have been the focus of in-terest for the AVPR1a receptor. Much less attention has been paid toLNPEP despite the potential for this enzyme in modulating OT–AVPneurotransmission and perhaps a likely target of drug interventionin disorders of social cognition. For other neurotransmitter systems,genes encoding the polymorphic metabolic enzymes viz., monoamineoxidase A (MAOA) (Buckholtz and Meyer-Lindenberg, 2009; Caspiet al., 2002; Deckert et al., 1999; Frydman et al., 2011; McDermottet al., 2009; Zhong et al., 2009b) and catechol-o-methyltransferase(COMT)(Egan et al., 2003; Lachman et al., 1996), have been widely

studied and shown to play an important role in modulating classicalneurotransmitter levels extending to the behavioral level. CD38 is anewly discovered mediator of the release of OXT (Jin et al., 2007).We will discuss neurogenetic and expression studies that strengthenthe provisional role of this gene in both normal and abnormal socialbehaviors (Ebstein et al., 2011; Lerer et al., 2010; Munesue et al.,2010; Riebold et al., 2011).

To summarize, our purpose in writing this review is to provide thereader with an up to date knowledge of five polymorphic genes thatencode elements of the OT–AVP neural pathways. Notably, increasingevidence suggests that sequence variations at the DNA level in thesegenes appears to partially underlie individual differences in socialskills and affiliative behaviors in both socially intact as well as inindividuals characterized by disorders of social cognition, especiallyautism.

Structural genes for OXT and AVP

OXT–AVP

Whereas many investigations discussed in the following sectionshave focused on the brain receptors for AVP (AVPR1a) and OT(OXTR) and their relation to social phenotypes, little attention hasbeen paid to the structural genes that encode the sequence forthese two hormones, AVP (AVP-neurophysin II [NPII]) and OXT (OXTneurophysin I [NPI]). A notable exception is diabetes insipidus (famil-ial central or neurohypophyseal diabetes insipidus) in which muta-tions in the AVP-NPII gene account for some cases of this disorder(Christensen et al., 2004). The human prepro-AVP-NPII locus andprepro-OT-NPI locus are closely linked on chr 20p13, separated byonly 12 kb of DNA, and are positioned in opposite transcriptional ori-entations (Rao et al., 1992; Summar et al., 1990). Interestingly, a re-cent linkage study by Allen-Brady and colleagues (Allen-Brady et al.,2009) provisionally identified a susceptibility locus for autism spec-trum disorders (ASD) near the AVP-NPII and OXT-NPI gene regionthat met genome-wide significance criteria. Yrigollen and colleagues(Yrigollen et al., 2008) examined two SNPs in the OXT-NPI andAVP-NPII gene region and identified a single SNP rs2740204 thatwas associated with one facet of autistic disorder, stereotyped behav-ior in the 177 probands with ASD studied.

To further explore the possibility that the OXT-NPI and AVP-NPIIgene region confer risk for ASD, we examined (Ebstein et al., 2009)using a robust family-basedmethod all tagging SNPs in this gene region.Altogether 170 subjects diagnosed with ASD from 149 families weregenotyped and both individual SNPs and haplotypes were tested for as-sociationwith ASD.Moreover, to better understand how variants in thisregion may mediate risk for ASD, we also examined association with IQand VinelandAdaptive Behavioral Scales (VABS) (Sparrow et al., 1984a)scores (Ebstein et al., 2009; Lerer et al., 2008). Significant association(P=0.047)was observedwith a single SNP (rs6133010) andASDas de-fined by DSM IV (Ebstein et al., 2009). Additionally, haplotype analysisshowed significant association between two-locus (and three)

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haplotypes and ASD DSM IV. Highly significant association (Pb0.001,Bonferroni corrected) was also observed with four-locus haplotypes(rs4813627-rs2770381-rs3761249-rs6084265) and IQ and the VABS.

It would be of considerable interest in healthy subjects to testSNPs across the OXT-NPI and AVP-NPII gene region for associationwith phenotypes relevant to the social brain such as empathy(Shamay-Tsoory, 2011; Singer et al., 2008), reading of the mind inthe eyes test or RMET (Baron-Cohen et al., 2001), pair bonding(Walum et al., 2008), parenting (Bakermans-Kranenburg and vanIjzendoorn, 2008) and other such behaviors that have been the sub-ject of intensive study by social neuroscientists for the past decade.

Genes for metabolism

Oxytocinase/vasopressinase

LNPEP (human leucyl/cystinyl aminopeptidase; aka P-LAP, IRAP,angiotensin IV receptor and others — see GeneCard for aliaseshttp://www.genecards.org/) located on 5q15 is the peptidase thatmetabolizes oxytocin and vasopressin (reviewed in (Tsujimoto andHattori, 2005)). Other natural hormones cleaved by the enzyme areangiotensin III, Met-enkephalin and dynorphin A. The placental leu-cine aminopeptidase (P-LAP), adipocyte-derived leucine aminopepti-dase (A-LAP) and leukocyte-derived aminopeptidase (L-RAP) belongto one distinct group of the M1 family of aminopeptidases, whichare termed the “Oxytocinase subfamily”. Intracellular localization isthe characteristic feature of the subfamily members. Human genesfor these three enzymes are located contiguously around chromo-some 5q15, suggesting the latest diversion of these genes from a sin-gle ancestral gene. While P-LAP (oxytocinase) is translocated fromintracellular vesicles to plasma membrane in a stimulus-dependentmanner, both A-LAP and L-RAP are retained in the endoplasmic retic-ulum. They contain sequences necessary for the specific localizationin the cell. It is increasingly evident that the subfamily membersplay important roles in the maintenance of homeostasis for a varietyof important and diverse physiological functions including mainte-nance of normal pregnancy (Klimek, 2005; Kozaki et al., 2001;Mizutani et al., 1982; Mizutani et al., 1976; Nomura et al., 2005;Pham et al., 2009), blood pressure regulation (Tsujimoto andHattori, 2005), antigen presentation (Tanioka et al., 2003) andremarkably, memory (Albiston et al., 2001; Gard, 2008; Gard et al.,2007; Tsujimoto and Hattori, 2005).

Intriguingly, oxytocinase is apparently the receptor for angioten-sin IV (Ang IV) (Albiston et al., 2001; Albiston et al., 2008; Chai etal., 2004; Chai et al., 2008; Gard, 2008; Wright et al., 2008). Ang IV fa-cilitates memory retention and retrieval. It also enhances long-termpotentiation (LTP) both in the dentate gyrus in vivo and the CA1region of the hippocampus in vitro (Albiston et al., 2003). Centraladministration of Ang IV and its analogs markedly enhance learningand memory in normal rodents and reverse memory deficitsobserved in animal models of amnesia.

Stimulus-dependent translocation is the most characteristic fea-ture of oxytocinase. Therefore, it is generally considered that thephysiological significance of the translocation is to enhance the cleav-age of peptide hormone substrates at the cell surface and regulatetheir local concentrations. Interestingly, oxytocin induces transloca-tion of oxytocinase and led to a three- to fourfold increase in the en-zyme at the cell surface (Nakamura et al., 2000). Overall, evidencesuggests that in various cell types oxytocinase is translocated fromintracellular vesicles to plasma membrane in a stimulus-dependentmanner.

In the brain, oxytocinase protein is detectable in various regionsincluding cerebral cortex, basal ganglion and cerebellar cortex. In allregions, oxytocinase immunoreactive staining was detected in neuro-nal cells, but not in non-neuronal cells (Matsumoto et al., 2001). Arecent study by Hernandez et al. (Hernandez et al., 2009) examined

acute immobilization stress on oxytocinase activity in rat brain. Inamygdala, oxytocinase activity decreased in stressed animals under-scoring its role in stress regulation. However, a mouse knock-out foroxytocinase using standard tests to assess maternal behavior, includ-ing pup retrieval, feeding and nurturing, found no differences be-tween knock out and wild type dams (Pham et al., 2009).

We are aware of only one published study that examined oxytoci-nase polymorphisms in a human disorder. Prompted by the role of va-sopressin as an essential peptide hormone regulating cardiovascularhomeostasis and an adjunctive vasopressor therapy for septic shockNakada et al. (Nakada et al., 2011) tested for association betweenSNPs in vasopressin pathway genes and altered outcome in patientswith septic shock. Of 17 tested tag SNPs in five vasopressin pathwaygenes (AVP, AVPR1a, AVPR1b, oxytocinase/LNPEP, and OXTR), onlyrs18059 in oxytocinase was associated with 28-day mortality. The au-thors resequenced the 160-kb haplotype block encompassing oxyto-cinase, including rs18059, and genotyped the 230 identified SNPs inthe derivation cohort. The strongest signal was found for rs4869317.They found that the TT genotype was associated with increased plas-ma vasopressin clearance, and the rs4869317 genotype accounted for80% of the variance of serum sodium concentrations (locus-specificheritability) in cardiac surgical patients.

We briefly mention that in unpublished observations (in prepara-tion) from our own group we have preliminary findings suggestive ofassociation between a common non-synonymous SNP polymorphismand ASD as well as VABS scores in the cohort of autism subjects wehave been studying for the past decade (Israel et al., 2008). To ourknowledge, this is the first evidence linking oxytocinase directly toautism and social skills.

To summarize, suggestive evidence indicates itwould be veryworth-while to examine oxytocinase/LNPEP SNP variants in human behavioralphenotypes. We speculate that LNPEP SNPs likely contribute to regula-tion of brain levels of both OXT and AVP and hence this gene could bepotentially important in shaping human social phenotypes and perhapsa target for drug intervention in some disorders of social cognition.

Overview of the AVP and OXT receptors

Although there are several receptors for the AVP nonapeptide in-cluding V1a (AVPR1a), V1b (AVPR1b) and V2 (AVPR2), there is onlyone receptor for oxytocin (OXTR). The AVP receptor family are Gprotein-coupled receptors: the V1a and V1b subtypes are bothcoupled to Gq/11and signal via phospholipase C (Jard et al., 1987;Thibonnier et al., 2001). The V2 receptor subtype is coupled to Gswhich, when activated, elevates cAMP levels by recruiting adenylatecyclase. The genomic characteristics, tissue expression, chromosomallocalization, and regional mapping of the human AVP/OXT receptorgenes are now established (Thibonnier et al., 2001). The genes forthe human AVPR1a, AVPR2 (renal), AVPR1b (pituitary), and OXTR re-ceptors are single-copy genes derived from a common ancestor, butthey are located on different chromosomes: respectively, chromo-somes 12, X,1, and 3. All these genes share the unique featureamong G protein–coupled receptors of an intron located before theseventh transmembrane domain of the receptor sequences. All recep-tors with the exception of V2 are expressed in the brain.

In contrast to AVP, OXT is known to have only one receptor, whichbelongs to the rhodopsin-type (class I) G protein (Gαq11)-coupled re-ceptor family and is coupled to PLC, which controls the generation ofInsP3 and diacylglycerol (DAG), which, in turn, leads to the liberationof Ca2+ from intracellular stores and the activation of protein kinasestype C (PKC), respectively. The oxytocin receptor couples to differentG proteins (for review see (Gimpl and Fahrenholz, 2001)). Indeed, thecoupling of OXTR to Gs and Gi proteins also takes place (Viero et al.,2010). Intriguingly, there is also some evidence for the formation ofheteromeric dimers between the V1a, V2 and OXTR proteins (e.g.V1a/OXTR)(Cottet et al., 2010; Devost and Zingg, 2003; Terrillon

et al., 2003). It is well established that V1a, V2 and OTXR can beexpressed in the same cell line but whether they are co-expressedin native tissues is less clear. Expression of V1a and OXTR in the myo-metrium, however, has been documented (Cottet et al., 2010). Inter-estingly, the V1b receptor has been suggested to dimerize with theCRH receptor (Young et al., 2007).

Formation of heteromeric dimers could have important in vivoimplications and possibly confound interpretations of hormone ef-fects since heterodimer formation introduces an element of uncer-tainty regarding the identity of which ‘receptor’ is activatedfollowing either experimental use of hormones (e.g. sniffing experi-ments) or following normal physiological stimulations. Conceivablyeffects currently attributed to activation of OXT or AVP receptorscould also reflect heterodimer involvement leaving some ambiguityin interpreting experimental findings especially in humans. In thissense, genetic studies may be informative regarding specificity of re-ceptor involvement when there is heterodimer involvement.

OXTR gene

The OXTR gene encodes 389 amino acids and is present as a singlecopy in the human genome mapped to the gene locus 3p25–3p26.2.The gene spans 17 kb and contains 3 introns and 4 exons. Exons 1and 2 correspond to the 5-prime noncoding region. Exons 3 and 4 en-code the amino acids of the OXTR. Intron 3, which is the largest at12 kb, separates the coding region immediately after the putativetransmembrane domain 6. Exon 4 contains the sequence encodingthe seventh transmembrane domain, the COOH terminus, and the en-tire 3′-noncoding region, including the polyadenylation signals. Dele-tion experiments show that approximately 1000 bp upstream of thecoding region are needed for expression of OXTR (Inoue et al., 1994).The transcription start sites are 618 and 621 base pairs upstream ofthe methionine initiation codon and nearby are located a TATA-likemotif and a potential SP-1 binding site. Other known binding sites oftranscription regulating factors, such as AP-1, AP-2, GATA-1, Myb,nucleofactor-interleukin 6 binding consensus sequence, and an acutephase reactant-responsive element, are also present in this region.No estrogen-responsive element was observed except for three half-palindromic estrogen-responsive element motifs (Inoue et al., 1994).However, such half-palindromic 5′-TGACC-3′ motifs can act synergis-tically to bind the estrogen receptor (Kato et al., 1992). The reader isreferred to the discussion in O'Lone et al. (O'Lone et al., 2004) for a full-er explanation of the complex nature of estrogen receptor bindingsites. In many species, OXTR is up-regulated by estrogen and downregulated by progesterone (Murata et al., 2000).

Curiously, despite an increasing number of studies of the poly-morphic OXTR gene in social behavior and cognition (Apicella et al.,2010; Bakermans-Kranenburg and van Ijzendoorn, 2008; Campbellet al., 2011; Costa et al., 2009; Ebstein et al., 2009; Furman et al.,2011a; Gillath et al., 2008; Israel et al., 2008; Israel et al., 2009;Jacob et al., 2007; Kawamura et al., 2010; Kelemenova et al., 2010;Kim et al., 2010; Lerer et al., 2008; Liao et al., 1996; Liu et al., 2010;Lucht et al., 2009; Michelini et al., 1995; Montag et al., 2011; Nakadaet al., 2011; Park et al., 2010; Rodrigues et al., 2009; Sakai et al., 2011;Striepens et al., 2011; Thompson et al., 2011; Wermter et al., 2010;Wu et al., 2005), to our knowledge genetic variants in the promoterregion have yet to be either identified or associated with behavioralphenotypes. Indeed, it is not clear whether there are functional poly-morphic variants in the promoter region of OXTR associated with so-cial traits. Clearly the promoter region of this gene should be a regionof great interest for future behavioral studies.

Autism and OXTR

In the Life Sciences, disease-oriented research often drives humangenetic studies and this is also true for the role of the oxytocin

receptor in human behavior. The study of Wu et al. (Wu et al.,2005) was the first to examine OXTR gene variants (SNPs) in a behav-ioral phenotype-autism. They genotyped four SNPs located within theOXTR gene of 195 Chinese Han autism trios. A family-based associa-tion test (FBAT)(Horvath et al., 2001) revealed a significant geneticassociation between autism and two of the SNPs tested for the A allele(rs2254298 G>A and rs53576 G>A). When haplotypes were con-structed with two, three, and four markers, the haplotype-specific,FBAT revealed that a number of haplotypes, particularly those involv-ing rs53576, were significantly associated with autism. Associationwas with DSM IV criteria for autistic disorder. The study by Wu etal. was followed up by Jacob et al. (Jacob et al., 2007). They testedwhether these associations replicated in a Caucasian sample withstrictly defined autistic disorder and genotyped the two previouslyassociated SNPs from Wu et al. (rs2254298 and rs53576) in a smallnumber of only 57 Caucasian autism trios. Significant associationwas detected at rs2254298 (p=0.03) but not surprisingly atrs53576 (perhaps an issue of power?). For rs2254298, over-transmission of the G allele to probands with autistic disorder wasfound which contrasts with the over-transmission of A previouslyreported in the Chinese Han sample. The authors suggest that over-transmission of different alleles in different populations may be dueto a different pattern of linkage disequilibrium (LD) between themarker rs2254298 and an as yet undetermined susceptibility variantin OXTR. See our discussion of this so-called ‘flip-flop’ phenomenon inthe section entitled “Failure to replicate”. The third study of OXTR andautism was carried out by our group (Lerer et al., 2008) and similar tothe first two investigations we observed significant associations be-tween some SNPs across the OXTR gene region and ASD. We exam-ined all the tagging SNPs in the OXTR gene region. Significantassociation with single SNPs and haplotypes (global P-valuesb0.05,following permutation test adjustment) were observed with ASD. Im-portantly associationwas also observedwith IQ and the Vineland Adap-tive Behavior Scales (VABS). In particular, a five-locus haplotype block(rs237897-rs13316193-rs237889-rs2254298-rs2268494) was signifi-cantly associated with ASD and a single haplotype (carried by 7% ofthe population)within that block showed highly significant association.One SNP (rs2254298 G allele) associated with VABS daily living skillsand communication subdomain scores was previously identified to beassociated with autism in the study by Jacob et al.(Jacob et al., 2007).A second SNP rs1042778 (G allele) was also significantly associationwith DSM IV autistic disorder.

A most interesting study of the OXTR gene and autism was carriedout by Gregory et al. (Gregory et al., 2009). Firstly, they looked at copynumber variations in a group of 119 unrelated probands. Intriguingly,the most significant CNV they observed was a heterozygous deletionof OXTR in a single individual with autism and his mother with putativeobsessive–compulsive disorder. Next, they investigated the relationshipbetween OXTR and autism by carrying out an epigenetic analysis of thepromoter region of OXTR and showed that the gene is hypermethylatedin independent cohorts with autism as compared to controls, in bothperipheral blood mononuclear cells (PBMCs) and the temporal cortex.The epigenetic signature appears to have predicted functional conse-quences; analysis of expression levels in the temporal cortex showsdecreased levels of OXTR expression in autism compared to controls.

Altogether, the importance of this investigation is two-fold. Firstly,it strengthens the connection between OXTR and autistic disordersand secondly, and most importantly, the study underscores the roleof the epigenome in contributing to deficits in social behavior mediat-ed by methylation of a CpG island in the receptor for a social hor-mone. Additionally, by showing a correlation between PBMCs andbrain methylation patterns in the OXTR gene this investigationshows ‘proof of principle’ that peripheral methylation patterns maybe relevant to brain function of this critical receptor.

Additional evidence for involvement of OXTR came from a Finnishstudy which identified chromosome region 3p24-26 containing the

OXTR gene as a region linked to autistic disorder(Ylisaukko-oja et al.,2006; Ylisaukko-oja et al., 2005) (see also (McCauley et al., 2005;Shao et al., 2002)). Association was also observed in a Japanese sam-ple(Liu et al., 2010). The authors analyzed 11 SNPs using both FBATand population-based case–control tests. No significant signal wasdetected in the family-based test. However, significant differenceswere observed in allelic frequencies of four SNPs, includingrs2254298 between patients and controls using a population-basedapproach. The risk allele of rs2254298 was ‘A’, which was consistentwith the previous study in Chinese, and not with the observationsin Caucasians. The difference in the risk allele of this SNP in previousstudies is likely attributable to an ethnic difference in the LD structurebetween the Asians and Caucasians.

Association was also observed in a large American sample byCampbell et al. (Campbell et al., 2011). They examined 25 markersspanning the OXTR locus in 1238 ASD pedigrees including 2333 indi-viduals with ASD. Association of three markers previously implicatedin ASD susceptibility, rs2268493, rs1042778, and rs7632287, was ob-served. Further, these genetic markers were associated with multiple,core ASD phenotypes, including social domain dysfunction. However,the results should be interpreted with caution because none of thesignificant associations would survive appropriate correction for mul-tiple comparisons.

In a sample from Slovakia (Kelemenova et al., 2010) no evidencewas obtained for association between OXTR SNPs and ASD. In a rela-tively large combined sample from Ireland, Portugal and the UK(Tansey et al., 2010) only nominal association was observed betweenASD and a single OXTR SNP, rs7632287. Interestingly, Campbell et al.(Campbell et al., 2011) also report association between this SNP andautism. As discussed below this SNP has also been associated withpair bonding in socially-intact subjects (Walum et al., 2011). Park etal. (Park et al., 2010) report an association between rs53576 andADHD and the AA genotype was associated with better social abilitycompared to the AG genotype. Additionally, significant associationwas also found for a second OXTR SNP, rs13316193 (CC genotype) as-sociated with poorer social ability. No significant association betweengenotype and OXTR mRNA expression was found. The authors con-clude that their study supports previous evidence that the OXTRgene is implicated in social cognition albeit not in autism. Interesting-ly, there is evidence for modest shared genetic influences betweenADHD- and autistic traits (Ronald et al., 2010). A study by Sakai etal. (Sakai et al., 2011) showed no evidence in a mixed sample (His-panics and Whites) for association between conduct disorder andOXTR tagging SNPs. However, SNP rs53576 was not examined.

There is considerable interest in the role of OXT (and AVP) neuro-modulators in psychopathology beyond autistic disorders. In an Ital-ian study (Costa et al., 2009) genotype distributions of the two, bynow familiar, OXTR SNPs, rs53576 (G>A) and rs2254298 (G>A),was determined among patient groups with depression (bipolar andunipolar) and compared to a healthy control group. In the unipolargroup, a reduced number of A-carriers for both SNPs were evidenced.The bipolar group did not reveal significant differences compared tocontrol subjects. Interestingly, GG (for both rs53576 and rs2254298)individuals showed high scores on Attachment Style Questionnairefactors that have been previously associated with depression. More-over, the GG genotype was also associated with high levels of adultseparation anxiety.

Non-genetic evidence for a role of OT in autism

Other evidence supporting a role of OXT in autistic disorderscomes from several sources. For example, there is some evidence forreduced OXT plasma levels in children with autism perhaps due todeficits in OXT peptide processing (Green et al., 2001; Modahl et al.,1998). From animal studies, there is evidence for social deficits reso-nating with human autism in the oxytocin receptor null mice (Braida

et al., 2010; Sala et al., 2011; Winslow and Insel, 2002). Oxytocin ad-ministration either by infusion (Hollander et al., 2003) or intranasalroute (Andari et al., 2010; Green and Hollander, 2010; Guastella etal., 2010; Hollander et al., 2007) leads to clinical improvement in sev-eral small clinical studies. As expected intranasal administration of OTin normal subjects has marked effects on the activation of the so-called social brain as evidenced by brain imaging studies (Domes etal., 2007; Domes et al., 2010; Febo et al., 2005; Kirsch et al., 2005;Petrovic et al., 2008; Riem et al., 2011; Shamay-Tsoory, 2011). Thereader is referred to an excellent review for a more detailed discus-sion of ‘sniffing’/intranasal effects of OXT on the human social brain(Macdonald and Macdonald, 2010).

Great interest has been generated regarding the role of the brainmirror neuron system in autism (Iacoboni and Dapretto, 2006;Martineau et al., 2010; Oberman et al., 2005; Oberman et al., 2008;Rizzolatti et al., 2009). Coupled with the role of social hormones inASD it seemed to us worthwhile to examine whether OXT modulatesmirror neurons. Electrophysiological studies in humans associatedthe suppression of EEG in the mu/alpha and beta bands with percep-tion of biological motion and social stimuli (Muthukumaraswamyand Johnson, 2004;Muthukumaraswamy et al., 2004). It has been sug-gested that mu and beta suppression over sensory-motor regions re-flects a resonance system in the human brain analogous to mirrorneurons in the monkey (Pineda, 2005). We therefore hypothesizedthat OXT, the paramount human and animal social hormone, wouldenhance this suppression. Indeed, our study (Perry et al., 2010) forthe first time linked the action of this neuropeptide with a human cor-relate of mirror neuron activity. Twenty-four students were adminis-tered 24 IU of OXT or placebo intranasally in a robust, double-blindwithin-subject design. 45 min later participants were shown a point-light display of continuous biological motion of a human figure'swalk. In the 8–10 Hz (low alpha/mu band) and in the 15–25 Hz betaband, a significant main effect of treatment showed that suppressionwas significantly enhanced in the OXT versus the placebo conditionsand that this suppression was widespread across the scalp (seeFig. 1). These results are a first step linking OXT to the modulation ofEEG rhythms in humans, suggesting that this neuropeptide mayhave a role in allocating cortical resources to social tasks partly medi-ated by mirror neuron activity. Moreover, the connection we haveshown here between OT and mirror neuron activity suggests the no-tion that one pathway by which this neuropeptide contributes toproblems of social cognition in autism might be mediated by thebrain mirror neuron system.

Genetic studies in healthy subjects

Of particular interest are molecular genetic studies of behavioralphenotypes in non-clinical subjects. For example, Lucht et al. (Luchtet al., 2009) tested associations between positive and negative affectas well as social and emotional loneliness in 285 adults, IQ in 117 ad-olescents and polymorphisms of OXTR (rs53576, rs2254298 andrs2228485) in normal subjects. Male subjects with the rs53576 A/Agenotype showed lower positive affect scores. Notably, haplotypesconstructed with the three markers were showed high significant as-sociation with positive and negative affect and emotional loneliness.Additionally, non-verbal intelligence was significantly reduced inrs53576 A/A adolescents.

A Dutch group (Bakermans-Kranenburg and van Ijzendoorn,2008) examined the role of the serotonin transporter (SLC6A4)promoter-region polymorphism 5-HTTLPR and OXTR rs53576 towardexplaining differences in sensitive parenting in a community sampleof 159 Caucasian, middle-class mothers with their 2-year-old toddlersat risk for externalizing behavior problems. Independent genetic ef-fects of 5-HTTLPR and OXTR rs53576 on observed maternal sensitivitywere found. The 5-HTTLPR short and OXTR rs53576 AA/AG genotypeshowed lower levels of sensitive responsiveness to their toddlers.

Fig. 1. (a) Suppression in the 8–10 Hz range, OT versus placebo. Both bars show sup-pression for the biological motion conditions compared to the non-biological condi-tion, but this suppression is enhanced significantly by OT. Error bars representstandard error (SE). (b) 8–10 Hz interaction between treatment x motion. OT had anopposite effect on EEG for perception of biological versus non-biological stimuli.(Perry et al., 2010).

In another study, however, of adult attachment variants of theOXTR rs53576 were not related to either attachment anxiety or avoid-ance (Gillath et al., 2008).

Rodrigues et al. (Rodrigues et al., 2009) genotyped a group of nor-mal subjects for OXTR rs53576 and tested association with two keysocial processes hypothesized to be related to OXT: empathy andstress reactivity. Compared with individuals homozygous for the G al-lele of rs53576 (GG), individuals with one or two copies of the A allele(AG/AA) exhibited lower behavioral and dispositional empathy, asmeasured by the “Reading the Mind in the Eyes Test” (Baron-Cohenet al., 2001) and an other-oriented empathy scale. Furthermore, AA/AG individuals displayed higher physiological and dispositional stressreactivity than GG individuals, as determined by heart rate responseduring a startle anticipation task and an affective reactivity scale.

Psychological resources-optimism, mastery, and self-esteem areoften hypothesized to buffer the deleterious effects of stress and arepredictors of neurophysiological and psychological health-relatedoutcomes. These resources have been shown to be highly heritable,yet the genetic basis for this heritability remains unknown. Interest-ingly, Saphire-Bernstein et al. (Saphire-Bernstein et al., 2011) reporta link between the OXTR rs53576 and psychological resources, suchthat carriers of the “A” allele have lower levels of optimism, mastery,and self-esteem, relative to G/G homozygotes. OXTR was also associ-ated with depressive symptomatology. Mediation analysis indicatesthat the effects of OXTR on depressive symptoms may be largely me-diated by the influence of OXTR on psychological resources.

In a recent studyWalum et al. (Walum et al., 2011), by leveraging alarge Swedish twin cohort, demonstrated that the OXTR rs7632287was significantly associated with two different measures of pair-bonding. Furthermore, when investigating the influence of the

rs7632287 SNP on marital problems assessed by the women and thequality of the marital relationship described by their spouses, signifi-cant associations were also detected. They also showed that, in girls,the rs7632287 “A” SNPwas associatedwith childhood social problems(which longitudinally predict behavior in romantic relationships inearly adulthood). Finally, this “A” SNPwas also shown to be associatedwith autism-related traits in their sample. The authors note that thedirection of allelic effect is discordant between their study and thestudies of this allele in DSM IV autism, a puzzling observation. In theCampbell et al. study (Campbell et al., 2011) the rs7632287 G allelewas associated with narrow autism using both the additive modeland the recessive model. In the Tansey et al. study (Tansey et al.,2010) nominal association was observed with rs7632287 for the G al-lele, which did not survive multiple testing. When all samples werecombined only rs7632287 was nominally associated with autism.This SNP is located in the 3′-UTR, a region with an often regulatoryfunction via interaction with miRNA(Krek et al., 2005).

Kogan et al. (Kogan et al., 2011) used a neurogenetic approach andexamined non-verbal prosocial displays. They hypothesized that thatif individual differences in rs53576 are indeed related to people's pro-clivity toward prosocial behavior, then it is likely that individuals ho-mozygous for the G allele will also display their prosociality in specificnonverbal displays. These nonverbal displays of prosocial behavior,they further reasoned, should reliably signal the prosociality of indi-viduals homozygous for the G allele to naive observers. Despite thesmall number of subjects involved in the experiment, the resultsfrom this study appeared to support their main hypotheses. For ex-ample, of the 10 most trusted targets, 6 were homozygous for the Gallele; of the 10 least trusted targets, 9 were carriers of the A allele.These results demonstrate that differences in rs53576 systematicallypredict outside observers' judgments of the prosociality of carriersbased on observations of 20 s of silent behavior.

A Dutch group (Tops et al., 2011) reports that compared to the AA/AG genotypes, the presumably more efficient OXTR rs53576 GG geno-type is related to less self-reported difficulty in hearing and under-standing people when there is background noise. Their resultsfurther extend the association between oxytocin and social proces-sing to a range of non-verbal human social behaviors.

A recent report investigated whether a common single nucleotidepolymorphism (rs53576) in the oxytocin receptor gene (OXTR) mightinteract with stress-protective effects of social support (Chen et al.,2011). Salivary cortisol samples and subjective stress ratings wereobtained from 194 healthy male participants before, during, and aftera standardized psychosocial laboratory stress procedure. Participantswere randomly assigned either to prepare alone or to receive social sup-port from their female partner or close female friend while preparingfor the stressful task. Differential stress responses between the geno-type groupswere observed dependingon the presence or absence of so-cial support. Only individuals with one or two copies of the G allele ofrs53576 showed lower cortisol responses to stress after social support,compared with individuals with the same genotype receiving no socialsupport. These results indicate that genetic variation of the oxytocinsystem modulates the effectiveness of positive social interaction as aprotective buffer against a stressful experience.

Johansson et al. (Johansson et al., 2011) examined 116 subjects inthe Response Choice Aggression Paradigm (RCAP) to measure aggres-sive behavior (Zeichner et al., 1999) and the Go-noGo paradigm, ameasure of behavioral control. Subjects were additionally screenedfor alcohol use (subjects with alcohol problems were excluded) andgenotyped for 12 OXTR SNPs. On the day of the experiments, partici-pants were given a measured dose of alcohol or placebo prior to theexperiment. The results showed that participants in the alcoholgroup showed higher levels of aggressive behavior. A significantmain effect of provocation on aggression was also found, with higherlevels of provocation being associated with higher levels of aggres-sion. One significant main effect of the OXTR polymorphisms on

aggressive behavior was found. Participants who were carriers of theG/G and T/G rs1042778 genotype, showed higher levels of aggressionthan T/T individuals. Moreover, the effect of alcohol intoxication onaggressive behavior was nominally moderated by rs1488467 andrs4564970. The interaction between rs4564970 and alcohol was sig-nificant following correction for multiple testing. Although thisstudy was done on a relatively small number of subjects, it is notableas the first to experimentally examine interactive effects betweenacute alcohol intoxication and OXTR on aggressive behavior inhumans.

To summarize, some but not all association studies suggest thatpolymorphisms in the OXTR gene contribute to social behavior inboth normal subjects as well as in individuals characterized by dys-functional social cognition. The suggested link between OXT andASD is strengthened by an accumulating body of indirect evidence in-cluding investigations of clinical syndromes such as ADHD and de-pression but also in studies of traits relevant to social cognition suchas empathy, mind-reading, and personality in non-clinical subjects.These investigations show that OXTR SNPs, particularly rs53576 butalso rs2254298 and rs1042778, are important in human social behav-ior including aggression. Moreover, brain imaging studies (discussedin the following sections), including morphology and functional im-aging, further strengthen the involvement of OXTR genetic variantsin shaping the social brain in humans.

An important issue in trying to understand how OXTR SNPs con-tribute to individual differences in social behaviors is the functionalityof these variants, especially since many of these SNPs that are locatedin introns or inter-gene regions. However, intronic enhancer elementsthat amplify mRNA levels are certainly not uncommon and manyexamples continue to be identified (Maeda et al., 2010; Menon et al.,2011; Sribudiani et al., 2011; Wang et al., 2011). Additionally, someintronic polymorphisms give rise to splice variants (Arenas et al.,2009; Oh et al., 2011; Raistrick et al., 2010; Weickert et al., 2008).Another mechanism by which intronic polymorphisms may conferfunctionality is by methylation of CpG island located in their vicinity(Xue et al., 2011).Overall, functionally relevant binding sites for tran-scription factors exist in regions outside of gene promoters, particular-ly in introns (Lin et al., 2007b; Stevens et al., 2004; Wang et al., 2005).Sites distal to genes or within introns might function through long-range interactions that involve looping of chromatin to bring the reg-ulatory elements within proximity of gene promoters (Wells andFarnham, 2002). Recent reports about intronic binding of other tran-scriptional factors provide further support that intronic binding maybe an axis of gene regulation.(Impey et al., 2004).

Neuroeconomics

Neuroeconomics is a burgeoning research field focused on theneural basis of decision making and firmly based on the twin preceptsof experimental and behavioral economics: incentivized choicegames (Hertwig and Ortmann, 2001) and no lying (no deceit) to sub-jects. This ‘put your money where your mouth is’ approach combinedwith complete transparency in experimental design including fulldisclosure to the subjects participating in the experiment, differsmarkedly from standard psychological experimentation in humans(Ariely and Norton, 2007).

In a first study of its kind, we used a classic experimental econom-ic paradigm — the Dictator Game (DG), to model human altruism inthe laboratory and found a relationship between the length of apromoter-region repeat in the AVPR1a receptor gene and allocationof funds (Knafo et al., 2008) (discussed in detail in the next sections).We followed up our initial observation by examining SNPs across theOXTR gene and testing for association with DG giving behavior (Israelet al., 2009). In addition to the DG paradigm we also employed theSocial Values Orientation (SVO) task (De Dreu and Van Lange, 1995;Van Lange, 1999; Van Lange et al., 2007; Van Lange et al., 1997).

Association (101 male and 102 female students) using a robust-family based test between 15 single tagging SNPs (htSNPs) acrossthe OXTRwas demonstrated with both the DG and SVO. Three taggingSNPs showed significant association with both of the two games. Themost significant association was observed with rs1042778 (p=0.001).Haplotype analysis also showed significant associations for bothDG andSVO. Following permutation test adjustment, significancewas observedfor 2–5 locus haplotypes (pb0.05). A second sample of 98 female sub-jects was subsequently and independently recruited to play the DGand was genotyped for the three significant SNPs found in the firstsample. The rs1042778 SNP was shown to be significant for the secondsample as well (p=0.004, Fisher's exact test).

However, in an attempted replication of the Israel et al. findings(Israel et al., 2009), Apicella and his colleagues (Apicella et al.,2010) tested associated between nine OXTR polymorphisms (includ-ing rs1042778 and rs237887) and behavior elicited from two stan-dard economic games, the DG and the Trust Game, in a sample of685 individuals. The experiments were also conducted with realmonetary consequences. After correction for multiple hypothesistesting, in contrast to the findings reported by our group (Israel etal., 2009), they found no significant associations between any of the9 single nucleotide polymorphisms (SNPs) and behavior in either ofthe games. The most significant association in the Apicella et al.study is between rs75775 located upstream of OXTR and prosocial be-havior in men. The authors are cautious whether to consider this atrue association since it is observed at nominally significant p levelsand only for the Trust Game.

Failure to replicate association studies

There are many reasons for failure to replicate in association stud-ies including the so-called ‘winner's curse’ (Zollner and Pritchard,2007). In large part, the difficulties of replication occur because evenmost genuine associations have modest effects; hence, there is gener-ally incomplete power to detect associations in any given study. Non-replication does not ipso facto imply that one's first finding is spurious(although it might well be!). Other reasons for non-replication in-clude genetic and cultural differences between t populations as wellas differences in LD between the causal variant SNP and the genotypedSNPs across ethnic groups each with its own LD structures.

Associations of opposite alleles at the same biallelic locus with thesame disease (as discussed above for some of the OXTR SNPs associat-ed with autism (Campbell et al., 2011; Gregory et al., 2009; Jacob etal., 2007; Liu et al., 2010; Lucht et al., 2009; Park et al., 2010; Wu etal., 2005)) are confusing findings, particularly when observed in thesame ethnic group (Lin et al., 2007a). For example, both the longand short alleles at the 5-HTTLPR locus of the serotonin transportergene have been found to be risk alleles for autistic disorder in differ-ent studies (Cook et al., 1997; Klauck et al., 1997; Yirmiya et al.,2001). Further examples of such ‘flip-flop’ associations are discussedin the review by Lin et al. (Lin et al., 2007a). Flip-flops of risk allelesmay be more easily explained by population differences. These asso-ciations may indicate heterogeneous effects of the same variant thatare due to differences in genetic background or environment. It iswell known that changing the genetic background (strain) in trans-genic mouse experiments can significantly change the resulting phe-notype. Differences in LD between populations could also lead toinconsistent patterns of association when noncausal variants are test-ed. Lin et al. (Lin et al., 2007a) used theoretical modeling to demon-strate that flip-flop associations can occur when the investigatedvariant is correlated, through interactive effects or linkage disequilib-rium, with a causal variant at another locus, and they show how thesefindings could explain previous reports of flip-flop associations.Despite such plausible explanations, it remains arguable whetherflip-flop associations in general suggest confirmation or perhapsspurious association.

Imaging genomics and OXTR

Several studies have used an imaging genomic strategy towardidentifying the neural correlates of OXTR SNPs (Furman et al.,2011b; Inoue et al., 2010; Tost et al., 2010). Tost et al. (Tost et al.,2010) used multimodal neuroimaging in a large sample of 212healthy human subjects to identify structural and functional alter-ations in OXTR rs53576 carriers (G>A) and their link to tempera-ment. Activation and interregional coupling of the amygdala duringthe processing of emotionally salient social cues was significantly af-fected by genotype. In addition, evidence for structural alterations inkey oxytocinergic regions emerged, particularly in the hypothalamus.The rs53576 minor allele (G>A “A”) carriers, which in some popula-tions is the risk allele in ASD (discussed above), showed a significantdecrease in hypothalamic gray matter. In addition, they observed asignificant genotype by sex interaction effect for rs53576, consistentwith an allele-load-dependent increase in GM volume in male “A”carriers in the right amygdala. They also examined the rs53576 geno-type on TPQ (Cloninger, 1986) Reward scale and found that homozy-gotes for the “A” allele showed the lowest Reward values, whereascarriers and homozygotes of the G allele displayed intermediate andhighest RD values. They also observed a more pronounced dose effectof rs53576 “A” in male participants. Additionally, consistent with theamygdala gray matter increase in male carriers of OXTR rs53576A,they observed a significant negative correlation between localamygdala volume and individual Reward scores in the total sample(r=−0.190, P=0.008). Finally, subjects homozygous for rs53576“A” showed the lowest task-related amygdala activations during emo-tionally salient social cues, and homozygotes for the G allele showedthe highest. In addition, the analysis provided evidence for significantlyincreased coupling of hypothalamus and amygdala in carriers ofrs53576 “A”. These findings identify sex-dependent mechanismsimpacting the structure and function of hypothalamic-limbic circuitsthat are clearly of potential clinical and translational significance.

A second SNP in the OXTR receptor gene has also been associatedwith brain morphology. Applying a manual tracing procedure to high-resolution structural magnetic resonance images, Furman et al. found(Furman et al., 2011b) that despite having greater gray matter volume,participants homozygous for the rs2254298(G>A) “G” allele werecharacterized by smaller volumes of both left and right amygdalasthan were carriers of the “A” allele. This SNP has also been associatedwith autistic disorder by our own group (Lerer et al., 2008) as well asin the original Wu et al. Chinese study (Wu et al., 2005) and more re-cently in a Japanese investigation (Liu et al., 2010). It has also been asso-ciated with depression and anxiety in adolescent girls (Thompson et al.,2011). A whole-brain voxel-based morphometry analysis revealed ad-ditional genotype-mediated volumetric group differences in the poste-rior brain stem and dorsomedial anterior cingulate cortex. As noted bythe authors, these findings highlight one neurobiological pathway bywhich an oxytocin gene variant may increase risk for psychopathology.

Overall, similar results reported by Furman et al. (Furman et al.,2011b) discussed above, were validated in a study by Inoue et al.(Inoue et al., 2010) with 208 socially-intact Japanese subjects. Thers2254298A allele of OXTR was significantly associated with larger bi-lateral amygdala volume. The larger the number of rs2254298 “A” al-leles an individual had, the larger their amygdala volume. Such anassociation was not observed with hippocampal volume or with glob-al brain volumes, including whole gray, white matter, andcerebrospinal-fluid space. Furthermore, two three-single nucleotidepolymorphism haplotypes, including rs2254298 “G” allele, showedsignificant associations with the smaller bilateral amygdala volume.

CD38 and autism spectrum disorders

The accumulating evidence discussed above, that OTplays an impor-tant role in both normal as well as dysfunctional social relationships/

cognition (Ebstein et al., 2009; Israel et al., 2008), ipso facto targetsCD38, a recently-discovered key mediator of OT brain release(Higashida et al., 2010; Higashida et al., 2007; Higashida et al., 2011;Jin et al., 2007; Salmina et al., 2010), as a focus of interest for contribut-ing to normal human social behaviors as well as disorders of social cog-nition especially autism (Bartz and McInnes, 2007; Young, 2007).Indeed, in the past year, two research groups have independentlyaddressed the role of CD38 in autism in human subjects. Higashidaand his colleagues (Munesue et al., 2010) analyzed 10 single nucleotidepolymorphisms (SNPs) and mutations of CD38 by re-sequencing DNAsmainly from a case–control study. CD38 SNPs, rs6449197 andrs3796863 showed significant associations with a subset of ASD sub-jects (IQ>70; designated as high functioning autism/HFA) in 104 Cau-casian family trios, but not with Japanese 188 HFA subjects.Interestingly, a mutation/rare polymorphism that caused tryptophanto replace arginine at amino acid residue 140 (R140W; (rs1800561,4693 C>T)) was found in 0.6–4.6% of the Japanese populationand was associated with ASD in the smaller case–control study.The SNP was clustered in pedigrees in which the fathers and brothersof T-allele-carrier probands had ASD or ASD traits. In this cohort(Munesue et al., 2010), OXT plasma levels were lower in subjects withthe T allele than in those without.

In our first study of CD38 (Lerer et al., 2010), we examined all tag-ging SNPs across the CD38 gene region in 170 subjects diagnosedwith ASD from 149 families (see (Lerer et al., 2008) for descriptionof the subjects). Individual SNPs and haplotypes were tested for asso-ciation with ASD. Additionally, the relationship between diabetes, au-tism and CD38 (Atladottir et al., 2009), as well as the use of CD38 as adisease marker (Malavasi et al., 2008), suggested to us that it wouldalso be worthwhile to explore CD38 expression in immune cell linesderived from ASD patients. These considerations prompted us tomeasure CD38 gene expression in lymphoblastoid cell lines (LBC) de-rived from both ASD subjects and unaffected parents. We also includ-ed in the gene expression and family-based association analysis theSNP (rs3796863), which proved significantly associated with ASD inthe Munesue et al. (Munesue et al., 2010) study. Importantly, theSNP (and the ‘C’ allele) identified in the Munesue et al. study(Munesue et al., 2010) (rs3796863), which they found significantlyassociated with ASD, is located in all except one of the significant hap-lotypes in our study.

CD38 expression in lymphoblastoid cells

We also examined CD38 mRNA levels in LBC derived from sub-jects with autism and unaffected parents (Ebstein et al., 2011;Lerer et al., 2010; Riebold et al., 2011) . In our initial study (Lereret al., 2009) highly significant reduction in CD38 expression was ob-served in cells from the DSM IV ASD subjects (N=44) compared to“unaffected” parents (N=40). These first results (Lerer et al., 2010)have now been partially replicated in a new study from our labora-tory (Riebold et al., 2011). In the new expanded study there was noeffect of gender. In our subsequent investigation (Riebold et al.,2011), we have re-analyzed the EBV lines described in the first re-port, significantly adding to the sample with 38 new cell lines sothat in the second investigation for each proband both of their par-ents were now included in the analysis. Cells in culture, or frozenlines were first thawed, and then cultured, and their CD38 mRNAlevels measured. It was important to determine whether expressionof CD38 is stable and is maintained despite repeated cycles of freez-ing and thawing. The new results confirm that CD38 expression inASD patient lines is substantially lower than in those derived fromthe patients' parents. Although these results are not a fully indepen-dent replication, we believe they nevertheless considerablystrengthen our first findings that reduced CD38 transcription is acharacteristic of peripheral lymphocyte cells derived from ASD sub-jects (Lerer et al., 2010).

Fig. 2. The effect of 48 h 0.1 μm ATRA treatment on CD38 mRNA levels in LBC lines.**, independent samples t test, t=−3.199; P=0.002; prolonged ATRA treatment el-evates reduced CD38 mRNA levels in LBC lines from ASD patients (n=42) above pa-rental (P) basal expression (n=78). Also, basal and induced CD38 mRNA levels aresignificantly reduced in ASD cell lines compared with parental (P) cell lines (***, in-dependent t test; Pb0.001).(Riebold et al., 2011).

Retinoids (Vitamin A) and CD38 expression

All-trans retinoic acid (ATRA) is a potent inducer of CD38(Ferrero and Malavasi, 2002) suggesting the possibility that thiscompound can be used to ‘rescue’ cells exhibiting low CD38 synthe-sis and hence might be a novel therapeutic strategy in treatment of

Fig. 3. Correlation between CD38 mRNA expression and IQ and VABS subscores in lymphn=42); VABS communication (r=0.487; P=0.001; n=42); VABS social skills (r=0.329;(Riebold et al., 2011).

autism. We wanted to determine whether the diminished expres-sion of CD38 in ASD could be reversed through simple treatmentwith ATRA. Such a demonstration would provide in vitro ‘proof ofprinciple’ that retinoids could play a role in the clinical treatmentof ASD. Following 48 h of ATRA treatment, the results indicate thatthe CD38 gene in the EBV lines obtained from the ASD probandsconserves its ability to respond with a significant induction ofCD38 mRNA (Fig. 2). The parental lines display the same ability, al-though to a lesser extent. These results, demonstrating that ATRAcan elevate CD38 levels in cells obtained from ASD subjects whoshow impaired CD38 transcription, strengthen the notion that vita-min A and related retinoids are potential therapeutic agents in thetreatment of ASD.

Link between CD38 expression and clinical characteristics in theASD sample

Our results showing that CD38 expression is reduced in ASDprompted us to examine whether its expression levels might also re-flect phenotypical characteristics of ASD further enhancing the valueof this ectoenzyme as a potential biomarker. We looked at social func-tioning measures that were available for these probands since suchdeficits are a core clinical characteristic of autism. The resultsobtained clearly show a significant correlation (Fig. 3) between tran-scriptional levels of CD38 mRNA and IQ and Vineland Adaptive Be-havioral Scores (VABS) scores (Sparrow et al., 1984b), except forVABS socialization. Nonetheless, the correlation with the VABS totalscores does prove significant (r=0.431, p=0.008 N=42).

CD38 mediates oxytocin brain release (Jin et al., 2007) and impor-tantly, oxytocin itself enhances social learning and memory in thelimbic system (Ferguson et al., 2002). If retinoids modulate CD38

oblast lines derived from ASD subjects. Pearson correlations (IQ r=0.431; P=0.004;P=0.034; n=42); VABS socialization (r=0.294; P=0.059; n=42).

transcription in the brain, which in turn mediates oxytocin release,then the relationship we have shown (Riebold et al., 2011) betweencognitive function and CD38 mRNA levels in LBC cells may be reflect-ing common state characteristics of OT-CD38-RA pathways in differ-ent tissues. Indeed, various studies have employed LBC lines tomodel brain dysfunctions in autism (Hu et al., 2009; Nishimura etal., 2007; Walker et al., 2006) and other neuropsychiatric disorders(Chagnon et al., 2008; De Luca et al., 2008; Kuratomi et al., 2008;Pandey et al., 2008; Tseng et al., 2008).

Plasma OXT levels

A number of investigations have measured plasma OXT andreported intriguing correlations with a broad range of behavioralphenotypes, summarized in Table 1. We have tried to cite the mostinstructive examples selected from the PubMed literature and consid-er that a number of important conclusions can be drawn from thesearch we conducted. Overall, examination of this ever-expandingcorpus of investigations would appear to lay to rest the notion thatplasma OXT measurements are unrelated to central activity of thisneuropeptide. Regardless of how OXT is measured viz., ELISA or RIA,many investigations across a diverse set up behaviors demonstrate arelationship between plasma OXT and behavior. How else to explainthese numerous reports except by the credible assumption that plas-ma OXT reflects in some measure central tone of this neuropeptide?Indeed, as discussed below animal experiments strengthen the con-clusions reached by surveying the many human studies (Table 1)and underscore the value of peripheral plasma OXT to inform on cen-tral oxytocinergic brain activity.

That peripheral OXT measurements indeed may partially indexcentral activity of this neuropeptide is biologically plausible and wesuggest as a model some persuasive studies that have been carriedout with brain derived neurotrophic factor (BDNF) (Blugeot et al.,2011; Lang et al., 2007; Sartorius et al., 2009). Blugeot et al.(Blugeot et al., 2011) showed that in rats vulnerable to ‘depression’in a social defeat model, they displayed lower serum BDNF concentra-tions as well as significantly lower BDNF hippocampal concentrations.Two distinct rat populations were observed, vulnerable and resistantto depression and serum BDNF was the sole predictor of vulnerability.A second study (Sartorius et al., 2009) showed correlations betweenserum BDNF and prefrontal cortex BDNF concentrations followingelectoconvulsive shock. Interestingly in humans, after 5 ECS treat-ments the serum BDNF changes were observed only one week afterthe last shock treatment (Bocchio-Chiavetto et al., 2006) suggestingthat examining immediate changes in plasma peptide levels maynot always be informative of central activity. An imaging studyshowed that in humans BDNF serum concentrations were correlatedwith N-acetylaspartate, a well-established marker for neuronal dam-age, in the anterior cingulate cortex.

Several animal investigations (Grippo et al., 2007a; Grippo et al.,2007b; Landgraf, 1995; Wotjak et al., 1998) address the specific re-lationship between plasma and central measure of OXT and theirconclusions are suggestive. As Landgraf (Landgraf, 1995) notes,“There is compelling evidence which indicates the possibility of coordi-nated as well as independent intracerebral and peripheral release. Thecomplex stimulus of suckling, for instance, results in an apparently par-allel release of OXT with the SON, limbic brain areas and into blood.”.Very similar conclusions are reached regarding the coupling ofbrain and peripheral plasma OXT measurements in experimentsmodeling depression using a social isolation paradigm in the vole(Grippo et al., 2007a; Grippo et al., 2007b). Chronic social isolationespecially in female prairie voles increased circulating levels of plas-ma OXT and an increased density of OXT-immunoreactive cells inthe PVN. Acute responses were elicited by the resident-intrudertest in combination with the chronic social isolation paradigm. Iso-lated females were characterized by an increased acute activation

of the OXT system as indexed by enhanced co-localization of c-Foswith OXT cells in the PVN and elevated plasma OXT levels. Mentionneeds to be made of the findings observed in the CD38−/−mice(Jin et al., 2007). Their results indicate that the deficit in OXT secre-tion due to the absence of CD38 in these knockout mice led to a sig-nificant reduction in brain, CSF and plasma OXT levels andpresumably is due to the reduced ADP-ribosyl cyclase activitywhich is a crucial mediator of brain OXT secretion. To summarize,in different species (voles, rats and mice) and using either behavior-al tasks (suckling versus social isolation) to manipulate brain OXT ormolecular genetic manipulations (knockout) very similar conclu-sions are reached, strongly suggesting that plasma OXT levels are in-formative regarding brain activity of this social hormone. Ofparticular interest is that in the vole, the social isolation model,that resonates with many human clinical conditions, and induceslong-term behavioral changes are indexed by measurements of plas-ma OXT.

Nevertheless, the relationship between basal plasma OXT levelsand overall brain activity of OXT neural pathways is likely complexmost likely reflecting overall brain “tone” and not always tightlycoupled ‘coordinated release.’ Plasma OXT levels reflect a multitudeof processes including direct transport to the peripheral circulationviz., hypothalamus — posterior pituitary, passage of OXT from theextra-cellular space to the CSF, the contribution of peripheral sourcesand finally the clearance of these peptides from the peripheral circula-tion perhaps related to plasma oxytocinase (LNPEP) levels. Releasefrom non-hypothalamic brain areas may enter the peripheral circula-tion from the CSF and have a cumulative effect followingmore chronicmodulations of the OXT neural pathways and over longer timeperiods. For example, in Table 1 there is suggestive evidence thatdepression which is a chronic disorder may be reflected in elevatedplasma OXT levels. Indeed, these human studies (Holt-Lunstad et al.,2011; Parker et al., 2010) similar to the vole model (Grippo et al.,2007a; Grippo et al., 2007b) show increased plasma OXT levels indepression. To summarize, Occam's razor (lex parsimoniae) suggeststhat plasma OXT is an informative measure of central activity of OXTneurons that modulate human social behaviors.

Notably, behavioral effects have been reported both for RIA andELISA measures of plasma OXT. The values for plasma OXT measuredusing ELISA are in the range of 150–250 pg/ml whereas in those re-ports employing RIA much lower levels of OXT are observed(1–10 pg/ml). The reason for this discrepancy is related to either theuse of extraction procedures or the direct measurement of plasmaOXT usually following dilution. Extraction markedly reduces thereported levels of OXT and although some authors claim it is neces-sary (Szeto et al., 2011) others disagree (Carter et al., 2007; Krameret al., 2004). A recent paper by Borg et al. (Borg et al., 2011) very per-suasively shows that increasing concentrations of infused OXT are re-liably monitored using the ‘standard’ Assay Design kit withoutextraction. Carter used unextracted samples (Carter et al., 2007)with the Assay Designs kit and validated that assay using multiplemethods both laboratory based as well as consistent with biology. Al-together, it appears that both methods are generating biologicallyplausible results consistent with what is known regarding the roleof OXT in modulating human behavior.

Our own laboratory has taken a unique approach and implemen-ted a genome-wide association study (GWAS) toward exploring themultiple factors undoubtedly contributing to plasma OXT levels.Genome-wide genotyping for both samples was performed on theIllumina OmniExpress Bead Chips at the Genome Institute of Singa-pore. We recruited 1158 (584 females; age, mean 21.2±S.D. 1.5)Han Chinese undergraduate students at the National University ofSingapore to participate in a study of the biological basis of humanbehavior. Subjects donated 10 to 20 cm3 of blood for analysisincluding plasma oxytocin (Assay Designs without extraction). Theaverage oxytocin level is 212±SD 229 pg/ml. As usually observed

Table 1Correlation of plasma OXT and behavioral phenotypes.

Phenotype Number of Ss Assay method Mean value Results Reference

Trust Game 60; 35 M, 25 F ELISA (Assay Designs) 218±86.6 SD pg/ml OXT>trust-related condition Keri and Kiss (2011)Trust Game 156 Ss

50% MELISA (Assay Designs) 198±165 pg/ml OXT>intention of trust Zak et al. (2005)

Stress 67 F RIA (Landgraf, 1985) b10 pg/ml No effect on OXT followingsocial stress

Ditzen et al. (2007)

Stress 28 F RIA 0.5–6.8 pg/ml OT modulates CV response Grewen and Light (2011)Stress RIA (Landgraf, 1981) 6.80 pg/ml No effect on OXT following

social stress in lactating womenHeinrichs et al. (2001)

Childhood stress 90 M ELISA (Assay Designs) 377.6±23.9 pg/ml Low OXT more anxiety anddepressive symptoms

Opacka-Juffry andMohiyeddini (2012)

Depression+intervention 34 couples ELISA (Assay Designs) Extracted 5–10 pg/ml OXT higher in depression;gender effect

Holt-Lunstad et al. (2011)

Depression and anxiety 25 with major depression RIA 3.6±71.3 ng/ml ?? Negative corr. OXT anxietyand depression

Scantamburlo et al. (2007)

Depression 40 depressed or Bipolar RIA 12 pg/ml OXT reduced in BP anddepressed patients mainlyfor females

Ozsoy et al. (2009)

Depression 30 Ss RIA 1–2 pg/ml hourly measure OXT elevated in depression Parker et al. (2010)Social anxiety 46 Ss

22 controlsELISA (Assay Designs) 145 pg/ml No difference between

patients and controlsHoge et al. (2008)

Emotion 32 F RIA 3.5 pg/ml +emotion OXT decreased Turner et al. (2002)Pair relationships 85 adults

62% FELISA (Assay Designs) 250 pg/ml OXT corr. with distress in

women; AVP corr. with malesTaylor et al. (2010)

Parental bonding 21 M24 F

ELISA (Assay Designs) 258 pg/ml OXT corr. with parentalbonding and inversely tostress/depression

Gordon et al. (2008)

Orgasm 10 M RIA Euro-Diagnostica,Malmö,

~75 pg/ml OXT rises post orgasm Kruger et al. (2003)

Schizophrenia 22 F-SCZ31 F-CON26 M-SCZ26 M-CON

ELISA (Assay Designs) 200–250 pg/ml Females>OXT happier faces Rubin et al. (2011)

Schizophrenia 22 ELISA (Assay Designs) 200–250 pg/ml OXT corr. with anteriorhippocampal volume

Goldman et al. (2008)

Schizophrenia 50 Scz50 controls

ELISA (Assay Designs) 200–250 pg/ml Change in OXT in controlsfollowing trust condition

Keri et al. (2008)

Autism 29 autism30 controls

RIA 0.64 pg/ml OXT lower in autism Modahl et al. (1998)

Parent–infant interaction 55 parents ELISA (Assay Designs) 356 pg/ml OXT corr. with affect synchronyand social engagement

(Feldman et al., 2010;Feldman et al., 2007)

Mother–fetus attachment 78 F ELISA (Assay Designs) 150–250 pg/ml Increase in OXT from early tolate pregnancy correlated withhigher maternal–fetal bonding

Levine et al. (2007)

Parent–infant interaction 26 F RIA NA Complex relationship BPand plasma OXT

Light et al. (2000)

Breast feeding 20 F ELISA (Assay Designs) Extracted4.8 pg/ml

Breast feeding>OXT Grewen et al. (2010)

Breast feeding 63 F ELISA (Assay Designs) Diluted144 pg/m

OXT corr. negatively withACTH levels

Handlin et al. (2009)

Pain sensitivity 48 F RIA 4–8 pg/ml Pain tolerance corr.with >plasma OXT

Grewen et al. (2008)

Addiction 35 F RIA 1 pg/ml Cocaine group had lowerOXT levels

Light et al. (2004)

Post-partum depression (PPD) 74 F RIA (Landgraf, 1981) 80.8±48 pg/ml 3rd trimester OXTpredicted PPD

(Skrundz et al., 2011)

Menstrual cycle 16 F R&D Systems(Abingdon, UK)

8 pg/ml Dysmenorrheic Ss>OXTthan controls at menstruation

Liedman et al. (2008)

Menstrual cycle 30 F RIA 1–3 pg/ml OXT fluctuates during cycle Salonia et al. (2005)Satiety 6 M

4 FELISA (Assay Designs) 150 pg/ml

baseline dilutionOXT perfusion reducessatiety; plasma OXT levelsproportional to perfusion conc.

Borg et al. (2011)

Music 40 open heart Ss ELISA (Assay Designs)Ethanol extracted

73 pg/ml OXT increased in musictherapy group

Nilsson (2009)

Massage 22 F — breast cancer ELISA (Assay Designs)Ethanol extracted

33 pg/ml No significant change in OXT Billhult et al. (2008)

(Ditzen et al., 2007; Grewen and Light, 2011; Heinrichs et al., 2001;Holt-Lunstad et al., 2011; Opacka-Juffry and Mohiyeddini, 2012;Turner et al., 2002), there is no significant gender difference in plas-ma OT levels (pb0.318). Following other investigations (Bick andDozier, 2010; Gordon et al., 2010), we exclude 21 subjects whoseplasma OT is higher than 3 times of standard deviation (>902) inthe subsequent analysis. GWAS results showed no single SNP

reaching genome wide significance levels (5×10−8) in this some-what underpowered sample (for GWAS studies) but a number ofSNPs, especially on chr 1, in our preliminary analysis showed sug-gested linkage to plasma OXT levels as shown in the Manhattanplot (Fig. 4).

Two candidate gene studies have reported associate betweenspecific SNPs and plasma OXT levels. Higham et al. (Higham et al.,

Fig. 4. Manhattan (upper panel) and Chromosome 1 regional association (lower panel) plots for genome-wide analysis of plasma oxytocin levels. The negative logarithm of single-point P-values (vertical axis) are plotted against chromosomal location (X-axis). The horizontal blue line indicates P=0.0001, a threshold for nominal evidence of association withplasma oxytocin levels.

2011) examined the relationship between a common polymorphism(OPRM1) and plasma oxytocin levels in rhesus monkeys. In rhesusmacaques, variation in OPRM1 predicts individual differences in in-fant affiliation for mothers. Specifically, infants carrying the G alleleshow increased distress on separation from their mothers, andspend more time with them upon reunion, than individuals homo-zygous for the C allele. In humans, individuals possessing the G al-lele report higher perceptions of emotional pain on receivingrejection by social partners (Way et al., 2009). Rhesus females pos-sessing the G allele restrain their infants more than females homo-zygous for the C allele. Females possessing the G allele also showhigher OT levels when lactating, and lower OT levels when neitherlactating nor pregnant, than females homozygous for the C allele.The second reported association was by the Higashida group thatfirst discovered the role of CD38 in brain release of OXT (Jin et al.,2007). They recently reported (Munesue et al., 2010) that a muta-tion that caused tryptophan to replace arginine at amino acid resi-due 140 (R140W; (rs1800561, 4693 C>T)) was associated (Tallele) with lower plasma OXT levels. The SNP was clustered in ped-igrees in which the fathers and brothers of T-allele-carrier probandshad ASD or ASD traits.

A few investigations have also examined CSF levels of OXT. Heimet al. (Heim et al., 2009) examined OXT concentrations in cerebro-spinal fluid (CSF) in women with varying exposure to childhoodabuse or neglect. Intriguingly, maltreatment was associated with de-creased CSF OT concentrations. In another study, no changes in CSFOXT levels were observed during human sexual activity (Krugeret al., 2006) despite the evidence that OXT plays a role in sexual

responses (Succu et al., 2011). CSF OXT levels have also been exam-ined in subjects with a DSM diagnosis of aggressive personality dis-order (Lee et al., 2009). Although presence or absence of personalitydisorder was not associated with CSF OXT levels, a possible inverserelationship between CSF OXT and a history of suicidal behaviorwas observed.

Fries et al. (Fries et al., 2005) examined urinary OXT levels inchildren who were institutionalized (orphanage) compared to non-institutionalized children. Children engaged in an interactive com-puter game while sitting on either their mother's or an unfamiliarfemale experimenter's lap. After the task, a urine sample was col-lected as soon as the child was able to void. The results showedthat children who had experienced early neglect had lower overalllevels of AVP than family-reared children. As predicted, OXT levelsfor family-reared children increased after physical contact withtheir mothers. Children who experienced early neglect did notshow this response after physical contact with their mothers.There were no group differences in OXT levels after interactionwith the unfamiliar adult. No difference was observed in AVPurine levels when interactions with mother or stranger were com-pared. In summary, the authors suggest that a failure to receivespecies-typical care disrupts the normal development of the OXTand AVP systems in young children.

AVPR1a receptor gene

The cloning and structure of the AVPR1a gene including key mi-crosatellite regions were resolved by Thibonnier and his colleagues

in a series of investigations starting in 1994 (Thibonnier, 2004;Thibonnier et al., 1994; Thibonnier et al., 1996). The structure of theAVPR1a gene region on 12q14–15 is shown in Fig. 5.

Most behavioral studies in humans of AVPR1a have examined themicrosatellite regions of this gene (Avinun et al., 2011; Bachner-Melman et al., 2005a; Bachner-Melman et al., 2007a; Bachner-Melman et al., 2005b; Bachner-Melman et al., 2004; Cherkas et al.,2004; Donaldson and Young, 2008; Ebstein et al., 2009; Geller et al.,2005; Granot et al., 2007; Insel, 2010; Israel et al., 2008; Kim et al.,2002; Knafo et al., 2008; Meyer-Lindenberg et al., 2009; Prichard etal., 2007; Ukkola et al., 2009; Walum et al., 2008; Wassink et al.,2004; Yang et al., 2010; Yirmiya et al., 2006), especially RS3, followingthe evidence from the voles that the promoter region repeat regionapparently plays a key role in determining affiliative behavior inthat model species (Hammock, 2007; Hammock and Young, 2004,2005, 2006).

Autism

The first molecular genetic study of AVPR1a and human behaviorwas carried out by Kim et al. (Kim et al., 2002) on autism. The catalystfor this and similar investigations of OXT and AVP in disorders of so-cial communication is to a large measure based on translational re-search carried out by Larry Young and his co-workers on the vole(Donaldson and Young, 2008), perhaps the preeminent model spe-cies for studying the molecular genetics of social behavior in mam-mals. This first study in humans was followed by two additionalinvestigations (Wassink et al., 2004; Yirmiya et al., 2006) and allthree reports suggested an association between autism and AVPR1apromoter repeat regions. Kim et al. (Kim et al., 2002) found 17 allelesof RS1, one of which showed increased transmission in a family-based study of 115 autism trios. Wassink et al. (Wassink et al.,2004) found significant disequilibrium with both RS1 and RS3 butonly in cases without language deficits. Although our investigation(Yirmiya et al., 2006) failed to find the direct association with eitherRS1 or RS3 significant transmission disequilibrium was observedwith an intronic microsatellite. Moreover, moderate linkage disequi-librium is seen between the intronic and the promoter microsatel-lites (RS1 and RS3). The most significant association in our study isbetween ADOS-G, a composite measure of autism deficits (especiallysocial skills) and the microsatellite haplotypes. A Korean study gen-otyped 148 triads and also found evidence for association betweenAVPR1a RS1 and RS3 microsatellites and autism (Yang et al., 2010).

Fig. 5. Location of AVPR1a microsatellite repeats (Thibonnier et al., 2001). The first codon iDNA plus the first 123 amino acids of the open reading frame. Exon 2 contains the last 95 ammicrosatellite regions is depicted below the gene map.(Knafo et al., 2008).

An Irish study found that the short alleles of RS1 and the SNPrs11174815 show weak association with autism. Altogether, thesepapers suggest a link between variations in AVPR1a repeat elementsand autism — results that resonate with the role of this receptor incontributing to affiliative behaviors in the vole (Donaldson andYoung, 2008; Hammock and Young, 2006; Insel, 2010).

Neuroeconomics and the AVPR1a receptor

An important step forward in the nascent field of Neuroeconomicswas taken by our group when in 2008 we carried out the first molec-ular genetic study of an experimental economic game (Knafo et al.,2008). Our seminal study has now been followed by an increasingnumber of investigations including several from our own group(Avinun et al., 2011; Israel et al., 2009; Knafo et al., 2011; Zhong etal., 2012; Zhong et al., 2009a; Zhong et al., 2010; Zhong et al.,2009b; Zhong et al., 2009c) leveraging a ‘games’ approach to model-ing human behavior and abiding by the ‘rules’ laid down by the prac-titioners of experimental economics (incentivized and no deceit). Inour first investigation using an experimental economic paradigm,the DG, we tested association between the AVPR1a promoter-regionrepeats and allocation by the ‘dictator’ (Knafo et al., 2008). It was a bi-ologically plausible hypothesis that a gene which in the vole is impor-tant in affiliative behaviors, and in humans is linked to autism whosecore deficits are in the realm of social cognition, would also contributeto shaping the complex architecture of human generosity. As we hy-pothesized, length of the RS3 promoter-region repeat region in theAVPR1a gene predicted giving in the Dictator Game with an effectsize of ~0.5 SD unit (Fig. 6).

Intriguingly we have also found an association between theAVPR1a RS3 repeat and generosity in a group of pre-schoolers(Avinun et al., 2011). The DG was modified to suit this young agegroup and attractive sticker charts replaced monetary units, asshown to be effective in previous studies. We observed an inverse re-lationship/association between the number of sticker's allocated andthe second most common RS3 repeat allele (Fig. 7). This allele hasbeen identified in a number of studies (Kim et al., 2002; Meyer-Lindenberg et al., 2009; Walum et al., 2008; Yang et al., 2010) as a‘risk’ allele (334 bp/327) contributing to lower levels of social skills.No relationship with generosity was observed using our originalshort-long classification (Knafo et al., 2008) of the promoter-regionmicrosatellite repeats.

s represented by ATG. Exons are represented as boxes. Exon 1 contains the 5′ flankingino acids of the open reading frame plus the 3′ untranslated region. The location of the

Fig. 6. Allocation amount (continuous variable) grouped by AVPR1a RS3 long vs. shortgenotype. Error bars are±SEM. One-way ANOVA: n=203, F=3.456, P=0.033. SPSSposthoc analysis using the Tukey's HSD test showed a significant difference betweenshort/short vs. long/long (P=0.025).(Knafo et al., 2008).

Affiliative behaviors

One of the first studies to explore the role of the AVPR1a receptorin human behavior was reported by Cherkas et al. (Cherkas et al.,2004). They report on a large study of over 1600 unselected UnitedKingdom female twin pairs who confidentially reported previous ep-isodes of infidelity and total lifetime number of sexual partners, aswell as attitudes toward infidelity. A genome-wide linkage scan iden-tified three suggestive but nonsignificant linkage areas associatedwith infidelity and number of sexual partners on chromosomes 3, 7and 20 with a maximum LOD score of 2.46. The authors also exam-ined the AVPR1a RS3 promoter-region repeat, and found no evidencefor association. It should be noted that the authors did not examinethe entire set of twins for association but restricted their genotypingto a subset of 147 dizygotic twins discordant for infidelity. It is notclear if this approach, compared to examining the entire cohort,

Fig. 7. The effect of AVPR1A RS3 ‘target allele’ on allocations in the DG. Percentage ofchildren according to the number of sticker charts allocated in the DG (0, 1 or 2 andmore), and the presence/absence of the ‘target allele’. Compared with non carriers, car-riers are much less likely to allocate more than 2 sticker charts, and more likely to al-locate nothing.(Avinun et al., 2011).

generates sufficient power to detect association. Nor is it clear fromthe article what strategy was used in the genetic analysis. For exam-ple, it would have been of keen interest to test association using theshort-long classification scheme or the RS3 334 second-most com-mon allele versus all others. Indeed, in a subsequent Swedish twinstudy of 552 same sex twin pairs, Walum et al. (Walum et al., 2008)report an association between quality of human pair bonding andthe AVPR1a RS3 334 bp allele. This is the ‘risk’ allele that has beenreported to be over-transmitted in autism by Kim et al. (Kim et al.,2002) The association with pair-bonding was for behavior in men, in-cluding partner bonding, perceived marital problems, andmarital sta-tus. They found that the RS3 genotype of the males also affects maritalquality as perceived by their spouses. These results suggest an associ-ation between a single gene and pair-bonding behavior in humans,and indicate that the well characterized influence of AVP on pair-bonding in voles may be of relevance also for humans.

Eating, social behavior and AVPR1a

Vasopressin is known for its anorectic effect in animal studies(Langhans et al., 1991). In the brain, AVP participates in glucose ho-meostasis as a neurotransmitter or neuromodulator, exciting neu-rons in the paraventricular nucleus (Inenaga and Yamashita, 1986)and ventromedial glucose-responsive neurons in the hypothalamus(Kow and Pfaff, 1986). Direct administration of micro doses of AVPinto the nucleus of the tractus solitarius of anesthetized or awakerats rapidly increased the levels of blood glucose concentrationand brain arteriovenous glucose difference (Yarkov et al., 2001).AVP also appears to mediate the effects of several neuropeptides in-cluding orexins on feeding behavior (Backberg et al., 2002). In addi-tion, a number of human studies suggest that vasopressin may playa role in the pathophysiology of anorexia nervosa (AN) and bulimia(BN) (Kaye, 1996). Elevated levels of AVP were observed in the ce-rebrospinal fluid of women recovered from AN and BN (Frank et al.,2000). Low serum activity of prolyl endopeptidase, a cytosolic endo-peptidase that cleaves peptide bonds on the carboxyl side of prolinein proteins such as vasopressin, has also been observed in AN (Maeset al., 2001).

Our group has had an interest for a number of years in eatingdisorders (Bachner-Melman et al., 2005a; Bachner-Melman et al.,2007a; Bachner-Melman et al., 2005b; Bachner-Melman et al.,2006a; Bachner-Melman et al., 2007b; Bachner-Melman et al.,2006b; Bachner-Melman et al., 2009a; Bachner-Melman et al., 2004;Bachner-Melman et al., 2009b; Bachner-Melman et al., 2005c). Com-bining our interests in eating disorders with our focus on the roleof neuropeptides in human social behavior, we genotyped 280 fam-ilies with same-sex siblings for two microsatellites in the promoterregion of the AVPR1a gene (Bachner-Melman et al., 2004). Siblingscompleted the 26-item Eating Attitudes Test (EAT) and the Drivefor Thinness (DT) and Body Dissatisfaction (BD) subscales of theEating Disorders Inventory (EDI). A significant association wasdetected between the RS3 microsatellite and EAT scores. The stron-gest association was between RS3 and the Dieting subscale of theEAT scale. A significant association was also observed between theEDI-DT and the RS3 microsatellite. To our knowledge this was thefirst demonstration of an association between a microsatellite poly-morphism in the AVPR1A promoter region and scores on the EAT aswell as with the EDI-DT. The strongest association was observed be-tween the RS3 microsatellite and the Dieting subscale of the EAT.The relevant phenotype appears to tap severe dietary restrictionfor weight loss purposes.

The connection between AVPR1a and eating disorders may reflectthe role of this receptor in mediating a broad range of human socialbehaviors and hence in our next studies we tested association be-tween AVPR1a and two self-report questionnaires designed to mea-sure two aspects of complex social behavior: Self-presentation

(Lennox and Wolfe, 1984) and sibling relationships (Buhrmester andFurman, 1990). Self-presentation styles reflect social orientationswith a high degree of concern for social cues and social approval.For sibling relationships we evaluated three dimensions including(1) Relative Status/Power, (2) Warmth/Closeness, and (3) Conflict.Self-report questionnaires were administered to 552 same-sex sib-lings from 248 families. Suggestive linkage was observed betweenboth microsatellites (RS1 and RS3) and the Sibling Relationship Ques-tionnaire Conflict scale and the Concern for Appropriateness ScaleSelf-presentational style.

These results provided some of the first provisional evidence thatAVPR1a mediates social behavior in humans and links a specific ge-netic element to perceived sibling interactions. We suggest that theobserved connection between AVPR1a and sibling relationships com-plements the findings of Walum et al. (Walum et al., 2008) on pairbonding and quality of partner relationships. It appears that AVPR1amight mediate dyadic relationships between closely related (siblings,spouses), and not necessarily genetically related, individuals.

Dance and music

Intriguingly, the vasopressin peptidergic signaling system plays arole in musical signaling across vertebrates including fishes(Goodson et al., 2003), mice (Bleickardt et al., 2009; Scattoni et al.,2008), and birds (Goodson, 2008). Hence the notion occurred tous that the AVPR1a gene is a likely candidate for also coding somefacets of the music phenotype in humans as well. In a first studyof its kind, highly significant differences in AVPR1a haplotype fre-quencies, especially when conditional on two serotonin transporter(SLC6A4) polymorphisms, were observed between dancers and ath-letes (Bachner-Melman et al., 2005a). We also observed associationbetween promoter region polymorphisms in the AVPR1a and SLC6A4genes and musical and phonological memory (Granot et al., 2007).Further support for a role of this receptor in the musical brain wasprovided by a Finnish study (Ukkola et al., 2009) that analyzedpolymorphisms of AVPR1a and several other genes in 19 multige-nerational families (comprising 343 members) with professionalmusicians and/or active amateurs. They found that creative func-tions in music not only have a strong genetic component but alsoconfirmed an association with AVPR1a.

Microsatellite functionality

An important question is whether the RS3 and RS1 promoter re-gions are involved in the regulation of gene transcription. In the prai-rie vole, promoter region microsatellite (expanded GA repeat) allelesof different lengths (differing in 19 bp) show different activity. Thelonger allele had significantly increased levels of in vitro expressioncompared with the shorter allele, demonstrating that intraspecificvariation in the microsatellite itself modifies gene expression(Hammock and Young, 2005). We first demonstrated that length ofthe RS3 microsatellite affected gene expression in human hippocam-pal specimens and the longer alleles enhanced transcription of theAVPR1a gene (Knafo et al., 2008). More recently Tansey et al.(Tansey et al., 2011) demonstrated that both RS1 and RS3 showed dif-ferences in relative promoter activity by length. Shorter repeat allelesof RS1 and RS3 decreased relative promoter activity in the humanneuroblastoma cell line SH-SY5Y.

Further evidence of functionality comes from imaging experi-ments (Meyer-Lindenberg et al., 2009). Human amygdala functionwas shown to be strongly associated with genetic variation inAVPR1a. Using an imaging genomic approach in a sample of 121 vol-unteers studied with an emotional face-matching paradigm, the au-thors found that differential activation of amygdala is observed incarriers of risk alleles for RS3 and RS1. Alleles in RS1 previouslyreported to be significantly over- and undertransmitted to autistic

probands showed opposing effects on amygdala activation. Of parti-cular interest is that the second most common 334 bp RS3 alleleshowed differential over activation of the left and right amygdala.Finally, they showed that for RS3, longer variants were associatedwith significantly stronger activation of amygdala, whereas for RS1,shorter variants showed stronger activity. These results with a longshort classification of RS3 are consistent with the results we firstreported for AVPR1a gene expression in hippocampal post-mortemspecimens (Knafo et al., 2008).

Finally, we note a study by our own group (Levin et al., 2009) thatstratified non-clinical subject response to an auditory stimulus thatevokes a startle response and measured prepulse inhibition (PPI).PPI is a largely autonomic response that resonates with social cogni-tion in both animal models and humans (Braff et al., 2001). ReducedPPI has been observed in disorders including schizophrenia that aredistinguished by deficits in social skills (Braff et al., 2001). We exam-ined association between PPI and the AVPR1a RS1 and RS repeat re-gions and PPI in a group of 113 nonclinical subjects (Levin et al.,2009). Using a robust family-based strategy, association was ob-served between AVPR1a promoter-region repeat length, especiallyRS3 and PPI. Notably, longer RS3 alleles were associated with greaterlevels of prepulse inhibition consistent with a role for the promoterrepeat region in partially molding social behavior in both animalsand humans.

To summarize, in vitro expression studies, brain imaging and anelectophysiological paradigm (PPI) all support that the long RS3promoter-region repeat region enhances AVPR1a gene transcriptionsimilar to what has been observed in the prairie vole.

AVPR1a SNP polymorphisms

Substance abuseMaher et al. examined in 757 subjects, 1536 single nucleotide

polymorphisms (SNPs) in 106 candidate genes and a drug use disor-der diagnosis (DUD)(Maher et al., 2011). Associations were detectedwith three SNPs in AVPR1a. Bioinformatic evidence points to a role ofone of these SNPs, rs11174811 as potentially disrupting a microRNAbinding site, and hence modulating AVPR1a expression. Based on lit-erature implicating AVPR1a in social bonding, they tested spousal sat-isfaction as a mediator of the association of rs11174811 with theDUD. Spousal satisfaction was significantly associated with DUD inmales. Moreover, rs11174811 was associated with spousal satisfac-tion in males and was a significant mediator of the relationship be-tween rs11174811 and DUD. The direction of the association isconsistent across the clinically-ascertained samples but unexplain-ably reversed in the epidemiologic sample. Lastly, they found a signif-icant impact of rs11174811 genotype on AVPR1a expression in a post-mortem brain sample.

This study is interesting not only for showing a provisional associ-ation between AVPR1a and substance abuse but also for its focus onSNPs — especially since most of the human behavioral studies haveso far almost exclusively examined the promoter region repeat re-gions. Particularly, rs11174811 is of considerable interest and isworth examining in those phenotypes relevant to social cognition.

AVPR1b

The role of the AVPR1b receptor in brain function is recentlyreviewed by Roper et al. (Roper et al., 2011). AVPR1b is primarily lo-cated in the anterior lobe corticotrophs of the pituitary gland. AVP inhypophysial portal blood acts on pituitary AVPR1b to release adreno-corticotrophic hormone (ACTH) as part of the neuroendocrine re-sponse to stress. Evidence suggests the distribution of AVPR1breceptors in other brain areas including the hypothalamus, amygdalaand cerebellum (Hernando et al., 2001). Elements in the AVPR1b pro-moter region may contribute to the regional distribution of this

receptor (Volpi et al., 2002). Studies with knockout mice suggest theimportance of the AVPR1b receptor in aggression (Caldwell et al.,2008) as well as social motivation and social memory (Wersingeret al., 2004). A number of studies have tested association betweenthe AVPR1b receptor and human stress (Murani et al., 2010), antide-pressant treatment (Binder et al., 2010), childhood mood disorders(Dempster et al., 2009) and ADHD (van West et al., 2009).

Conclusions

Oxytocin has endured as an important hormone in the animalkingdom for more than 500 Ma (Donaldson and Young, 2008; Gimpland Fahrenholz, 2001). In birds, amphibians and fishes the single hor-mone vasotocin modulates affiliative behaviors such as singing andsexual activity (Goodson and Bass, 2000; Goodson and Kingsbury,2011). Somewhere in the early divergence of the mammals fromthe reptiles a gene duplication and inversion led to the evolution oftwo closely related nonapeptides, arginine vasopressin and oxytocinand their corresponding receptors (Gimpl and Fahrenholz, 2001).More than a decade's research has now shown that oxytocin and va-sopressin orchestrate a wide range of affiliative and bonding behav-iors and these two neuropeptides are the paramount ‘social’hormones in many species.

More recently, two main research tracks, viz., neurogenetic andpharmacology aka ‘sniffing’ experiments, have generated convincingevidence that both hormones are also modulating human social be-havior. The OXT–AVP neural pathways appear to be the first well-characterized example of regulation of broad social phenotypes by ahormonal system in our own species. The current review has focusedattention on five of the polymorphic genes that are key players in thearchitecture of OT–AVP neural pathways. These polymorphic genescode for the neuropeptide hormones (AVP-neurophysin II [NPII])and OXT (OXT neurophysin I [NPI]), their receptors (AVPR1a and1b), the peptidase LNPEP and CD38. Importantly, these genes notonly account for individual differences in behavior in socially intactindividuals but in also contribute the vulnerability to disorders of so-cial cognition especially autism. Investigators in the field of humansocial biology have leveraged cutting edge neuroscience methods(imaging, pharmacology and neurogenetics) often in combinationwith novel (to neuroscience) behavioral economic paradigms(Ariely and Norton, 2007; Fehr and Camerer, 2007; Loewensteinet al., 2008; Sanfey, 2007; Schultz, 2008) to study these paramountsocial hormones and the molecular genetic architecture underpinningthe dynamic functions of this system. The continuing story of howtwo nonapeptide hormones originating before the emergence of ver-tebrates, and existing over the course of eons of evolutionary time,shapes human social behavior is a tribute to the power of translation-al research in informing behavior in our own species(Insel, 2010). Animportant challenge to future investigations is to use our increasingknowledge of these two social hormones to help alleviate disordersof social cognition that exact such a high price in both human andeconomic terms (Knapp et al., 2009). We suggest that targeting ele-ments of the OXT–AVP neural pathways is a potentially fruitful ap-proach for both pharmacological developments as well as a sourceof potential biomarkers in the early diagnosis of diseases of the socialbrain, especially autism.

Acknowledgments

Financial support from the National University of Singapore(Decision Making Under Urbanization: A Neurobiological andExperimental Economics Approach), Ministry of Education atSingapore (Biological Economics and Decision Making), the AXAResearch Foundation (Biology of Decision Making under Risk) andthe Templeton Foundation (Genes, God and Generosity: The YinYang of DNA and Culture), is gratefully acknowledged.

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The contributions of oxytocin and vasopressin pathway genes to human behavior

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