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Psynomics, Inc.◦ Offers genetic testing in psychiatry
Symptoms of mood:◦ Low mood, sadness, or sometimes irritability◦ Loss of interest and pleasure◦ Hopelessness◦ Suicidality
Cognitive symptoms:◦ Problems with memory & concentration (often most
prominent symptom in older people)◦ Indecisiveness◦ Low self esteem, worthless, guilt
Somatic symptoms:◦ Low energy◦ Insomnia, hypersomnia, early morning awakening◦ Loss of appetite, weight loss or increased appetite and
wt. gain
DSM4 Criteria◦ 5 of 9 criteria◦ Two week duration◦ Clinically significant distress or impairment
Other Associated Symptoms◦ Decreased libido◦ Anxiety or panic attacks◦ Somatization◦ Psychosis
Mood congruent◦ “Pseudo-dementia”◦ Alcohol and substance abuse
DSM4 Criteria◦ One week duration◦ Elevated or irritable mood◦ Inflated self esteem or grandiosity◦ Decreased need for sleep◦ Increased or pressured speech◦ Flight of ideas or racing thoughts◦ Distractibility◦ Increased goal directed activity◦ Risky pleasures◦ Functional impairment
Severity◦ Mania – Bipolar I◦ Hypomania
No functional impairment Bipolar II
Other Associated Symptoms◦ Increased libido◦ Spending sprees◦ Psychosis◦ Antisocial behavior◦ Alcohol and substance abuse◦ Suicidality
Age of onset early twenties 1-2% prevalence Unipolar depression is about 5 times
more common Male and Female prevalence equal 60-80% of cases begin with mania 4-18% of those with depression later
have mania Stable features
◦ Seasonality (Seasonal Affective Disorder)◦ Psychosis◦ Rapid cycling
Related syndromes and disorders◦ Mixed states◦ Schizoaffective disorder◦ Substance abuse and alcoholism
Affective Illness In First Degree RelativesAffective Illness In First Degree Relatives
Bipolar Probands Relatives Morbid Risk (%)
at Risk BP UP
Perris, 1966 627 10.2 0.5Winokur and Clayton, 1967 167 10.2 20.4Mendlewicz and Rainer, 1974 606 17.7 22.4Goetzl et al., 1974 212 2.8 13.7Helzer and Winokur, 1974 151 4.6 10.6Gershon et al., 1975 341 3.8 6.8James and Chapman, 1975 239 6.4 13.2Johnson and Leeman, 1977 126 15.5 19.8Petterson, 1977 472 3.6 7.2Smeraldi et al., 1977 172 5.8 7.1Trzeblatowska-Trzeciak 11.4 0.0Angst, 1980 400 2.5 7.0Dunner, Go, and Fieve, 1980 1199 4.2 8.2Taylor, Abrams, and Hayman, 1980 600 4.8 4.2Gershon et al., 1982 598 8.0 14.9Tsuang et al., 1985 608 3.9 9.1Rice et al., 1987 557 5.7 23.0Total 7364 6.8 10.4
Twin Studies of Affective IllnessTwin Studies of Affective Illness
Study Monozygotic Dizygotic Concordance (%) Concordance (%)
Luxenberger, 1930 3/4 75.0 0/13 0.0Rosanoff et al., 1935 16/23 69.6 11/67 16.4Slater, 1953 4/7 57.1 4/17 23.5Kallman, 1954 25/27 92.6 13/55 23.6Harvald and Hauge, 1965 10/15 66.7 2/40 5.0Allen et al., 1974 5/15 33.3 0/34 0.0Bertelsen, 1979 32/55 58.3 9/52 17.3
TOTAL 95/146 65.0 39/278 14.0
Spectrum disorders are partially genetically distinctSpectrum disorders are partially genetically distinct
Twins are partially concordant for polarity
Concordance in Monozygotic Pairs
Polarity
BP-BP 14UP-UP 11BP-UP 7
32
25/32 (78%) of monozygotic pairs were specific for polarity.
Bertelsen, 1979
Bipolar II has been observed to occur more often in the families of bipolar II probands than bipolar I probands
A subset of genes may be specific for bipolar II
Probands Relatives (%)Bipolar I Bipolar II Non-bipolar
Bipolar I 8.5 6.1 61Bipolar II 3.0 30.3 63.6Non-bipolar 1.9 6.6 59
Coryell et al, 1984
Forms that cluster together in the same families◦Psychotic mania (Potash)◦Bipolar disorder with panic attacks
(MacKinnon)◦Suicidality (MacKinnon)
Tsuang 1980
*** **
*
Significantly different from control rate*
Proband Co-twin MZconcordance(%)
DZ concordance(%)
MZcorrelation
DZcorrelation
Schizophrenic Schizophrenic 40.8 5.3 0.83 0.31
Manic Manic 36.4 7.4 0.83 0.46
Schizoaffective Schizoaffective 39.1 4.5 0.85 0.37
Schizophrenic Manic 8.2 0.0
Manic Schizophrenic 13.6 3.7 0.51 0.12
Schizophrenic Schizoaffective 8.2 5.3
Schizoaffective Schizophrenic 26.1 4.5 0.60 0.37
Schizoaffective Manic 26.1 0.0
Manic Schizoaffective 31.8 3.7 0.78 0.24
Cardno 2002
Family members have a 7 fold increased risk for illness
Only about 65% of what causes bipolar disorder is inherited (reduced penetrance)
Milder forms of the phenotype are frequently found in relatives of bipolar probands
Some aspects of the spectrum are more like quanitatitve traits
While other bipolar spectrum traits are in part genetically distinct.
The bipolar spectrum overlaps with other psychiatric diagnoses
Single Major Locus◦One gene of large effect transmits the trait◦Mendelian patterns of transmission◦Heterogeneity - different genes in different
families Polygenic or Multifactorial Transmission◦Many genes each contribute a small effect◦Quantitative traits◦Additive◦Epistatic
Mixed Model
B
B B
A
AA
•One gene explains most of the genetic variance in a single family•Different genes in different families
More Psychosis Genes
Pop
ulat
ion
Fre
quen
cy
Major depression
Bipolar II
Bipolar I
Schizoaffective Disorder
Affective Temperaments
Schizophrenia
More Bipolar Genes
Pop
ulat
ion
Fre
quen
cy
Bipolar DisorderHyperthymia
Less fit
More fit
Primary genetictransmission
Unipolar
Bipolar 3
Bipolar 1
Bipolar 2
Gene A
Gene B
Gene C
Gene D Gene E
Spectrumtemperaments
Allelic Heterogeneity
Gene A
X
XMutation B
Mutation S
Schizophrenia
Bipolar Disorder
Non-specific gene+ Gene B
+ Gene S Schizophrenia
Bipolar Disorder
Gene-gene interactions
Non-specific gene+ Environment B
+ Environment S Schizophrenia
Bipolar Disorder
Gene-environmental interactions
All of the above
Sequence◦ Sequenced all 3 billion base pairs in the human
genome◦ Only ~18,000 human genes
HapMap Project◦ Identified over 8M SNPs◦ 4 populations◦ SNPs occur in haplotype blocks◦ Tools for Genome-wide association
Step Methods ResolutionLinkage Microsatellite markers 5-20 Mb
Association Single Nucleotide Polymorphisms (SNP) 5-25kb
Positional candidates Database
Mutation screening Sequencing 1 bp
Functional testing Cellular and animal models
Success when a variant is found that 1. affects function of the gene2. is associated with illness
Hu
man
Gen
om
e P
roje
ct
0
1
2
3
4
960 1160 1360 1560
5 6 7 8
0
1
2
3
4
0 100 200 300 400 500 600 700 800 900 1000
1 2 3 4
0
1
2
3
4
1700 1900 2100 2300 2500
14131211109
0
1
2
3
4
2550 2750 2950 3150 3350
15 17 19 21 22201816
Genome Survey of 20 Bipolar FamiliesM
axi
mu
m L
OD
Sco
re
Genetic Distance (cM)
LocusD22S420D22S264D22S427D22S425D22S539D22S303D22S257
D22S1174D22S315
D22S1164D22S926D22S925D22S421D22S419D22S429
D22S1144D22S689D22S684D22S693D22S691D22S1juD22S5ju
D22S277D22S683D22S278
D22S1142D22S283D22S692
D22S1045D22S445D22S307D22S270ata5f505D22S274
Chromosome 22Summary of results in Bipolar Disorder and Schizophrenia
13
11.2
11.1
11.22
12.1
12.3
13.2
13.32
UCSD genome scan, LOD 2.2
Detera-Wadleigh et al., NIMH intramural, LOD 2.5
NIMH GIBP consortium, LOD 2.5
Myles Worsley et al., LOD 3.5
GRK3
Bipolar DisorderSchizophrenia
Pulver et al., LOD 2.8
UCSD genome scan, LOD 3.8
Moises et al., linkage, p<0.01
Coon et al., LOD 2.1
Vallada et al., LD p<0.001
Sz Collaborative Linkage Group, LD, p<0.0009
}VCFS
GPCR
arrestin
PP
GPCR
PP
Endocytosis
arrestin
Agonist
PP GRK3
GPCR
HeLaCortex
50X G3 50X G350X P5 50X P5
Sp4 -Sp1
G3 G3 G3 G3 G3 G3 G3P5P5 P5 P5 P5 P5 P5 P5G3
0123456789
WT P5
x1
00
00
0
hGRK3 SNP P5 in mouse cortical neurons
Zhou 2008, Biological Psychiatry
Bipolar
Schizophrenia
1 2 3 4 5 6 7 8 9 10 11
12 13 14 15 16 17 18 19 20 21 22 X Y
Association has greater power to detect genes of small effect
Common disease – common variant
Screen entire genome with high density of markers◦ Microarray based technologies◦ Large number of SNPs
identified by HapMap◦ 1M SNPs now routinely run
Little power if many rare SNPs of strong effect
Study Type Sample Platform Results
WTCCC / Craddock
Case control
2000/3000
Affy 500K PALB2, p=10-8
STEP-BD/ Sklar Case control
1461/2008
Affy 500K MYO5B; TSPAN8 p=10-8
CACNA1C (WTCCC)
W1-4 + German / Baum
Pooling 500/500800/800
Illumina 550K
DGKH; p=10-8
W1-4Scott / Pritizker
Pooling + ind GTing
1203/729 Illumina 550K
MAN2A1; p=10-7
German consortium / Cichon
Case control
702/1396 Illumina 550K
Chr 1??? p=10-7
Limited success to date Inadequate sample size
◦ Diabetes 2 required meta-analysis of over 15,000 cases Is the CDCV model wrong? Are there instead numerous rare strong
mutations? What role does Copy Number Variation play? Meta-analysis of all bipolar GWAS data worldwide
is now underway
New understanding of basic pathophysiology Reduction of stigma New methods of diagnosis
◦ New classification of disease based on pathophysiology◦ May subdivide or cut across behavioral definitions of
disease New medications to novel targets Pharmacogenomics Gene therapy Ethical issues of risk testing
Chip based assay of hundreds of SNPs
DNA provided by sputum or blood
Symptoms and Genes
Biology BasedDiagnosis
Prognosis Medication Response
Genes explain about 65% of the cause of bipolar disorder
Affective temperaments and bipolar spectrum disorders are genetically related to bipolar disorder
Some bipolar genes likely play a role in other psychiatric disorders
Numerous genes likely interact to produce the spectrum of bipolar related traits
GWAS promises the discovery of many new genes The discovery of the genes will lead to a new system
of diagnosis and new more specific treatments
San DiegoTom BarrettNik Schork Xian Jin ZhouRichard Hauger Mark GeyerHagop AkiskalTiffany Greenwood Tatyana ShektmanBecky McKinney
CincinnatiPaul KeckSue McElroy
VancouverRonald RemickDessa Sadovnick
IrvineAnne Spence
TorontoJim KennedyEmanuela Mundo
NIMH Genetics Initiative for Bipolar DisorderJohn NurnbergerJohn RiceElliot GershonWilliam ScheftnerWilliam CoryellWade BerrettiniJimmy PotashFrancis McMahonMelvin McInnisWilliam Byerley
How does genetics help clarify the relationship between the different presentations of the bipolar spectrum?◦ Family epidemiology?◦ Molecular studies?
How might genes cause these varied presentations?
How are genes mapped? What is GWAS and how might it help?
How might DNA testing be used in psychiatry? Would you use it in your practice? What would be the advantages? What would be the concerns? When will it be ready? Should we do risk testing? What would we do with the results of risk testing?