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Mendelian Form 1 (.5%)
Mendelian Form 2 (1%)
Mendelian Form 3(1.5%)
Major Locus 1 (8%)
Major Locus 2 (4%)
Polygenic (75%)
Phenocopies (10%)
The Pie of Schizophrenia (Theoretical: Early Molecular Biology)
Mendelian Form 1 (.5%)
Mendelian Form 2 (1%)
Mendelian Form 3(1.5%)
Major Locus 1 (8%)
Major Locus 2 (4%)
Polygenic (75%)
Phenocopies (10%)
The Pie of Schizophrenia (Theoretical: Current)
Table 23.1. Risks for schizophrenia in genetic relatives of schizophrenics. Adapted from Gottesman (1991, Figure 10). Genetic Relation: Type of relation: Risk: General Population 1% Third-degree Cousins 2% Second-degree Uncles/aunts 2% Nieces/nephews 3% Grandchildren 4% Half-siblings 6% First degree Children 13% Parents 6% Siblings 9% DZ twins 17% Identical MZ twins 48%
Specific Genetic Liability-3 -2 -1 0 1 2 3
General Genetic Liability-3 -2 -1 0 1 2 3
Specific Environmental Liability-3 -2 -1 0 1 2 3
Total Liability-3 -2 -1 0 1 2 3
Fre
quen
cy
Sch
izot
ypal
Sch
izop
hre
nic
General Environmental Liability-3 -2 -1 0 1 2 3
-3 -2 -1 0 1 2 3 4
Total Liability
Fre
quen
cy
Schi
zoty
pal
Schi
zoph
ren
ic
Relatives ofSchizophrenics
GeneralPopulation
Summary of Linkage Results in Schizophrenia
From Owen et al., Trends in Genetics (2005), 21, 518-525
Red lines = genome-wide significanceBlue lines = significant in more than 1 sampleRed arrow = possible chromosomal anomoliesYellow = potential candidate genes
Lee et al., Neuro & Biobeh Rev (2012)
GWAS genes of interest in schizophrenia
Replication
Replication
? Replication
“Whilst GWAS have identified new and novel genes that are associated with SZ and BPD, the extent of phenotypic variance that is explained by these genes is disappointingly low.”
Lee et al., Neuro & Biobeh Rev (2012), p. 565
Summary of Results:
• 22q11 microdeletion --> velocardiofacial syndrome (VCFS) aka DiGeorge syndrome; increased risk for mental retardation, autism, bipolar disorder, and schizophrenia.
• only 6 good CNV studies as of 2010 but evidence for rare CNV deletions in 1q21.1 and 15q13.3 which affect psychosis and other behavioral problems
• strong effect, but account for about 1% percent of cases
Tam et al. (2009). Biol Psychiatry; Bassett et al. (2010) Am J PsychiatLee et al., Neuro & Biobeh Rev (2012), p. 565
Lee et al., Neuro & Biobeh Rev (2012)
GeneRegion CNV
Sometimes, CNVs are notgene specific
? Lession: Mucking something up in a region is not good.
Summary of Results in Psychiatric Genetics:(oversimplified)
• No single gene, Mendelian forms detected (exception: mental retardation)
• Hardly any major loci found
• Few established phenocopies
• GWAS data suggest very polygenic
• Promising early results for CNVs
Notable Exceptions:
• Many Mendelian forms of mental retardation
• Major Loci: ALD and ALDH & Alcoholism
• Amphetamine psychosis = phenocopy for schizophrenia
Odds ratios for ADHD & 7 repeat allele in DRD4
From 7 meta-analyses on European or mostly European Ancestry
“None of these [5] papers reports any associations thatare formally genome-wide significant after correction formultiple testing.”
Franke, Neale, Faraone (2009). Genome-wide associationstudies in ADHD. Human Genetics, 126:13-50
But a summary of GWAS studies says:
Endophenotype:(“within” phenotype)
A phenotype closer to gene action than the phenotype of study; usually an
anatomical, physiological, or biochemical variable.
Strategy of Endophenotypes:
Detect genes that influence the endophenotype insteadof genes for the disorder.
Examples for schizophrenia:
• Ventricular size• Abnormal eye tracking
From Caspi et al., Science 301, 386-389
Depression as a function of stressful life events and the short-longpolymorphism in the serotonin transporter gene
Paraphrase of Erlenmeyer-Kimling lecture, c. 1972 trying to explain the paradoxof high heritability and low fitness in schizophrenia.See Keller (2006) Brain & Behavioral Science.
Perhaps there are so many genesinvolved in schizophrenia that new mutations
in several of these genes could replenishthe loss from selection.
Rare Variant Hypothesis:
• Could be mutations in a gene or CNVs
• Rare gene mutations hard to find inGWAS.
• Need sequencing to find them.