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Chunk #25 — Using intermediate phenotypes to find disease mechanisms

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Assessing the utility of intermediate phenotypes for genetic mapping of psychiatric disease.
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We reviewed the literature for intermediate phenotype analyses of markers identified in GWAS studies of psychiatric disease. Two loci have received considerable interest: one marker associated with susceptibility to bipolar disorder, rs1006737 (MAF = 0.305) in the CACNA1C gene [65] and one marker associated with schizophrenia, rs1344706 (MAF = 0.345) in the ZNF804A gene [66]. We identified 35 relevant studies (Supplemental Table). The range of phenotypes tested (brain imaging, cognitive phenotypes), the differences in subjects included (healthy, bipolar disorder, schizophrenia), and the mixture of study designs (case control or quantitative variation) precluded a meta-analysis. However, we can use the information gleaned about expected effect sizes to provide a simple estimate of power. Using the minor allele frequency of 0.305 (for rs1006737) and assuming the causative variant is in high linkage disequilibrium (r2 = 1) with this marker, then for an OR of 1.5 we need a sample size of 801 to obtain 80% power at a significance threshold of 0.05 [46]. For an OR of 1.2 (a more reasonable, but still conservative, estimate of effect size) the required sample size