Testing the role of circadian genes in conferring risk for psychiatric disorders

Disturbed sleep and disrupted circadian rhythms are a common feature of psychiatric disorders, and many groups have postulated an association between genetic variants in circadian clock genes and psychiatric disorders. Using summary data from the association analyses of the Psychiatric Genomics Consortia (PGC) for schizophrenia, bipolar disorder and major depressive disorder, we evaluated the evidence that common SNPs in genes encoding components of the molecular clock influence risk to psychiatric disorders. Initially, gene-based and SNP P-values were analyzed for 21 core circadian genes. Subsequently, an expanded list of genes linked to control of circadian rhythms was analyzed. After correcting for multiple comparisons, none of the circadian genes were significantly associated with any of the three disorders. Several genes previously implicated in the etiology of psychiatric disorders harbored no SNPs significant at the nominal level of

Role of Nicotine Dependence in the Association between the Dopamine Receptor Gene DRD3 and Major Depressive Disorder

Peer reviewe

Does smoking among friends explain apparent genetic effects on current smoking in adolescence and young adulthood?

We used data from a prospective cohort study of twins to investigate the influence of unmeasured genetic and measured and unmeasured environmental factors on the smoking behaviour of adolescents and young adults. Twins were surveyed in 1988 (aged 11–18 years), 1991, 1996 and 2004 with data from 1409, 1121, 732 and 758 pairs analysed from each survey wave, respectively. Questionnaires assessed the smoking behaviour of twins and the perceived smoking behaviour of friends and parents. Using a novel logistic regression analysis, we simultaneously modelled individual risk and excess concordance for current smoking as a function of zygosity, survey wave, parental smoking and peer smoking. Being concordant for having peers who smoked was a predictor of concordance for current smoking (P<0.001). After adjusting for peer smoking, monozygotic (MZ) pairs were no more alike than dizygotic pairs for current smoking at waves 2, 3 and 4. Genetic explanations are not needed to explain the greater concordance for current smoking among adult MZ pairs. However, if they are invoked, the role of genes may be due to indirect effects acting through the social environment. Smoking prevention efforts may benefit more by targeting social factors than attempting to identify genetic factors associated with smoking

Multiple Independent Loci at Chromosome 15q25.1 Affect Smoking Quantity: a Meta-Analysis and Comparison with Lung Cancer and COPD

Recently, genetic association findings for nicotine dependence, smoking behavior, and smoking-related diseases converged to implicate the chromosome 15q25.1 region, which includes the CHRNA5-CHRNA3-CHRNB4 cholinergic nicotinic receptor subunit genes. In particular, association with the nonsynonymous CHRNA5 SNP rs16969968 and correlates has been replicated in several independent studies. Extensive genotyping of this region has suggested additional statistically distinct signals for nicotine dependence, tagged by rs578776 and rs588765. One goal of the Consortium for the Genetic Analysis of Smoking Phenotypes (CGASP) is to elucidate the associations among these markers and dichotomous smoking quantity (heavy versus light smoking), lung cancer, and chronic obstructive pulmonary disease (COPD). We performed a meta-analysis across 34 datasets of European-ancestry subjects, including 38,617 smokers who were assessed for cigarettes-per-day, 7,700 lung cancer cases and 5,914 lung-cancer-free controls (all smokers), and 2,614 COPD cases and 3,568 COPD-free controls (all smokers). We demonstrate statistically independent associations of rs16969968 and rs588765 with smoking (mutually adjusted p-values<10$^{−35}$ and <10$^{−8}$ respectively). Because the risk alleles at these loci are negatively correlated, their association with smoking is stronger in the joint model than when each SNP is analyzed alone. Rs578776 also demonstrates association with smoking after adjustment for rs16969968 (p<10$^{−6}$). In models adjusting for cigarettes-per-day, we confirm the association between rs16969968 and lung cancer (p<10$^{−20}$) and observe a nominally significant association with COPD (p = 0.01); the other loci are not significantly associated with either lung cancer or COPD after adjusting for rs16969968. This study provides strong evidence that multiple statistically distinct loci in this region affect smoking behavior. This study is also the first report of association between rs588765 (and correlates) and smoking that achieves genome-wide significance; these SNPs have previously been associated with mRNA levels of CHRNA5 in brain and lung tissue