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Despite moderate heritability, only one study has identified genomewide significant loci for cannabis-related phenotypes. We conducted meta-analyses of genomewide association study (GWAS) data on 2,080 DSM-IV cannabis dependent cases and 6,435 cannabis exposed controls of European descent. A cluster of correlated single nucleotide polymorphisms (SNPs) in a novel region on chromosome 10 was genomewide significant (lowest p = 1.3E-8). Among the SNPs, rs1409568 showed enrichment for H3K4me1 and H3K427ac marks, suggesting its role as an enhancer in addiction-relevant brain regions, such as the dorsolateral prefrontal cortex and the angular and cingulate gyri. This SNP is also predicted to modify binding scores for several transcription factors. We found modest evidence for replication for rs1409568 in an independent cohort of African-American (896 cases and 1591 controls; p=0.03) but not European-American (781 cases and 1905 controls) participants. The combined meta-analysis (3,757 cases and 9,931 controls) indicated trend-level significance for rs1409568 (p=2.85E-7). No genomewide significant loci emerged for cannabis dependence criterion count (n=8,050). There was also evidence that the minor allele of rs1409568 was associated with a 2.1% increase in right hippocampal volume in an independent sample of 430 European-American college students (fwe-p=.007). The identification and characterization of genomewide significant loci for cannabis dependence is amongst the first steps towards understanding the biological contributions to the etiology of this psychiatric disorder, which appears to be rising in some developed nations.

Item does not contain fulltext Cigarette smoking is a leading cause of preventable mortality worldwide. Nicotine dependence, which reduces the likelihood of quitting smoking, is a heritable trait with firmly established associations with sequence variants in nicotine acetylcholine receptor genes and at other loci. To search for additional loci, we conducted a genome-wide association study (GWAS) meta-analysis of nicotine dependence, totaling 38,602 smokers (28,677 Europeans/European Americans and 9925 African Americans) across 15 studies. In this largest-ever GWAS meta-analysis for nicotine dependence and the largest-ever cross-ancestry GWAS meta-analysis for any smoking phenotype, we reconfirmed the well-known CHRNA5-CHRNA3-CHRNB4 genes and further yielded a novel association in the DNA methyltransferase gene DNMT3B. The intronic DNMT3B rs910083-C allele (frequency=44-77%) was associated with increased risk of nicotine dependence at P=3.7 [times] 10-8 (odds ratio (OR)=1.06 and 95% confidence interval (CI)=1.04-1.07 for severe vs mild dependence). The association was independently confirmed in the UK Biobank (N=48,931) using heavy vs never smoking as a proxy phenotype (P=3.6 [times] 10-4, OR=1.05, and 95% CI=1.02-1.08). Rs910083-C is also associated with increased risk of squamous cell lung carcinoma in the International Lung Cancer Consortium (N=60,586, meta-analysis P=0.0095, OR=1.05, and 95% CI=1.01-1.09). Moreover, rs910083-C was implicated as a cis-methylation quantitative trait locus (QTL) variant associated with higher DNMT3B methylation in fetal brain (N=166, P=2.3 [times] 10-26) and a cis-expression QTL variant associated with higher DNMT3B expression in adult cerebellum from the Genotype-Tissue Expression project (N=103, P=3.0 [times] 10-6) and the independent Brain eQTL Almanac (N=134, P=0.028). This novel DNMT3B cis-acting QTL variant highlights the importance of genetically influenced regulation in brain on the risks of nicotine dependence, heavy smoking and consequent lung cancer. 9 p.

We report a GWAS of alcohol dependence (AD) in European-American (EA) and African-American (AA) populations, with replication in independent samples of EAs, AAs and Germans. Our sample for discovery and replication was 16 087 subjects, the largest sample for AD GWAS to date. Numerous genome-wide significant (GWS) associations were identified, many novel. Most associations were population specific, but in several cases were GWS in EAs and AAs for different SNPs at the same locus,showing biological convergence across populations. We confirmed well-known risk loci mapped to alcohol-metabolizing enzyme genes, notably ADH1B (EAs: Arg48His, P ¼ 1.17 � 10 � 31 ; AAs: Arg369Cys, P ¼ 6.33 � 10 � 17 ) and ADH1C in AAs (Thr151Thr, P ¼ 4.94 � 10 � 10 ), and identified novel risk loci mapping to the ADH gene cluster on chromosome 4 and extending centromerically beyond it to include GWS associations at LOC100507053 in AAs (P ¼ 2.63 � 10 � 11 ), PDLIM5 in EAs (P ¼ 2.01 � 10 � 8 ), and METAP in AAs (P ¼ 3.35 � 10 � 8 ). We also identified a novel GWS association (1.17 � 10 � 10 ) mapped to chromosome 2 at rs1437396, between MTIF2 and CCDC88A, across all of the EA and AA cohorts, with supportive gene expression evidence, and population-specific GWS for markers on chromosomes 5, 9 and 19. Several of the novel associations implicate direct involvement of, or interaction with, genes previously identified as schizophrenia risk loci. Confirmation of known AD risk loci supports the overall validity of the study; the novel loci are worthy of genetic and biological follow-up. The findings support a convergence of risk genes (but not necessarily risk alleles) between populations, and, to a lesser extent, between psychiatric traits.

Correction to: Translational Psychiatry (2014) 4, e391; doi:10.1038/tp.2014.29; published online 20 May 2014 Following publication of the above article, the authors noticed that the twelfth author’s name was misspelled. The correct spelling is F Kiefer.