Association of the OPRM1 Variant rs1799971 (A118G) with Non-Specific Liability to Substance Dependence in a Collaborative de novo Meta-Analysis of European-Ancestry Cohorts.

The mu1 opioid receptor gene, OPRM1, has long been a high-priority candidate for human genetic studies of addiction. Because of its potential functional significance, the non-synonymous variant rs1799971 (A118G, Asn40Asp) in OPRM1 has been extensively studied, yet its role in addiction has remained unclear, with conflicting association findings. To resolve the question of what effect, if any, rs1799971 has on substance dependence risk, we conducted collaborative meta-analyses of 25 datasets with over 28,000 European-ancestry subjects. We investigated non-specific risk for "general" substance dependence, comparing cases dependent on any substance to controls who were non-dependent on all assessed substances. We also examined five specific substance dependence diagnoses: DSM-IV alcohol, opioid, cannabis, and cocaine dependence, and nicotine dependence defined by the proxy of heavy/light smoking (cigarettes-per-day >20 vs. ≤ 10). The G allele showed a modest protective effect on general substance dependence (OR = 0.90, 95% C.I. [0.83-0.97], p value = 0.0095, N = 16,908). We observed similar effects for each individual substance, although these were not statistically significant, likely because of reduced sample sizes. We conclude that rs1799971 contributes to mechanisms of addiction liability that are shared across different addictive substances. This project highlights the benefits of examining addictive behaviors collectively and the power of collaborative data sharing and meta-analyses.

Genome-Wide Association Study of Behavioral Disinhibition in a Selected Adolescent Sample.

Behavioral disinhibition (BD) is a quantitative measure designed to capture the heritable variation encompassing risky and impulsive behaviors. As a result, BD represents an ideal target for discovering genetic loci that predispose individuals to a wide range of antisocial behaviors and substance misuse that together represent a large cost to society as a whole. Published genome-wide association studies (GWAS) have examined specific phenotypes that fall under the umbrella of BD (e.g. alcohol dependence, conduct disorder); however no GWAS has specifically examined the overall BD construct. We conducted a GWAS of BD using a sample of 1,901 adolescents over-selected for characteristics that define high BD, such as substance and antisocial behavior problems, finding no individual locus that surpassed genome-wide significance. Although no single SNP was significantly associated with BD, restricted maximum likelihood analysis estimated that 49.3 % of the variance in BD within the Caucasian sub-sample was accounted for by the genotyped SNPs (p = 0.06). Gene-based tests identified seven genes associated with BD (p ≤ 2.0 × 10(-6)). Although the current study was unable to identify specific SNPs or pathways with replicable effects on BD, the substantial sample variance that could be explained by all genotyped SNPs suggests that larger studies could successfully identify common variants associated with BD.

Imputation of behavioral candidate gene repeat variants in 486,551 publicly-available UK Biobank individuals.

Some of the most widely studied variants in psychiatric genetics include variable number tandem repeat variants (VNTRs) in SLC6A3, DRD4, SLC6A4, and MAOA. While initial findings suggested large effects, their importance with respect to psychiatric phenotypes is the subject of much debate with broadly conflicting results. Despite broad interest, these loci remain absent from the largest available samples, such as the UK Biobank, limiting researchers' ability to test these contentious hypotheses rigorously in large samples. Here, using two independent reference datasets, we report out-of-sample imputation accuracy estimates of >0.96 for all four VNTR variants and one modifying SNP, depending on the reference and target dataset. We describe the imputation procedures of these candidate variants in 486,551 UK Biobank individuals, and have made the imputed variant data available to UK Biobank researchers. This resource, provided to the scientific community, will allow the most rigorous tests to-date of the roles of these variants in behavioral and psychiatric phenotypes.

Genome-wide association meta-analysis of age at first cannabis use.

BACKGROUND AND AIMS: Cannabis is one of the most commonly used substances among adolescents and young adults. Earlier age at cannabis initiation is linked to adverse life outcomes, including multi-substance use and dependence. This study estimated the heritability of age at first cannabis use and identified associations with genetic variants. METHODS: A twin-based heritability analysis using 8055 twins from three cohorts was performed. We then carried out a genome-wide association meta-analysis of age at first cannabis use in a discovery sample of 24 953 individuals from nine European, North American and Australian cohorts, and a replication sample of 3735 individuals. RESULTS: The twin-based heritability for age at first cannabis use was 38% [95% confidence interval (CI) = 19-60%]. Shared and unique environmental factors explained 39% (95% CI = 20-56%) and 22% (95% CI = 16-29%). The genome-wide association meta-analysis identified five single nucleotide polymorphisms (SNPs) on chromosome 16 within the calcium-transporting ATPase gene (ATP2C2) at P < 5E-08. All five SNPs are in high linkage disequilibrium (LD) (r2  > 0.8), with the strongest association at the intronic variant rs1574587 (P = 4.09E-09). Gene-based tests of association identified the ATP2C2 gene on 16q24.1 (P = 1.33e-06). Although the five SNPs and ATP2C2 did not replicate, ATP2C2 has been associated with cocaine dependence in a previous study. ATP2B2, which is a member of the same calcium signalling pathway, has been associated previously with opioid dependence. SNP-based heritability for age at first cannabis use was non-significant. CONCLUSION: Age at cannabis initiation appears to be moderately heritable in western countries, and individual differences in onset can be explained by separate but correlated genetic liabilities. The significant association between age of initiation and ATP2C2 is consistent with the role of calcium signalling mechanisms in substance use disorders.

Cannabis receptor haplotype associated with fewer cannabis dependence symptoms in adolescents.

Cannabis is a major substance of abuse, and the gene encoding for the central cannabinoid receptor (CNR1) is a logical candidate gene for vulnerability toward developing symptoms of cannabis dependence. We studied four single-nucleotide polymorphisms (SNPs) in the CNR1 gene for association with having one or more symptoms of cannabis dependence in 541 adolescent subjects who had all tried cannabis five or more times. Cases (327) were defined as those who had tried marijuana and developed one or more symptoms, and controls (214) as those who had tried marijuana but developed no dependence symptoms. Cannabis dependence symptoms were assessed in these youth when they were 17 or older with the Composite International Diagnostic Interview--Substance Abuse Module. Univariate (single-marker) association tests demonstrated that SNP rs806380, located in intron 2 of the CNR1 gene, was significantly associated with developing one or more cannabis dependence symptoms, with the G allele having a protective effect (P < 0.02). This was consistent with the results of the global haplotype test (P < 0.01). One of the common haplotypes examined (present in 21% of the subjects) was significantly associated with a lower rate of having one or more cannabis dependence symptoms. Our findings provide evidence suggesting that a common CNR1 haplotype is associated with developing fewer cannabis dependence symptoms among adolescents who have experimented with cannabis.