Association of substance dependence phenotypes in the COGA sample.
- Authors
- Wetherill, Leah; Agrawal, Arpana; Kapoor, Manav; Bertelsen, Sarah; Bierut, Laura J; Brooks, Andrew; Dick, Danielle; Hesselbrock, Michie; Hesselbrock, Victor; Koller, Daniel L; Le, Nhung; Nurnberger, John I; Salvatore, Jessica E; Schuckit, Marc; Tischfield, Jay A; Wang, Jen-Chyong; Xuei, Xiaoling; Edenberg, Howard J; Porjesz, Bernice; Bucholz, Kathleen; Goate, Alison M; Foroud, Tatiana
- Year
- 2015
- Journal
- Addiction biology
- PMID
- 24832863
- DOI
- 10.1111/adb.12153
- PMCID
- PMC4233207
Alcohol and drug use disorders are individually heritable (50%). Twin studies indicate that alcohol and substance use disorders share common genetic influences, and therefore may represent a more heritable form of addiction and thus be more powerful for genetic studies. This study utilized data from 2322 subjects from 118 European-American families in the Collaborative Study on the Genetics of Alcoholism sample to conduct genome-wide association analysis of a binary and a continuous index of general substance dependence liability. The binary phenotype (ANYDEP) was based on meeting lifetime criteria for any DSM-IV dependence on alcohol, cannabis, cocaine or opioids. The quantitative trait (QUANTDEP) was constructed from factor analysis based on endorsement across the seven DSM-IV criteria for each of the four substances. Heritability was estimated to be 54% for ANYDEP and 86% for QUANTDEP. One single-nucleotide polymorphism (SNP), rs2952621 in the uncharacterized gene LOC151121 on chromosome 2, was associated with ANYDEP (P = 1.8 × 10(-8) ), with support from surrounding imputed SNPs and replication in an independent sample [Study of Addiction: Genetics and Environment (SAGE); P = 0.02]. One SNP, rs2567261 in ARHGAP28 (Rho GTPase-activating protein 28), was associated with QUANTDEP (P = 3.8 × 10(-8) ), and supported by imputed SNPs in the region, but did not replicate in an independent sample (SAGE; P = 0.29). The results of this study provide evidence that there are common variants that contribute to the risk for a general liability to substance dependence.
Mean and standard error of ANYQUANT scores for individuals used in analysis based on: Number of substance dependence diagnoses; B. Each DSM-IV substance dependence endorsed (includes comorbidities)
Association results: A. ANYDEP, genomic-control p-values; B. QUANTDEP.
Sample characterization by SNP genotype. A: Dependence on each substance by genotype of rs2952621 in LOC151121 for all individuals meeting criteria for alcohol, cannabis, cocaine, and opioid dependence; 3B: Mean QUANTDEP by genotype of rs2567261 in ARHGAP28 for all individuals meeting criteria for alcohol, cannabis, cocaine, and opioid.
Association resultsA. ANYDEP with genotyped and imputed SNPs in the region flanking LOC151121; Y-axis denotes the −log10(p-value) for association. X-axis is the physical position on the chromosome (Mb). The most significantly associated SNP is shown in purple. The extent of linkage disequilibrium (as measured by r2) between each SNP and the most significantly associated SNP is indicated by the color scale at top right. Larger values of r2 indicate greater linkage disequilibrium. Genotyped SNPs are indicated as circles, and imputed SNPs by squares. B. QUANTDEP with genotyped and imputed SNPs in the region flanking ARHGAP28. Y-axis denotes the −log10(p-value) for association. X-axis is the physical position on the chromosome (Mb). The most significantly associated SNP is shown in purple. The extent of linkage disequilibrium (as measured by r2) between each SNP and the most significantly associated SNP is indicated by the color scale at top right. Larger values of r2 indicate greater linkage disequilibrium. Genotyped SNPs are indicated as circles, and imputed SNPs by squares.
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