A genome-wide association study of alcohol-dependence symptom counts in extended pedigrees identifies C15orf53.
paper
Primary
Public
- Authors
- Wang, J-C; Foroud, T; Hinrichs, A L; Le, N X H; Bertelsen, S; Budde, J P; Harari, O; Koller, D L; Wetherill, L; Agrawal, A; Almasy, L; Brooks, A I; Bucholz, K; Dick, D; Hesselbrock, V; Johnson, E O; Kang, S; Kapoor, M; Kramer, J; Kuperman, S; Madden, P A F; Manz, N; Martin, N G; McClintick, J N; Montgomery, G W; Nurnberger, J I; Rangaswamy, M; Rice, J; Schuckit, M; Tischfield, J A; Whitfield, J B; Xuei, X; Porjesz, B; Heath, A C; Edenberg, H J; Bierut, L J; Goate, A M
- Year
- 2013
- Journal
- Molecular psychiatry
- PMID
- 23089632
- DOI
- 10.1038/mp.2012.143
- PMCID
- PMC3752321
Several studies have identified genes associated with alcohol-use disorders (AUDs), but the variation in each of these genes explains only a small portion of the genetic vulnerability. The goal of the present study was to perform a genome-wide association study (GWAS) in extended families from the Collaborative Study on the Genetics of Alcoholism to identify novel genes affecting risk for alcohol dependence (AD). To maximize the power of the extended family design, we used a quantitative endophenotype, measured in all individuals: number of alcohol-dependence symptoms endorsed (symptom count (SC)). Secondary analyses were performed to determine if the single nucleotide polymorphisms (SNPs) associated with SC were also associated with the dichotomous phenotype, DSM-IV AD. This family-based GWAS identified SNPs in C15orf53 that are strongly associated with DSM-IV alcohol-dependence symptom counts (P=4.5 Γ 10(-8), inflation-corrected P=9.4 Γ 10(-7)). Results with DSM-IV AD in the regions of interest support our findings with SC, although the associations were less significant. Attempted replications of the most promising association results were conducted in two independent samples: nonoverlapping subjects from the Study of Addiction: Genes and Environment (SAGE) and the Australian Twin Family Study of AUDs (OZALC). Nominal association of C15orf53 with SC was observed in SAGE. The variant that showed strongest association with SC, rs12912251 and its highly correlated variants (D'=1, r(2)ξΆ 0.95), have previously been associated with risk for bipolar disorder.
Distribution of DSM_IV alcohol dependence symptom count in the genotyped GWAS sample
Manhattan plot of genome-wide association results for DSM-IV alcohol dependence symptom count using negative binomial analysisβlog10 values shown here were not corrected for inflation factor.
Plot of chromosome 15q14 association with DSM_IV alcohol dependence symptom countSquares represent genotyped SNPs; Circles represent imputed SNPs. SNP rs7165988 (in red) is a non-synonymous coding variant. SNP rs12916379 (in blue) is in 3β²un-translated region of C15orf53.
Correlation between symptom count effect and DSM-IV alcohol dependence effect in COGA sample
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| Name | Type |
|---|---|
| 118 extended families local | cohort |
| 118 families local | cohort |
| 275 subjects local | cohort |
| AD probands local | cohort |
| AD symptoms | phenotype |
| Adult drinkers cohort local | cohort |
| age | phenotype |
| Age-squared local | phenotype |
| alcohol | phenotype |
| alcohol abuse | phenotype |
| alcohol dependence | phenotype |
| alcoholism | phenotype |
| alcohol-related phenotypes | phenotype |
| Alcohol Symptom Count local | phenotype |
| Alcohol Use Disorder | phenotype |
| Alzheimer's disease | phenotype |
| Attention deficit hyperactivity disorder (ADHD) local | phenotype |
| AUD | phenotype |
| Australian sample of related individuals local | cohort |
| Australian Twin Registry | cohort |
| bipolar disorder | phenotype |
| bipolar I disorder | phenotype |
| bipolar II disorder | phenotype |
| brain | anatomy |
| brain tissue | anatomy |
| C15orf53 | gene |
| case-control GWAS local | cohort |
| Case-control series local | cohort |
| chromosome 15q14 local | variant |
| cocaine | phenotype |
| COGA family-based sample local | cohort |
| COGA sample | cohort |
| Collaborative Genetics Study of Nicotine Dependence local | cohort |
| Collaborative Study on the Genetics of Alcoholism (COGA) | cohort |
| Cxcr7 | gene |
| densely affected families | cohort |
| Dependence symptoms | phenotype |
| DSM-IV alcohol dependence | phenotype |
| DSM-IV symptom count (SC) local | phenotype |
| Electrophysiology measures local | phenotype |
| European population | cohort |
| Extended families cohort local | cohort |
| Family study of cocaine dependence | cohort |
| frontal cortex | anatomy |
| HapMap EUR reference sample local | cohort |
| Human frontal cortices local | anatomy |
| Large unselected sibships local | cohort |
| nicotine dependence | phenotype |
| non-drinkers | phenotype |
| OZALC | cohort |
| population-based sample | cohort |
| problematic alcohol use | phenotype |
| Psychiatric GWAS Consortium Bipolar Disorder Working Group local | cohort |
| rs12899449 local | variant |
| rs12903120 | variant |
| rs12912251 local | variant |
| rs12916379 local | variant |
| rs2132157 local | variant |
| rs2172835 | variant |
| rs7165988 local | variant |
| SAGE | cohort |
| SAGE dataset | cohort |
| SC local | gene |
| schizophrenia | phenotype |
| SC phenotype local | phenotype |
| sex | phenotype |
| SLC9A9 | gene |
| SNP | cohort |
| SNP_set_18 local | variant |
| SNP_set_5 local | variant |
| SNPs in 7 chromosome regions local | variant |
| structural connectivity | phenotype |
| study cohort | cohort |
| subjects | cohort |
| symptom count | phenotype |
| tobacco smoking initiation local | phenotype |
| Treatment seeking subjects local | cohort |
| unaffected | phenotype |
| Unknown local | phenotype |
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