Abstract
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 × 10 -8, inflation-corrected P=9.4 × 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 ≥ 0.95), have previously been associated with risk for bipolar disorder.
| Original language | English |
|---|---|
| Pages (from-to) | 1218-1224 |
| Number of pages | 7 |
| Journal | Molecular Psychiatry |
| Volume | 18 |
| Issue number | 11 |
| DOIs | |
| State | Published - Nov 2013 |
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Keywords
- C15orf53; DSM-IV alcohol-dependence symptoms
- Family-based GWAS
- Quantitative traits
ASJC Scopus subject areas
- Molecular Biology
- Psychiatry and Mental health
- Cellular and Molecular Neuroscience
Cite this
A genome-wide association study of alcohol-dependence symptom counts in extended pedigrees identifies C15orf53. / Wang, J. C.; Foroud, Tatiana; 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, Jeanette; Montgomery, G. W.; Nurnberger, John; Rangaswamy, M.; Rice, J.; Schuckit, M.; Tischfield, J. A.; Whitfield, J. B.; Xuei, Xiaoling; Porjesz, B.; Heath, A. C.; Edenberg, Howard; Bierut, L. J.; Goate, A. M.
In: Molecular Psychiatry, Vol. 18, No. 11, 11.2013, p. 1218-1224.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - A genome-wide association study of alcohol-dependence symptom counts in extended pedigrees identifies C15orf53
AU - Wang, J. C.
AU - Foroud, Tatiana
AU - Hinrichs, A. L.
AU - Le, N. X H
AU - Bertelsen, S.
AU - Budde, J. P.
AU - Harari, O.
AU - Koller, D. L.
AU - Wetherill, L.
AU - Agrawal, A.
AU - Almasy, L.
AU - Brooks, A. I.
AU - Bucholz, K.
AU - Dick, D.
AU - Hesselbrock, V.
AU - Johnson, E. O.
AU - Kang, S.
AU - Kapoor, M.
AU - Kramer, J.
AU - Kuperman, S.
AU - Madden, P. A F
AU - Manz, N.
AU - Martin, N. G.
AU - McClintick, Jeanette
AU - Montgomery, G. W.
AU - Nurnberger, John
AU - Rangaswamy, M.
AU - Rice, J.
AU - Schuckit, M.
AU - Tischfield, J. A.
AU - Whitfield, J. B.
AU - Xuei, Xiaoling
AU - Porjesz, B.
AU - Heath, A. C.
AU - Edenberg, Howard
AU - Bierut, L. J.
AU - Goate, A. M.
PY - 2013/11
Y1 - 2013/11
N2 - 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 × 10 -8, inflation-corrected P=9.4 × 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 ≥ 0.95), have previously been associated with risk for bipolar disorder.
AB - 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 × 10 -8, inflation-corrected P=9.4 × 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 ≥ 0.95), have previously been associated with risk for bipolar disorder.
KW - C15orf53; DSM-IV alcohol-dependence symptoms
KW - Family-based GWAS
KW - Quantitative traits
UR - http://www.scopus.com/inward/record.url?scp=84888296398&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84888296398&partnerID=8YFLogxK
U2 - 10.1038/mp.2012.143
DO - 10.1038/mp.2012.143
M3 - Article
C2 - 23089632
AN - SCOPUS:84888296398
VL - 18
SP - 1218
EP - 1224
JO - Molecular Psychiatry
JF - Molecular Psychiatry
SN - 1359-4184
IS - 11
ER -