A genome-wide association study of alcohol-dependence symptom counts in extended pedigrees identifies C15orf53

J. C. Wang; T. Foroud; A. L. Hinrichs; N. X.H. Le; S. Bertelsen; J. P. Budde; O. Harari; D. L. Koller; L. Wetherill; A. Agrawal; L. Almasy; A. I. Brooks; K. Bucholz; D. Dick; V. Hesselbrock; E. O. Johnson; S. Kang; M. Kapoor; J. Kramer; S. Kuperman; P. A.F. Madden; N. Manz; N. G. Martin; J. N. McClintick; G. W. Montgomery; J. I. Nurnberger; M. Rangaswamy; J. Rice; M. Schuckit; J. A. Tischfield; J. B. Whitfield; X. Xuei; B. Porjesz; A. C. Heath; H. J. Edenberg; L. J. Bierut; A. M. Goate

doi:10.1038/mp.2012.143

A genome-wide association study of alcohol-dependence symptom counts in extended pedigrees identifies C15orf53

J. C. Wang, T. Foroud, A. L. Hinrichs, N. X.H. Le, S. Bertelsen, J. P. Budde, O. Harari, D. L. Koller, L. Wetherill, A. Agrawal, L. Almasy, A. I. Brooks, K. Bucholz, D. Dick, V. Hesselbrock, E. O. Johnson, S. Kang, M. Kapoor, J. Kramer, S. KupermanP. A.F. Madden, N. Manz, N. G. Martin, J. N. McClintick, G. W. Montgomery, J. I. Nurnberger, M. Rangaswamy, J. Rice, M. Schuckit, J. A. Tischfield, J. B. Whitfield, X. Xuei, B. Porjesz, A. C. Heath, H. J. Edenberg, L. J. Bierut, A. M. Goate

Research output: Contribution to journal › Article › peer-review

58 Scopus citations

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 (US)
Pages (from-to)	1218-1224
Number of pages	7
Journal	Molecular Psychiatry
Volume	18
Issue number	11
DOIs	https://doi.org/10.1038/mp.2012.143
State	Published - Nov 2013

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

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10.1038/mp.2012.143

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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., ... Goate, A. M. (2013). A genome-wide association study of alcohol-dependence symptom counts in extended pedigrees identifies C15orf53. Molecular Psychiatry, 18(11), 1218-1224. https://doi.org/10.1038/mp.2012.143

A genome-wide association study of alcohol-dependence symptom counts in extended pedigrees identifies C15orf53. / 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.

In: Molecular Psychiatry, Vol. 18, No. 11, 11.2013, p. 1218-1224.

Research output: Contribution to journal › Article › peer-review

Wang, JC, Foroud, T, Hinrichs, AL, Le, NXH, Bertelsen, S, Budde, JP, Harari, O, Koller, DL, Wetherill, L, Agrawal, A, Almasy, L, Brooks, AI, Bucholz, K, Dick, D, Hesselbrock, V, Johnson, EO, Kang, S, Kapoor, M, Kramer, J, Kuperman, S, Madden, PAF, Manz, N, Martin, NG, McClintick, JN, Montgomery, GW, Nurnberger, JI, Rangaswamy, M, Rice, J, Schuckit, M, Tischfield, JA, Whitfield, JB, Xuei, X, Porjesz, B, Heath, AC, Edenberg, HJ, Bierut, LJ & Goate, AM 2013, 'A genome-wide association study of alcohol-dependence symptom counts in extended pedigrees identifies C15orf53', Molecular Psychiatry, vol. 18, no. 11, pp. 1218-1224. https://doi.org/10.1038/mp.2012.143

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. / A genome-wide association study of alcohol-dependence symptom counts in extended pedigrees identifies C15orf53. In: Molecular Psychiatry. 2013 ; Vol. 18, No. 11. pp. 1218-1224.

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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.",

keywords = "C15orf53; DSM-IV alcohol-dependence symptoms, Family-based GWAS, Quantitative traits",

author = "Wang, {J. C.} and T. Foroud and Hinrichs, {A. L.} and Le, {N. X.H.} and S. Bertelsen and Budde, {J. P.} and O. Harari and Koller, {D. L.} and L. Wetherill and A. Agrawal and L. Almasy and Brooks, {A. I.} and K. Bucholz and D. Dick and V. Hesselbrock and Johnson, {E. O.} and S. Kang and M. Kapoor and J. Kramer and S. Kuperman and Madden, {P. A.F.} and N. Manz and Martin, {N. G.} and McClintick, {J. N.} and Montgomery, {G. W.} and Nurnberger, {J. I.} and M. Rangaswamy and J. Rice and M. Schuckit and Tischfield, {J. A.} and Whitfield, {J. B.} and X. Xuei and B. Porjesz and Heath, {A. C.} and Edenberg, {H. J.} and Bierut, {L. J.} and Goate, {A. M.}",

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AU - Almasy, L.

AU - Brooks, A. I.

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AU - Kang, S.

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AU - Rice, J.

AU - Schuckit, M.

AU - Tischfield, J. A.

AU - Whitfield, J. B.

AU - Xuei, X.

AU - Porjesz, B.

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