Genome-wide survival analysis of age at onset of alcohol dependence in extended high-risk COGA families

Manav Kapoor, Jen Chyong Wang, Leah Wetherill, Nhung Le, Sarah Bertelsen, Anthony L. Hinrichs, John Budde, Arpana Agrawal, Laura Almasy, Kathleen Bucholz, Danielle M. Dick, Oscar Harari, Xuei Xiaoling, Victor Hesselbrock, John Kramer, John I. Nurnberger, John Rice, Marc Schuckit, Jay Tischfield, Bernice PorjeszHoward J. Edenberg, Laura Bierut, Tatiana Foroud, Alison Goate

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Background: The age at onset of alcohol dependence (AD) is a critical moderator of genetic associations for alcohol dependence. The present study evaluated whether single nucleotide polymorphisms (SNPs) can influence the age at onset of AD in large high-risk families from the Collaborative Study on the Genetics of Alcoholism (COGA). Methods: Genomewide SNP genotyping was performed in 1788 regular drinkers from 118 large European American families densely affected with alcoholism. We used a genome-wide Cox proportional hazards regression model to test for association between age at onset of AD and SNPs. Results: This family-based analysis identified an intergenic SNP, rs2168784 on chromosome 3 that showed strong evidence of association (P=5×10-9) with age at onset of AD among regular drinkers. Carriers of the minor allele of rs2168784 had 1.5 times the hazard of AD onset as compared with those homozygous for the major allele. By the age of 20 years, nearly 30% of subjects homozygous for the minor allele were alcohol dependent while only 19% of those homozygous for the major allele were. We also identified intronic SNPs in the ADP-ribosylation factor like 15 (ARL15) gene on chromosome 5 (P=1.11×10-8) and the UTP20 small subunit (UTP20) gene on chromosome 12 (P=4.32×10-8) that were associated with age at onset of AD. Conclusions: This extended family based genome-wide cox-proportional hazards analysis identified several loci that might be associated with age at onset of AD.

Original languageEnglish (US)
Pages (from-to)56-62
Number of pages7
JournalDrug and Alcohol Dependence
Volume142
DOIs
StatePublished - Sep 1 2014

Fingerprint

Survival Analysis
Age of Onset
Alcoholism
Genes
Alcohols
Genome
Polymorphism
Single Nucleotide Polymorphism
Nucleotides
Chromosomes
Alleles
Hazards
ADP-Ribosylation Factors
Genetics
Moderators
Chromosomes, Human, Pair 12
Chromosomes, Human, Pair 5
Chromosomes, Human, Pair 3
Proportional Hazards Models

Keywords

  • Age at onset
  • Alcohol dependence
  • GWAS
  • SNP
  • Survival analysis

ASJC Scopus subject areas

  • Psychiatry and Mental health
  • Toxicology
  • Pharmacology
  • Pharmacology (medical)
  • Medicine(all)

Cite this

Genome-wide survival analysis of age at onset of alcohol dependence in extended high-risk COGA families. / Kapoor, Manav; Wang, Jen Chyong; Wetherill, Leah; Le, Nhung; Bertelsen, Sarah; Hinrichs, Anthony L.; Budde, John; Agrawal, Arpana; Almasy, Laura; Bucholz, Kathleen; Dick, Danielle M.; Harari, Oscar; Xiaoling, Xuei; Hesselbrock, Victor; Kramer, John; Nurnberger, John I.; Rice, John; Schuckit, Marc; Tischfield, Jay; Porjesz, Bernice; Edenberg, Howard J.; Bierut, Laura; Foroud, Tatiana; Goate, Alison.

In: Drug and Alcohol Dependence, Vol. 142, 01.09.2014, p. 56-62.

Research output: Contribution to journalArticle

Kapoor, M, Wang, JC, Wetherill, L, Le, N, Bertelsen, S, Hinrichs, AL, Budde, J, Agrawal, A, Almasy, L, Bucholz, K, Dick, DM, Harari, O, Xiaoling, X, Hesselbrock, V, Kramer, J, Nurnberger, JI, Rice, J, Schuckit, M, Tischfield, J, Porjesz, B, Edenberg, HJ, Bierut, L, Foroud, T & Goate, A 2014, 'Genome-wide survival analysis of age at onset of alcohol dependence in extended high-risk COGA families', Drug and Alcohol Dependence, vol. 142, pp. 56-62. https://doi.org/10.1016/j.drugalcdep.2014.05.023
Kapoor, Manav ; Wang, Jen Chyong ; Wetherill, Leah ; Le, Nhung ; Bertelsen, Sarah ; Hinrichs, Anthony L. ; Budde, John ; Agrawal, Arpana ; Almasy, Laura ; Bucholz, Kathleen ; Dick, Danielle M. ; Harari, Oscar ; Xiaoling, Xuei ; Hesselbrock, Victor ; Kramer, John ; Nurnberger, John I. ; Rice, John ; Schuckit, Marc ; Tischfield, Jay ; Porjesz, Bernice ; Edenberg, Howard J. ; Bierut, Laura ; Foroud, Tatiana ; Goate, Alison. / Genome-wide survival analysis of age at onset of alcohol dependence in extended high-risk COGA families. In: Drug and Alcohol Dependence. 2014 ; Vol. 142. pp. 56-62.
@article{ec6ab11d96ef4fe19fe0065f6db21483,
title = "Genome-wide survival analysis of age at onset of alcohol dependence in extended high-risk COGA families",
abstract = "Background: The age at onset of alcohol dependence (AD) is a critical moderator of genetic associations for alcohol dependence. The present study evaluated whether single nucleotide polymorphisms (SNPs) can influence the age at onset of AD in large high-risk families from the Collaborative Study on the Genetics of Alcoholism (COGA). Methods: Genomewide SNP genotyping was performed in 1788 regular drinkers from 118 large European American families densely affected with alcoholism. We used a genome-wide Cox proportional hazards regression model to test for association between age at onset of AD and SNPs. Results: This family-based analysis identified an intergenic SNP, rs2168784 on chromosome 3 that showed strong evidence of association (P=5×10-9) with age at onset of AD among regular drinkers. Carriers of the minor allele of rs2168784 had 1.5 times the hazard of AD onset as compared with those homozygous for the major allele. By the age of 20 years, nearly 30{\%} of subjects homozygous for the minor allele were alcohol dependent while only 19{\%} of those homozygous for the major allele were. We also identified intronic SNPs in the ADP-ribosylation factor like 15 (ARL15) gene on chromosome 5 (P=1.11×10-8) and the UTP20 small subunit (UTP20) gene on chromosome 12 (P=4.32×10-8) that were associated with age at onset of AD. Conclusions: This extended family based genome-wide cox-proportional hazards analysis identified several loci that might be associated with age at onset of AD.",
keywords = "Age at onset, Alcohol dependence, GWAS, SNP, Survival analysis",
author = "Manav Kapoor and Wang, {Jen Chyong} and Leah Wetherill and Nhung Le and Sarah Bertelsen and Hinrichs, {Anthony L.} and John Budde and Arpana Agrawal and Laura Almasy and Kathleen Bucholz and Dick, {Danielle M.} and Oscar Harari and Xuei Xiaoling and Victor Hesselbrock and John Kramer and Nurnberger, {John I.} and John Rice and Marc Schuckit and Jay Tischfield and Bernice Porjesz and Edenberg, {Howard J.} and Laura Bierut and Tatiana Foroud and Alison Goate",
year = "2014",
month = "9",
day = "1",
doi = "10.1016/j.drugalcdep.2014.05.023",
language = "English (US)",
volume = "142",
pages = "56--62",
journal = "Drug and Alcohol Dependence",
issn = "0376-8716",
publisher = "Elsevier Ireland Ltd",

}

TY - JOUR

T1 - Genome-wide survival analysis of age at onset of alcohol dependence in extended high-risk COGA families

AU - Kapoor, Manav

AU - Wang, Jen Chyong

AU - Wetherill, Leah

AU - Le, Nhung

AU - Bertelsen, Sarah

AU - Hinrichs, Anthony L.

AU - Budde, John

AU - Agrawal, Arpana

AU - Almasy, Laura

AU - Bucholz, Kathleen

AU - Dick, Danielle M.

AU - Harari, Oscar

AU - Xiaoling, Xuei

AU - Hesselbrock, Victor

AU - Kramer, John

AU - Nurnberger, John I.

AU - Rice, John

AU - Schuckit, Marc

AU - Tischfield, Jay

AU - Porjesz, Bernice

AU - Edenberg, Howard J.

AU - Bierut, Laura

AU - Foroud, Tatiana

AU - Goate, Alison

PY - 2014/9/1

Y1 - 2014/9/1

N2 - Background: The age at onset of alcohol dependence (AD) is a critical moderator of genetic associations for alcohol dependence. The present study evaluated whether single nucleotide polymorphisms (SNPs) can influence the age at onset of AD in large high-risk families from the Collaborative Study on the Genetics of Alcoholism (COGA). Methods: Genomewide SNP genotyping was performed in 1788 regular drinkers from 118 large European American families densely affected with alcoholism. We used a genome-wide Cox proportional hazards regression model to test for association between age at onset of AD and SNPs. Results: This family-based analysis identified an intergenic SNP, rs2168784 on chromosome 3 that showed strong evidence of association (P=5×10-9) with age at onset of AD among regular drinkers. Carriers of the minor allele of rs2168784 had 1.5 times the hazard of AD onset as compared with those homozygous for the major allele. By the age of 20 years, nearly 30% of subjects homozygous for the minor allele were alcohol dependent while only 19% of those homozygous for the major allele were. We also identified intronic SNPs in the ADP-ribosylation factor like 15 (ARL15) gene on chromosome 5 (P=1.11×10-8) and the UTP20 small subunit (UTP20) gene on chromosome 12 (P=4.32×10-8) that were associated with age at onset of AD. Conclusions: This extended family based genome-wide cox-proportional hazards analysis identified several loci that might be associated with age at onset of AD.

AB - Background: The age at onset of alcohol dependence (AD) is a critical moderator of genetic associations for alcohol dependence. The present study evaluated whether single nucleotide polymorphisms (SNPs) can influence the age at onset of AD in large high-risk families from the Collaborative Study on the Genetics of Alcoholism (COGA). Methods: Genomewide SNP genotyping was performed in 1788 regular drinkers from 118 large European American families densely affected with alcoholism. We used a genome-wide Cox proportional hazards regression model to test for association between age at onset of AD and SNPs. Results: This family-based analysis identified an intergenic SNP, rs2168784 on chromosome 3 that showed strong evidence of association (P=5×10-9) with age at onset of AD among regular drinkers. Carriers of the minor allele of rs2168784 had 1.5 times the hazard of AD onset as compared with those homozygous for the major allele. By the age of 20 years, nearly 30% of subjects homozygous for the minor allele were alcohol dependent while only 19% of those homozygous for the major allele were. We also identified intronic SNPs in the ADP-ribosylation factor like 15 (ARL15) gene on chromosome 5 (P=1.11×10-8) and the UTP20 small subunit (UTP20) gene on chromosome 12 (P=4.32×10-8) that were associated with age at onset of AD. Conclusions: This extended family based genome-wide cox-proportional hazards analysis identified several loci that might be associated with age at onset of AD.

KW - Age at onset

KW - Alcohol dependence

KW - GWAS

KW - SNP

KW - Survival analysis

UR - http://www.scopus.com/inward/record.url?scp=84905585043&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84905585043&partnerID=8YFLogxK

U2 - 10.1016/j.drugalcdep.2014.05.023

DO - 10.1016/j.drugalcdep.2014.05.023

M3 - Article

C2 - 24962325

AN - SCOPUS:84905585043

VL - 142

SP - 56

EP - 62

JO - Drug and Alcohol Dependence

JF - Drug and Alcohol Dependence

SN - 0376-8716

ER -