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.

Fig. 1

Parts A-B: Distribution of age at last interview among DSM-IV alcohol dependent subjects (A) and non- alcohol dependent subjects (B). X axis represents the age at last interview and Y axis represents the density of subjects. The observed values of age at last interview were used to construct the relative likelihoods (density) at given age.

Fig. 2

Parts A-B: (A) Quantile-Quantile (QQ) plot and (B) Manhattan plot for the genome-wide association analysis of the age at onset of DSM-IV alcohol dependence in COGA (a) Observed p values for the 4,058,415 SNPs (black dots) were plotted against the expected p value (x--axis). The genomic inflation factor value (lambda) was 1.037. (b) Observed log p values for the 4,058,415 SNPs were plotted according to chromosomal position.

Fig. 3

Part A: Cumulative Incidence plot for rs2168784 on chromosome 3 X-axis represents the age at onset for alcohol dependence. Y-axis represents the cumulative incidence of AD. The red, blue and black lines show the cumulative incidence of AD for subjects with CC, CT and TT genotypes respectively. Steps on each line represent the occurrence of event (AD). Part B: Cumulative Incidence plot for rs35951 on chromosome 5 X-axis represents the age at onset for alcohol dependence. Y-axis represents the cumulative incidence of AD. The red, blue and black lines show the cumulative incidence of AD for subjects with GG, GT and TT genotypes respectively. Steps on each line represent the occurrence of event (AD). Part C: Cumulative Incidence plot for rs57083693 on chromosome 12 X-axis represents the age at onset for alcohol dependence. Y-axis represents the cumulative incidence of AD. The red, blue and black lines show the cumulative incidence of AD for subjects with CC, CT and TT genotypes respectively. Steps on each line represent the occurrence of event (AD).

Fig. 3

Part A: Cumulative Incidence plot for rs2168784 on chromosome 3 X-axis represents the age at onset for alcohol dependence. Y-axis represents the cumulative incidence of AD. The red, blue and black lines show the cumulative incidence of AD for subjects with CC, CT and TT genotypes respectively. Steps on each line represent the occurrence of event (AD). Part B: Cumulative Incidence plot for rs35951 on chromosome 5 X-axis represents the age at onset for alcohol dependence. Y-axis represents the cumulative incidence of AD. The red, blue and black lines show the cumulative incidence of AD for subjects with GG, GT and TT genotypes respectively. Steps on each line represent the occurrence of event (AD). Part C: Cumulative Incidence plot for rs57083693 on chromosome 12 X-axis represents the age at onset for alcohol dependence. Y-axis represents the cumulative incidence of AD. The red, blue and black lines show the cumulative incidence of AD for subjects with CC, CT and TT genotypes respectively. Steps on each line represent the occurrence of event (AD).

Fig. 3

Part A: Cumulative Incidence plot for rs2168784 on chromosome 3 X-axis represents the age at onset for alcohol dependence. Y-axis represents the cumulative incidence of AD. The red, blue and black lines show the cumulative incidence of AD for subjects with CC, CT and TT genotypes respectively. Steps on each line represent the occurrence of event (AD). Part B: Cumulative Incidence plot for rs35951 on chromosome 5 X-axis represents the age at onset for alcohol dependence. Y-axis represents the cumulative incidence of AD. The red, blue and black lines show the cumulative incidence of AD for subjects with GG, GT and TT genotypes respectively. Steps on each line represent the occurrence of event (AD). Part C: Cumulative Incidence plot for rs57083693 on chromosome 12 X-axis represents the age at onset for alcohol dependence. Y-axis represents the cumulative incidence of AD. The red, blue and black lines show the cumulative incidence of AD for subjects with CC, CT and TT genotypes respectively. Steps on each line represent the occurrence of event (AD).