Exploring the impact of extended phenotype in stratified samples

Area of Science:

• Genetics
• Psychiatry
• Addiction Research

Background:

• Alcoholism (ALDX1) is a complex etiological trait with potential genetic underpinnings.
• Previous studies have identified potential linkage regions for alcoholism.
• Stratification by age of onset may reveal distinct genetic factors.

Purpose of the Study:

• To investigate the influence of age of onset on genetic linkage for alcoholism.
• To examine linkage at the ADH3 candidate gene in early and late-onset alcoholism subgroups.
• To assess the impact of phenotypic definitions and subgrouping on linkage analysis.

Main Methods:

• Nonparametric sib-pair genome scans were conducted on early (N=52) and late (N=53) onset subgroups of the Collaborative Study on the Genetics of Alcoholism (COGA) pedigrees.
• Traits analyzed included alcoholism (ALDX1), smoking, and addiction (alcoholism or smoking).
• Linkage analyses were corrected for the number of traits analyzed.

Main Results:

• Evidence for linkage to the ALDX1 alcoholism phenotype at the ADH3 gene was significantly increased in the late-onset subgroup (Bonferroni corrected p < 0.002).
• This finding replicated previous COGA linkage results in the unstratified sample.
• No evidence for linkage was found at this locus in the early-onset subgroup.

Conclusions:

• Stratifying alcoholism by age of onset can enhance the detection of genetic linkage.
• The late-onset subgroup, potentially more homogeneous, showed stronger evidence for linkage at ADH3.
• Subgrouping can overcome the loss of statistical power from reduced sample size by increasing etiological homogeneity.