Linkage of chromosome 1 markers to alcoholism-related phenotypes by sib pair linkage analysis of principal components.

Using the Collaborative Study on the Genetics of Alcoholism data and affected-sib-pair linkage methods, Reich et al. [1998] reported linkage of alcohol dependence to a region near D1S1588 on chromosome 1. In this paper, we assessed the ability of multivariate sib-pair linkage analysis of the neurophysiologic measurements (including age and sex) to evaluate evidence for linkage to chromosome 1. Principal components of 16 neurophysiologic measurements, plus age and sex, were analyzed separately using sib-pair linkage analysis, and a cumulative sum of the resulting t2-statistics computed at each point on the chromosome. The first four principal components, which accounted for 74% of the total variation, showed little or no evidence for linkage in the D1S1588 region, while the remaining components showed substantial evidence for linkage. We conclude that potentially important linkage results can be missed if investigators limit attention only to major sources of variability.