Can single genes matter in a polygenic world?

摘要

Like dogs chasing a car down the street, investigators in psychiatric genetics sometimes appear uncertain about what we will do once we actually catch up with our prey. As putative risk genes begin to appear more consistently in large-scale disease-association studies, the need for clarity about how they can be followed up becomes more acute. Two articles in this issue frame the challenge well. The first, by Terracciano et al. (1), describes a meta-analysis of two genome-wide association studies (GWAS) of trait depression, a subscale derived from the Revised NEO Personality Inventory. Using eight items from that scale in population-based cohorts not screened for psychiatric illness, the authors seek to identify common variation associated with trait depression-really a predisposition that may indicate risk for mood or anxiety disorders or current symptoms of such disorders. The study builds on a tradition within psychiatric genetics emphasizing the pheno-type, one that long predated the preoccupation with endopheno-types or intermediate phenotypes. The notion is simply that using a more refined understanding of diseases or traits will facilitate identification of risk markers. Although intuitively appealing, it bears noting that even singie-gene deletions may exhibit remarkably pleiotropy (2).