Role of gene-stress interactions in gene-finding studies.

Identification of genetic variants underlying common complex traits and diseases can be viewed as a three-stage process that jump-started with the sequencing of the human genome. The second phase, characterization of genetic variants in different human populations, has shown major progress in recent years. The increased availability of single nucleotide polymorphisms (SNPs) has already spawned two important developments in genetic association studies. Increasingly, rather than focusing on one or two functional SNPs, candidate gene studies consider all variants within the gene jointly. The second development is that of the whole genome association study. This chapter illustrates two distinct ways in which gene-stress interactions may aid such gene finding studies. We have recently shown for heart rate variability--an index of autonomic dysfunction related to both psychopathology and cardiovascular disease--that exposure to an acute stressful challenge in a standardized lab setting may produce a more heritable endophenotype, facilitating identification of underlying genes. The second example shows how the creation of a cumulative index of chronic stress based on multiple questionnaire- and interview-based measures of stress exposure may be applied in a genome-wide association study of (high) blood pressure to find genes that only come to expression in stressful environments. We conclude that investigation ofgene-environment interactions in the context of both gene- and genome-wide association studies may offer important advantages in gene finding efforts for complex traits and diseases.