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To the Editor: In their meta-analysis, Dr Risch and colleagues¹ concluded that the study of gene-environment interaction in mental disorders should await the identification of "robust marginal gene associations." We believe that this conclusion extends well beyond the data, and an alternate explanation of their findings suggests other courses of action. The absence of replicable findings across studies that assessed both direct genotype-depression associations and gene-environment interactions may be explained by mismeasurement and undermeasurement of relevant environmental contexts.

Two compelling strands of evidence support this hypothesis. First, there is a sharp contrast in the consistency of success in studies that have sought genotype-phenotype associations in animals and in humans. For example, animal models of depression and anxiety disorders have consistently demonstrated genotype-phenotype associations.² By contrast, a recent genome-wide association study (GWAS) of depression found no significant associations.³ One central difference between these 2 research approaches lies in control over potentially . . . [Full Text of this Article]

Karestan C. Koenen, PhD
kkoenen@hsph.harvard.edu
Department of Society, Human Development, and Health
Harvard School of Public Health
Boston, Massachusetts

Sandro Galea, MD, DrPH
Department of Epidemiology
School of Public Health
University of Michigan
Ann Arbor

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