A Meta-Analytic Evaluation of the Endophenotype Hypothesis: Effects of Measurement Paradigm in the Psychiatric Genetics of Impulsivity

Recent transitions in psychiatric nosology have stimulated discussion about what constructs and what level of analysis are most appropriate for the study of psychopathology. The endophenotype hypothesis suggests that neurobiological and neuropsychological phenotypes will be superior to trait or diagnostic measures in elucidating the substrates of psychopathology, as the former are more proximal, and therefore more sensitive, to underlying etiology. This meta-analysis explores these issues by comparing the magnitude of genetic effects associated with phenotypes at different levels of analysis. Studies of 3 common polymorphisms-the short and long variants of the serotonin-transporter-linked polymorphic region (5-HTTLPR), the variable number tandem repeat polymorphism in the 3' untranslated region of the dopamine active transporter gene (DAT1 3' UTR VNTR), and the 48 base-pair VNTR in exon-3 of the dopamine D4 receptor gene (DRD4)-and their effects on phenotypes of impulsivity were examined. Consistent with endophenotype theory, level of phenotype moderated the magnitude of genetic effects. Diagnostic, trait and neuropsychological, then neurobiological phenotypes yielded successively larger effects. However, consistent with emerging meta-analytic findings, neurobiological phenotypes were most susceptible to bias and inflation, raising questions about the validity of reported effects.