Psychiatric genetics: a methodologic critique.

Psychiatric genetics, which is growing in size and influence within psychiatry, employs four major research paradigms: 1) basic genetic epidemiology, 2) advanced genetic epidemiology, 3) gene finding methods, and 4) molecular genetics. Paradigms 1 and 2 study aggregate genetic risk factors inferred from patterns of resemblance in relatives. Paradigms 3 and 4 study individual susceptibility genes localized on the human genome. Paradigms 1, 2, and 3 are statistical in nature, while paradigm 4 is biological. Genetic risk factors reflect the statistical signals from susceptibility genes. Whether it will be possible to identify all the susceptibility genes that underlie genetic risk factors is uncertain. Furthermore, given current research methods, the inability to detect susceptibility genes cannot disconfirm evidence for genetic risk factors. While paradigms 3 and 4 can provide great explanatory power by tracing etiologic pathways back to basic biological mechanisms, genetic epidemiology can also provide important etiologic insights, albeit of a less basic nature. While paradigms 3 and 4 may eventually replace paradigms 1 and 2, this shift is unlikely to occur quickly. Therefore, the field of psychiatric genetics would do best to integrate these four paradigms, stressing their relative strengths and limitations. This integration can be best done within an overall framework of explanatory pluralism that values a range of reductive explanations across varying levels of biological and psychological complexity.