Etiology in psychiatry: embracing the reality of poly-gene-environmental causation of mental illness

Abstract

Intriguing findings on genetic and environmental causation suggest a need to reframe the etiology of mental disorders. Molecular genetics shows that thousands of common and rare genetic variants contribute to mental illness. Epidemiological studies have identified dozens of environmental exposures that are associated with psychopathology. The effect of environment is likely conditional on genetic factors, resulting in gene-environment interactions. The impact of environmental factors also depends on previous exposures, resulting in environment-environment interactions. Most known genetic and environmental factors are shared across multiple mental disorders. Schizophrenia, bipolar disorder and major depressive disorder, in particular, are closely causally linked. Synthesis of findings from twin studies, molecular genetics and epidemiological research suggests that joint consideration of multiple genetic and environmental factors has much greater explanatory power than separate studies of genetic or environmental causation. Multi-factorial gene-environment interactions are likely to be a generic mechanism involved in the majority of cases of mental illness, which is only partially tapped by existing gene-environment studies. Future research may cut across psychiatric disorders and address poly-causation by considering multiple genetic and environmental measures across the life course with a specific focus on the first two decades of life. Integrative analyses of poly-causation including gene-environment and environment-environment interactions can realize the potential for discovering causal types and mechanisms that are likely to generate new preventive and therapeutic tools.

Keywords: Psychiatric genetics; autism; bipolar disorder; classification of mental disorders; depression; environmental risk factors; gene-environment interactions; life course research; schizophrenia.

Figure 1

The heritability gap. Heritability (the proportion of causation attributable to genetic factors) has been estimated from differences of concordance between identical and fraternal twins (twin estimates) and from hundreds of thousands of single nucleotide polymorphisms across the human genome (molecular estimates). The large difference between the twin and molecular estimates is referred to as the “heritability gap”. Twin estimates are based on same‐sex twin pairs from a recent comprehensive meta‐analysis5. Molecular estimates are from large case‐control genome‐wide association studies8, 9, 10, 11.

Figure 2

Shared environment paradox. Twin studies have consistently allocated little or no role in the causation of mental illness to environmental factors that are shared by members of the same family. The estimates plotted here are from a recent comprehensive meta‐analysis of twin studies5, based on same‐sex twin pairs. Estimates for schizophrenia and depression were actually negative, but since a negative contribution to variance is not possible, we plotted them at 0%.

Figure 3

Framework for discovery. Life‐course developmental perspective and an open search space for unique combinations of genetic and environmental factors (including gene‐gene, gene‐environment, and environment‐environment interactions) are core elements that will enhance the potential for discovery in etiological research. Genetic and environmental data reduction – polygenic sensitivity scores, polygenic risk scores, genetic pathway scores, poly‐environmental scores (E‐scores) – may be a necessary intermediate step towards the discovery of broad poly‐gene‐environmental causal mechanisms, but the reduction process should be reversible to enable fine mapping of specific molecular and behavioral mechanisms.