Environmental Risk Factors for Schizophrenia and Bipolar Disorder and Their Relationship to Genetic Risk: Current Knowledge and Future Directions

Abstract

Schizophrenia (SZ) and bipolar disorder (BD) are severe psychiatric disorders which result from complex interplay between genetic and environmental factors. It is well-established that they are highly heritable disorders, and considerable progress has been made identifying their shared and distinct genetic risk factors. However, the 15-40% of risk that is derived from environmental sources is less definitively known. Environmental factors that have been repeatedly investigated and often associated with SZ include: obstetric complications, infections, winter or spring birth, migration, urban living, childhood adversity, and cannabis use. There is evidence that childhood adversity and some types of infections are also associated with BD. Evidence for other risk factors in BD is weaker due to fewer studies and often smaller sample sizes. Relatively few environmental exposures have ever been examined for SZ or BD, and additional ones likely remain to be discovered. A complete picture of how genetic and environmental risk factors confer risk for these disorders requires an understanding of how they interact. Early gene-by-environment interaction studies for both SZ and BD often involved candidate genes and were underpowered. Larger samples with genome-wide data and polygenic risk scores now offer enhanced prospects to reveal genetic interactions with environmental exposures that contribute to risk for these disorders. Overall, although some environmental risk factors have been identified for SZ, few have been for BD, and the extent to which these account for the total risk from environmental sources remains unknown. For both disorders, interactions between genetic and environmental risk factors are also not well understood and merit further investigation. Questions remain regarding the mechanisms by which risk factors exert their effects, and the ways in which environmental factors differ by sex. Concurrent investigations of environmental and genetic risk factors in SZ and BD are needed as we work toward a more comprehensive understanding of the ways in which these disorders arise.

Keywords: adverse childhood experiences; bipolar disorder; gene-environment interaction; marijuana use; migration; pregnancy complications; risk factors; schizophrenia.

FIGURE 1

Summary of the types of G×E interactions. (A) Genetic effect with no exposure effects, meaning the variation in disease probability is stable across a range of environments; (B) Environmental effect with no genetic effects, meaning the variation in disease probability is stable across different genotypes; (C) Additive effects occur when disease probability results from the addition of the genetic and environmental factors. The exposure results in the same degree of increase in disease probability; (D) Interaction effects when genetic risk determines sensitivity to environmental factors. When there is no exposure, disease probability is low regardless of genetic risk, but in the presence of an exposure, those with high genetic risk have markedly increased probability of disease.

FIGURE 2

Hypothesized relationships between risk factors and genetics in the development of schizophrenia and bipolar disorder. Genetic factors present from birth may interact with environmental factors across the life course to increase the risk of SZ and BD. There may also be complex interrelationships between the environmental risk factors. Dashed lines indicate potential relationships between the identified environmental risk factors. OCs, obstetric complications; ACEs, adverse childhood experiences; SNPs, single nucleotide polymorphisms; CNVs, copy number variants.