Association between Genetic Risk for Psychiatric Disorders and the Probability of Living in Urban Settings

Importance: Urban residence has been highlighted as an environmental risk factor for schizophrenia and, to a lesser extent, several other psychiatric disorders. However, few studies have explored genetic effects on the choice of residence. Objective: To investigate whether individuals with genetic predisposition to a range of psychiatric disorders have an increased likelihood to live in urban areas. Design, Setting, and Participants: A cross-sectional retrospective cohort study including genotypes, address history, and geographic distribution of population density in the UK based on census data from 1931-2011 was conducted. Polygenic risk score (PRS) analyses, genome-wide association studies, genetic correlation, and 2-sample mendelian randomization analyses were applied to 385793 UK Biobank participants with self-reported or general practitioner registration-based address history. The study was conducted from February 2018 to May 2021, and data analysis was performed from April 2018 to May 2021. Main Outcomes and Measures: Population density of residence at different ages and movement during the life span between urban and rural environments. Results: In this cohort study of 385793 unrelated UK Biobank participants (207 963 [54%] were women; age, 37-73 years; mean [SD], 56.7 [8] years), PRS analyses showed significant associations with higher population density across adult life (age 25 to >65 years) reaching highest significance at the 45- to 55-year age group for schizophrenia (88 people/km2; 95% CI, 65-98 people/km2), bipolar disorder (44 people/km2; 95% CI, 34-54 people/km2), anorexia nervosa (36 people/km2; 95% CI, 22-50 people/km2), and autism spectrum disorder (35 people/km2; 95% CI, 25-45 people/km2). The schizophrenia PRS was also significantly associated with higher birthplace population density (37 people/km2; 95% CI, 19-55 people/km2; P = 8 × 10-5). Attention-deficit/hyperactivity disorder PRS was significantly associated with reduced population density in adult life (-31 people/km2; 95% CI, -42 to -20 people/km2 at age 35-45 years). Individuals with higher PRS for schizophrenia, bipolar disorder, anorexia nervosa, and autism spectrum disorder and lower PRS for attention-deficit/hyperactivity disorder preferentially moved from rural environments to cities (difference in PRS with Tukey pairwise comparisons for schizophrenia: 0.05; 95% CI, 0.03 to 0.60; bipolar disorder: 0.10; 95% CI, 0.08 to 0.13; anorexia nervosa: 0.05; 95% CI, 0.03 to 0.07; autism spectrum disorder: 0.04; 95% CI 0.03 to 0.06; and attention-deficit/hyperactivity disorder: -0.09, 95% CI, -0.12 to -0.06). Genetic correlation results were largely consistent with PRS analyses, whereas mendelian randomization provided support for associations between schizophrenia and bipolar disorder and living in high population-density areas. Conclusions and Relevance: These findings suggest that a high genetic risk for a variety of psychiatric disorders may affect an individual's choice of residence. This result supports the hypothesis of genetic selection of an individual's environment, which intersects the traditional gene-environment dichotomy.