Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, United Kingdom.
National Institute for Health Research Maudsley Biomedical Research Centre, South London and Maudsley NHS Trust, London, United Kingdom.
JAMA Psychiatry. 2021 Dec 1;78(12):1355-1364. doi: 10.1001/jamapsychiatry.2021.2983.
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.
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 385 793 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.
Population density of residence at different ages and movement during the life span between urban and rural environments.
In this cohort study of 385 793 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.
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.
重要性：城市居住已被强调为精神分裂症和其他一些精神疾病的环境风险因素，在一定程度上也是如此。然而，很少有研究探讨遗传对居住选择的影响。
目的：研究具有一系列精神疾病遗传易感性的个体是否更有可能居住在城市地区。
设计、地点和参与者：本研究为一项横断面回顾性队列研究，纳入了英国基于 1931-2011 年人口普查数据的基因型、地址历史和人口密度地理分布。多基因风险评分（PRS）分析、全基因组关联研究、遗传相关性和 2 样本孟德尔随机化分析应用于 385793 名具有自我报告或全科医生登记地址历史的英国生物银行参与者。该研究于 2018 年 2 月至 2021 年 5 月进行，数据分析于 2018 年 4 月至 2021 年 5 月进行。
主要结果和措施：不同年龄的居住人口密度和在城市和农村环境之间的生活期间的迁移。
结果：在这项涉及 385793 名无关英国生物银行参与者的队列研究中（207963 名参与者为女性[54%]；年龄为 37-73 岁；平均[SD]为 56.7[8]岁），PRS 分析显示与成年期（25 岁至>65 岁）的人口密度呈显著相关，在 45-55 岁年龄组，精神分裂症的相关性最高（88 人/km2；95%CI，65-98 人/km2）、双相情感障碍（44 人/km2；95%CI，34-54 人/km2）、神经性厌食症（36 人/km2；95%CI，22-50 人/km2）和自闭症谱系障碍（35 人/km2；95%CI，25-45 人/km2）。精神分裂症 PRS 也与较高的出生地人口密度显著相关（37 人/km2；95%CI，19-55 人/km2；P=8×10-5）。注意缺陷多动障碍 PRS 与成年期人口密度降低显著相关（-31 人/km2；95%CI，35-45 岁时为-42 至-20 人/km2）。具有较高精神分裂症、双相情感障碍、神经性厌食症和自闭症谱系障碍 PRS 以及较低注意缺陷多动障碍 PRS 的个体更倾向于从农村环境迁移到城市（精神分裂症的 Tukey 两两比较 PRS 差异：0.05；95%CI，0.03 至 0.60；双相情感障碍：0.10；95%CI，0.08 至 0.13；神经性厌食症：0.05；95%CI，0.03 至 0.07；自闭症谱系障碍：0.04；95%CI 0.03 至 0.06；注意缺陷多动障碍：-0.09；95%CI，-0.12 至 -0.06）。遗传相关性结果与 PRS 分析基本一致，而孟德尔随机化为精神分裂症和双相情感障碍与居住在人口密度高的地区之间的关联提供了支持。
结论和相关性：这些发现表明，多种精神疾病的遗传高风险可能会影响个体的居住选择。这一结果支持了个体环境遗传选择的假设，该假设与传统的基因-环境二分法相交。
