Environmental profiles of urban living relate to regional brain volumes and symptom groups of mental illness through distinct genetic pathways

The majority of people worldwide live in cities, yet how urban living affects brain and mental illness is scarcely understood. Urban lives are exposed to a a wide array of environmental factors that may combine and interact to influence mental health. While individual factors of the urban environment have been investigated in isolation, to date no attempt has been made to model how the complex, real life exposure to living in the city relates to brain and mental illness, and how it is moderated by genetic factors. Using data of over 150,000 participants of the UK Biobank, we carried out sparse canonical correlation analyses (sCCA) to investigate the relation of urban living environment with symptoms of mental illness. We found three mental health symptom groups, consisting of affective, anxiety and emotional instability symptoms, respectively. These groups were correlated with distinct profiles of urban environments defined by risk factors related to social deprivation, air pollution and urban density, and protective factors involving green spaces and generous land use. The relations between environment and symptoms of mental illness were mediated by the volume of brain regions involved in reward processing, emotional processing and executive control, and moderated by genes regulating stress response, neurotransmission, neural development and differentiation, as well as epigenetic modifications. Together, these findings indicate distinct biological pathways by which different environmental profiles of urban living may influence mental illness. Our results also provide a quantitative measure of the contribution of each environmental factor to brain volume and symptom group. They will aid in targeting and prioritizing important decisions for planning and public health interventions. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was funded by the organisations mentioned in the acknowledgement. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: U.K. biobank I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors