Spatial fine-mapping for gene-by-environment effects identifies risk hot spots for schizophrenia

Abstract

Spatial mapping is a promising strategy to investigate the mechanisms underlying the incidence of psychosis. We analyzed a case-cohort study (n = 24,028), drawn from the 1.47 million Danish persons born between 1981 and 2005, using a novel framework for decomposing the geospatial risk for schizophrenia based on locale of upbringing and polygenic scores. Upbringing in a high environmental risk locale increases the risk for schizophrenia by 122%. Individuals living in a high gene-by-environmental risk locale have a 78% increased risk compared to those who have the same genetic liability but live in a low-risk locale. Effects of specific locales vary substantially within the most densely populated city of Denmark, with hazard ratios ranging from 0.26 to 9.26 for environment and from 0.20 to 5.95 for gene-by-environment. These findings indicate the critical synergism of gene and environment on the etiology of schizophrenia and demonstrate the potential of incorporating geolocation in genetic studies.

Familial and socioeconomic contributions to premorbid functioning in psychosis: Impact on age at onset and treatment response

“…This observation is in agreement with previous studies indicating that familial loading for mental illness and environmental risk factors for psychosis (i.e., urbanicity, social disadvantage, childhood adversity, cannabis use) may act in synergy to increase disease liability [46,51,[67][68][69][70]. Moreover, population-wide analyses underscore the contribution of upbringing locale, likely related with European Psychiatry socioeconomic profile, to psychosis manifestation and the modifiable role of genetic liability in the incidence of psychotic disorders [71]. We observed that individuals with presumably higher genetic risk for psychosis and growing up in families of lower SES could be more vulnerable to social maladjustment in childhood.…”

Factors that contribute to urban–rural gradients in risk of schizophrenia: Comparing Danish and Western Australian registers

“…In particular, studies based on Danish registers have found that urbanicity of the place of birth and longer duration of being raised in urban settings both contributed to a higher risk of schizophrenia (Pedersen, 2015;Pedersen and Mortensen, 2006b;Vassos et al, 2012Vassos et al, , 2016. More recent population-based studies have found that individuals with higher polygenic risk scores related to risk of schizophrenia (but without the clinical diagnosis) are more likely to live in more densely populated settings (Engemann et al, 2020;Fan et al, 2018;Paksarian et al, 2018). However, this effect is relatively small, and it is not sufficient to explain the association between the urbanicity and risk of schizophrenia (Plana-Ripoll et al, 2018).…”

Association of Childhood Exposure to Nitrogen Dioxide and Polygenic Risk Score for Schizophrenia With the Risk of Developing Schizophrenia

“…Nitrogen dioxide concentrations vary geographically, with the highest levels in cities, major transport corridors, and coastal land areas near international shipping routes. 21 Individuals with higher genetic loading for schizophrenia tend to live in more densely urbanized areas, 7,22,23 possibly owing to intergenerational and intragenerational migration. Although this gene-environment correlation cannot explain the urban residence and later risk of schizophrenia, 23,24 it highlights the utility of the polygenic risk score in helping to identify novel risk factors.…”