Spatial gene-by-environment mapping for schizophrenia reveals locale of upbringing effects beyond urban-rural differences

Fan, C. C.; McGrath, J. J.; Appadurai, V.; Buil, A.; Gandal, M. J.; Schork, A. J.; Mortensen, P. B.; Agerbo, E.; Geschwind, S. A.; Geschwind, D.; Werge, T.; Thompson, W. K.; Pedersen, C. B.

doi:10.1101/315820

bioRxiv · 10.1101/315820

Spatial gene-by-environment mapping for schizophrenia reveals locale of upbringing effects beyond urban-rural differences

Fan, C. C.·McGrath, J. J.·Appadurai, V.·Buil, A.·Gandal, M. J.·Schork, A. J.·Mortensen, P. B.·Agerbo, E.·Geschwind, S. A.·Geschwind, D.·Werge, T.·Thompson, W. K.·Pedersen, C. B.

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Abstract

Identification of mechanisms underlying the incidence of psychiatric disorders has been hampered by the difficulty in discovering highly-predictive environmental risk factors. For example, prior efforts have failed to establish environmental effects predicting geospatial clustering of schizophrenia incidence beyond urban-rural differences. Here, we employ a novel statistical framework for decomposing the geospatial risk for schizophrenia based on locale of upbringing (place of residence, ages 0-7 years) and its synergistic effects with genetic liabilities (polygenic risk for schizophrenia). We use this statistical framework to analyze unprecedented geolocation and genotyping data in a case-cohort study of n=24,028 subjects, drawn from the 1.47 million Danish persons born between 1981 and 2005. Using this framework we estimate the effects of upbringing locale (E) and gene-by-locale interactions (GxE). After controlling for potential confounding variables, upbringing at high-risk locales increases the risk for schizophrenia on average by 122%, while GxE modulates genetic risk for schizophrenia on average by 78%. Within the boundaries of Copenhagen (the largest and most densely populated city of Denmark) specific locales vary substantially in their E and GxE effects, with hazard ratios ranging from 0.26 to 9.26 for E and from 0.20 to 5.95 for GxE. This study provides insight into the degree of geospatial clustering of schizophrenia risk, and our novel analytic procedure provides a framework for decomposing variation in geospatial risk into G, E, and GxE components.

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Fan, C. C., McGrath, J. J., Appadurai, V., Buil, A., Gandal, M. J., Schork, A. J., Mortensen, P. B., Agerbo, E., Geschwind, S. A., Geschwind, D., Werge, T., Thompson, W. K., Pedersen, C. B.. 2018-05-11. Spatial gene-by-environment mapping for schizophrenia reveals locale of upbringing effects beyond urban-rural differences. https://doi.org/10.1101/315820

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