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The shared genetic architecture of schizophrenia, bipolar disorder and lifespan

Abstract

Psychiatric disorders such as Schizophrenia (SCZ) and Bipolar Disorder (BD) represent an evolutionary paradox, as they exhibit strong negative effects on fitness, such as decreased fecundity and early mortality, yet they persist at a worldwide prevalence of approximately 1%. Molecular mechanisms affecting lifespan, which may be widely common among complex diseases with fitness effects, can be studied by the integrated analysis of data from genome-wide association studies (GWAS) of human longevity together with any disease of interest. Here, we report the first of such studies, focusing on the genetic overlap—pleiotropy—between two psychiatric disorders with shortened lifespan, SCZ and BD, and human parental lifespan (PLS) as a surrogate of life expectancy. Our results are twofold: first, we demonstrate extensive polygenic overlap between SCZ and PLS and to a lesser extent between BD and PLS. Second, we identified novel loci shared between PLS and SCZ (n = 39), and BD (n = 8). Whereas most of the identified SCZ (66%) and BD (62%) pleiotropic risk alleles were associated with reduced lifespan, we also detected some antagonistic protective alleles associated to shorter lifespans. In fact, top-associated SNPs with SCZ seems to explain longevity variance explained (LVE) better than many other life-threatening diseases, including Type 2 diabetes and most cancers, probably due to a high overlap with smoking-related pathways. Overall, our study provides evidence of a genetic burden driven through premature mortality among people with SCZ, which can have profound implications for understanding, and potentially treating, the mortality gap associated with this psychiatric disorder.

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Acknowledgements

This work was supported by Ministerio de Ciencia e Innovación, Spain, the Agencia Estatal de Investigación (AEI) and the Fondo Europeo de Desarrollo Regional (FEDER) with project grants BFU2016-77961-P and PGC2018-101927-B-I00 to EB and AN, respectively, by the Spanish National Institute of Bioinformatics (PT17/0009/0020 to AN), the Direcció General de Recerca, the Generalitat de Catalunya (2017SGR444 to EV, 2017SGR702 to EB and 2017SGR880 to AN) and the “Unidad de Excelencia María de Maeztu”, funded by the AEI (CEX2018-000792-M).

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Correspondence to Gerard Muntané.

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Muntané, G., Farré, X., Bosch, E. et al. The shared genetic architecture of schizophrenia, bipolar disorder and lifespan. Hum Genet 140, 441–455 (2021). https://doi.org/10.1007/s00439-020-02213-8

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  • DOI: https://doi.org/10.1007/s00439-020-02213-8