Author, as appears in the article.: Muntané G; Farré X; Bosch E; Martorell L; Navarro A; Vilella E

Department: Medicina i Cirurgia

URV's Author/s: Martorell Bonet, Lourdes / Vilella Cuadrada, Elisabet

Keywords: Worldwide Positive selection Mortality Metaanalysis Identification Heritability Genome-wide association Expectancy Common variants Adaptive evolution

Abstract: © 2020, Springer-Verlag GmbH Germany, part of Springer Nature. 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.

Thematic Areas: Saúde coletiva Odontología Medicina ii Medicina i Interdisciplinar Genetics (clinical) Genetics & heredity Genetics General medicine Farmacia Engenharias iii Enfermagem Ciências biológicas iii Ciências biológicas ii Ciências biológicas i Biotecnología Biodiversidade

licence for use: https://creativecommons.org/licenses/by/3.0/es/

ISSN: 03406717

Author's mail: lourdes.martorell@urv.cat elisabet.vilella@urv.cat

Author identifier: 0000-0003-4999-2197 0000-0002-1887-5919

Record's date: 2023-02-23

Papper version: info:eu-repo/semantics/acceptedVersion

Link to the original source: https://link.springer.com/article/10.1007%2Fs00439-020-02213-8

Licence document URL: http://repositori.urv.cat/ca/proteccio-de-dades/

Papper original source: Human Genetics. 140 (3): 441-455

APA: Muntané G; Farré X; Bosch E; Martorell L; Navarro A; Vilella E (2021). The shared genetic architecture of schizophrenia, bipolar disorder and lifespan. Human Genetics, 140(3), 441-455. DOI: 10.1007/s00439-020-02213-8

Article's DOI: 10.1007/s00439-020-02213-8

Entity: Universitat Rovira i Virgili

Journal publication year: 2021

Publication Type: Journal Publications