Journal Article

DZNE-2020-07409

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Common schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection.

Pardiñas, A. F. ; Holmans, P. ; Pocklington, A. J. ; Escott-Price, V. ; Ripke, S. ; Carrera, N. ; Legge, S. E. ; Bishop, S. ; Cameron, D. ; Hamshere, M. L. ; Han, J. ; Hubbard, L. ; Lynham, A. ; Mantripragada, K. ; Rees, E. ; MacCabe, J. H. ; McCarroll, S. A. ; Baune, B. T. ; Breen, G. ; Byrne, E. M. ; Dannlowski, U. ; Eley, T. C. ; Hayward, C. ; Martin, N. G. ; McIntosh, A. M. ; Plomin, R. ; Porteous, D. J. ; Wray, N. R. ; Caballero, A. ; Geschwind, D. H. ; Huckins, L. M. ; Ruderfer, D. M. ; Santiago, E. ; Sklar, P. ; Stahl, E. A. ; Won, H. ; Agerbo, E. ; Als, T. D. ; Andreassen, O. A. ; Bækvad-Hansen, M. ; Mortensen, P. B. ; Pedersen, C. B. ; Børglum, A. D. ; Bybjerg-Grauholm, J. ; Djurovic, S. ; Durmishi, N. ; Pedersen, M. G. ; Golimbet, V. ; Grove, J. ; Hougaard, D. M. ; Mattheisen, M. ; Molden, E. ; Mors, O. ; Nordentoft, M. ; Pejovic-Milovancevic, M. ; Sigurdsson, E. ; Silagadze, T. ; Hansen, C. S. ; Stefansson, K. ; Stefansson, H. ; Steinberg, S. ; Tosato, S. ; Werge, T. ; Consortium, G. ; Consortium, C. ; Collier, D. A. ; Rujescu, D. ; Kirov, G. ; Owen, M. J. ; O'Donovan, M. C. ; Walters, J. T. R. ; Harold, D. ; Sims, R. ; Gerrish, A. ; Chapman, J. ; Escott-Price, V. ; Abraham, R. ; Hollingworth, P. ; Pahwa, J. ; Denning, N. ; Thomas, C. ; Taylor, S. ; Powell, J. ; Proitsi, P. ; Lupton, M. ; Lovestone, S. ; Passmore, P. ; Craig, D. ; McGuinness, B. ; Johnston, J. ; Todd, S. ; Maier, W. ; Jessen, F. ; Heun, R. ; Schurmann, B. ; Ramirez, A. ; Becker, T.DZNE* ; Herold, C.DZNE* ; Lacour, A.DZNE* ; Drichel, D.DZNE* ; Nothen, M. ; Goate, A. ; Cruchaga, C. ; Nowotny, P. ; Morris, J. C. ; Mayo, K. ; Holmans, P. ; O'Donovan, M. ; Owen, M. ; Williams, J. ; Achilla, E. ; Agerbo, E. ; Barr, C. L. ; Böttger, T. W. ; Breen, G. ; Cohen, D. ; Collier, D. A. ; Curran, S. ; Dempster, E. ; Dima, D. ; Sabes-Figuera, R. ; Flanagan, R. J. ; Frangou, S. ; Frank, J. ; Gasse, C. ; Gaughran, F. ; Giegling, I. ; Grove, J. ; Hannon, E. ; Hartmann, A. M. ; Heißerer, B. ; Helthuis, M. ; Horsdal, H. T. ; Ingimarsson, O. ; Jollie, K. ; Kennedy, J. L. ; Köhler, O. ; Konte, B. ; Lang, M. ; Legge, S. E. ; Lewis, C. ; MacCabe, J. ; Malhotra, A. K. ; McCrone, P. ; Meier, S. M. ; Mill, J. ; Mors, O. ; Mortensen, P. B. ; Nöthen, M. M. ; O'Donovan, M. C. ; Owen, M. J. (Corresponding author) ; Pardiñas, A. F. ; Pedersen, C. B. ; Rietschel, M. ; Rujescu, D. ; Schwalber, A. ; Sigurdsson, E. ; Sørensen, H. J. ; Spencer, B. ; Stefansson, H. ; Støvring, H. ; Strohmaier, J. ; Sullivan, P. ; Vassos, E. ; Verbelen, M. ; Walters, J. T. R. ; Werge, T.

2018
Macmillan Publishers Limited, part of Springer Nature London

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Please use a persistent id in citations: doi:10.1038/s41588-018-0059-2

Abstract: Schizophrenia is a debilitating psychiatric condition often associated with poor quality of life and decreased life expectancy. Lack of progress in improving treatment outcomes has been attributed to limited knowledge of the underlying biology, although large-scale genomic studies have begun to provide insights. We report a new genome-wide association study of schizophrenia (11,260 cases and 24,542 controls), and through meta-analysis with existing data we identify 50 novel associated loci and 145 loci in total. Through integrating genomic fine-mapping with brain expression and chromosome conformation data, we identify candidate causal genes within 33 loci. We also show for the first time that the common variant association signal is highly enriched among genes that are under strong selective pressures. These findings provide new insights into the biology and genetic architecture of schizophrenia, highlight the importance of mutation-intolerant genes and suggest a mechanism by which common risk variants persist in the population.

Keyword(s): Alleles (MeSH) ; Case-Control Studies (MeSH) ; Gene Frequency (MeSH) ; Genes, Lethal: genetics (MeSH) ; Genetic Loci (MeSH) ; Genetic Predisposition to Disease (MeSH) ; Genome-Wide Association Study (MeSH) ; Humans (MeSH) ; Inheritance Patterns (MeSH) ; Polymorphism, Single Nucleotide (MeSH) ; Schizophrenia: genetics (MeSH) ; Selection, Genetic (MeSH)

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Contributing Institute(s):

1. Genomic Mathematics in Neuroepidemiology (GenomMathematik)
2. Implementation Science & Person-Centered Dementia Care (AG Roes)

Research Program(s):

1. 345 - Population Studies and Genetics (POF3-345) (POF3-345)
2. 344 - Clinical and Health Care Research (POF3-344) (POF3-344)

Appears in the scientific report 2018

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Database coverage:
; BIOSIS Previews ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Ebsco Academic Search ; IF >= 40 ; JCR ; Nationallizenz ; SCOPUS ; Web of Science Core Collection

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Linked articles:

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Journal Article (Erratum/Correction) Pardiñas, A. F. ; Holmans, P. ; Pocklington, A. J. ; et al
Publisher Correction: Common schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection.
Nature genetics 51(7), 1193-1193 (2019) [10.1038/s41588-019-0450-7]2019 BibTeX | EndNote: XML, Text | RIS

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