Common schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection

Pardiñas, Antonio F, Holmans, Peter, Pocklington, Andrew J, Escott-Price, Valentina, Ripke, Stephan, Carrera, Noa, Legge, Sophie E, Bishop, Sophie, Cameron, Darren, Hamshere, Marian L, Han, Jun, Hubbard, Leon, Lynham, Amy, Mantripragada, Kiran, Rees, Elliott, MacCabe, James H, McCarroll, Steven A, Baune, Bernhard T, Breen, Gerome, Byrne, Enda M., Dannlowski, Udo, Eley, Thalia C, Hayward, Caroline, Martin, Nicholas G., McIntosh, Andrew M, Plomin, Robert, Porteous, David J, Wray, Naomi R, Caballero, Armando, Geschwind, Daniel H, Huckins, Laura M, Ruderfer, Douglas M, Santiago, Enrique, Sklar, Pamela, Stahl, Eli A, Won, Hyejung, Agerbo, Esben, Als, Thomas D, Andreassen, Ole A, Bækvad-Hansen, Marie, Mortensen, Preben Bo, Pedersen, Carsten Bøcker, Børglum, Anders D, Bybjerg-Grauholm, Jonas, Djurovic, Srdjan, Durmishi, Naser, Pedersen, Marianne Giørtz, Golimbet, Vera, Grove, Jakob, Hougaard, David M, Mattheisen, Manuel, Molden, Espen, Mors, Ole, Nordentoft, Merete, Pejovic-Milovancevic, Milica, Sigurdsson, Engilbert, Silagadze, Teimuraz, Hansen, Christine Søholm, Stefansson, Kari, Stefansson, Hreinn, Steinberg, Stacy, Tosato, Sarah, Werge, Thomas, GERAD1 Consortium:, CRESTAR Consortium:, Collier, David A, Rujescu, Dan, Kirov, George, Owen, Michael J, O'Donovan, Michael C, Walters, James T R, GERAD1 Consortium, CRESTAR Consortium, GERAD1 Consortium and CRESTAR Consortium (2018) Common schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection. Nature Genetics, 50 3: 381-389. doi:10.1038/s41588-018-0059-2


Author Pardiñas, Antonio F
Holmans, Peter
Pocklington, Andrew J
Escott-Price, Valentina
Ripke, Stephan
Carrera, Noa
Legge, Sophie E
Bishop, Sophie
Cameron, Darren
Hamshere, Marian L
Han, Jun
Hubbard, Leon
Lynham, Amy
Mantripragada, Kiran
Rees, Elliott
MacCabe, James H
McCarroll, Steven A
Baune, Bernhard T
Breen, Gerome
Byrne, Enda M.
Dannlowski, Udo
Eley, Thalia C
Hayward, Caroline
Martin, Nicholas G.
McIntosh, Andrew M
Plomin, Robert
Porteous, David J
Wray, Naomi R
Caballero, Armando
Geschwind, Daniel H
Huckins, Laura M
Ruderfer, Douglas M
Santiago, Enrique
Sklar, Pamela
Stahl, Eli A
Won, Hyejung
Agerbo, Esben
Als, Thomas D
Andreassen, Ole A
Bækvad-Hansen, Marie
Mortensen, Preben Bo
Pedersen, Carsten Bøcker
Børglum, Anders D
Bybjerg-Grauholm, Jonas
Djurovic, Srdjan
Durmishi, Naser
Pedersen, Marianne Giørtz
Golimbet, Vera
Grove, Jakob
Hougaard, David M
Mattheisen, Manuel
Molden, Espen
Mors, Ole
Nordentoft, Merete
Pejovic-Milovancevic, Milica
Sigurdsson, Engilbert
Silagadze, Teimuraz
Hansen, Christine Søholm
Stefansson, Kari
Stefansson, Hreinn
Steinberg, Stacy
Tosato, Sarah
Werge, Thomas
GERAD1 Consortium:
CRESTAR Consortium:
Collier, David A
Rujescu, Dan
Kirov, George
Owen, Michael J
O'Donovan, Michael C
Walters, James T R
GERAD1 Consortium
CRESTAR Consortium
GERAD1 Consortium
CRESTAR Consortium
Title Common schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection
Journal name Nature Genetics   Check publisher's open access policy
ISSN 1546-1718
1061-4036
Publication date 2018-02-26
Year available 2018
Sub-type Article (original research)
DOI 10.1038/s41588-018-0059-2
Open Access Status Not yet assessed
Volume 50
Issue 3
Start page 381
End page 389
Total pages 9
Place of publication New York, NY., United States
Publisher Nature Publishing Group
Language eng
Subject 1311 Genetics
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 Genome-Wide Association
Ld Score Regression
De-Novo Mutations
Positive Selection
Natural-Selection
Human-Populations
Human-Disease
Developmental Disorders
Functional Annotation
Regulatory Elements
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID R01 MH110927
Institutional Status UQ

 
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Created: Wed, 07 Mar 2018, 11:08:31 EST