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

GERAD1 Consortium:; Antonio F.  Pardiñas; Peter A Holmans; Andrew J Pocklington; Valentina Escott-Price; Stephan Ripke; Noa Carrera; Sophie E. Legge; Sophie Bishop; Darren Cameron; Marian L Hamshere; Jun Han; Leon Hubbard; Amy Lynham; Kiran Mantripragada; Elliott Rees; James H MacCabe; Steven A. McCarroll; Bernhard T. Baune; Gerome Breen; Enda M Byrne; Udo Dannlowski; Thalia C Eley; Caroline Hayward; Nicholas G Martin; Andrew M McIntosh; Robert Plomin; David J Porteous; Naomi R Wray; Armando Caballero; Daniel H Geschwind; Laura M Huckins; Douglas M Ruderfer; Enrique Santiago; Pamela Sklar; Eli A Stahl; Hyejung Won; Esben Agerbo; Thomas D. Als; Ole A Andreassen; Marie Bækvad-Hansen; Preben Bo Mortensen; Carsten Bøcker Pedersen; Anders D Børglum; Jonas Bybjerg-Grauholm; Srdjan Djurovic; Naser Durmishi; Marianne Giørtz Pedersen; Vera Golimbet; Jakob Grove; David M Hougaard

doi:10.1038/s41588-018-0059-2

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

GERAD1 Consortium:, Antonio F. Pardiñas, Peter A Holmans, Andrew J Pocklington, Valentina Escott-Price, Stephan Ripke, Noa Carrera, Sophie E. Legge, Sophie Bishop, Darren Cameron, Marian L Hamshere, Jun Han, Leon Hubbard, Amy Lynham, Kiran Mantripragada, Elliott Rees, James H MacCabe, Steven A. McCarroll, Bernhard T. Baune, Gerome BreenEnda M Byrne, Udo Dannlowski, Thalia C Eley, Caroline Hayward, Nicholas G Martin, Andrew M McIntosh, Robert Plomin, David J Porteous, Naomi R Wray, Armando Caballero, Daniel H Geschwind, Laura M Huckins, Douglas M Ruderfer, Enrique Santiago, Pamela Sklar, Eli A Stahl, Hyejung Won, Esben Agerbo, Thomas D. Als, Ole A Andreassen, Marie Bækvad-Hansen, Preben Bo Mortensen, Carsten Bøcker Pedersen, Anders D Børglum, Jonas Bybjerg-Grauholm, Srdjan Djurovic, Naser Durmishi, Marianne Giørtz Pedersen, Vera Golimbet, Jakob Grove, David M Hougaard

Research output: Contribution to journal › Article › peer-review

Abstract / Description of output

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.

Original language	English
Journal	Nature Genetics
Early online date	26 Feb 2018
DOIs	https://doi.org/10.1038/s41588-018-0059-2
Publication status	E-pub ahead of print - 26 Feb 2018

Keywords / Materials (for Non-textual outputs)

Journal Article

Access to Document

10.1038/s41588-018-0059-2

2018-01-07 Nat Gen Accepted ManuscriptAccepted author manuscript, 266 KB

Stratifying Resilience and Depression Longitudinally
McIntosh, A., Deary, I., Evans, K., Haley, C. & Porteous, D.
UK-based charities
1/01/15 → 30/06/21
Project: Research
Generation Scotland
Porteous, D.
UK central government bodies/local authorities, health and hospital authorities
1/04/11 → 31/03/14
Project: Research
Genetic Health 21st Century
Porteous, D., Laurie, G. & Tait, J.
UK central government bodies/local authorities, health and hospital authorities
1/10/03 → 31/08/07
Project: Research

Cite this

GERAD1 Consortium:, Pardiñas, A. F., Holmans, P. A., 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., ... Hougaard, D. M. (2018). Common schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection. Nature Genetics. Advance online publication. https://doi.org/10.1038/s41588-018-0059-2

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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.",

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GERAD1 Consortium:, Pardiñas, AF, Holmans, PA, Pocklington, AJ, Escott-Price, V, Ripke, S, Carrera, N, Legge, SE, Bishop, S, Cameron, D, Hamshere, ML, Han, J, Hubbard, L, Lynham, A, Mantripragada, K, Rees, E, MacCabe, JH, McCarroll, SA, Baune, BT, Breen, G, Byrne, EM, Dannlowski, U, Eley, TC, Hayward, C, Martin, NG, McIntosh, AM, Plomin, R, Porteous, DJ, Wray, NR, Caballero, A, Geschwind, DH, Huckins, LM, Ruderfer, DM, Santiago, E, Sklar, P, Stahl, EA, Won, H, Agerbo, E, Als, TD, Andreassen, OA, Bækvad-Hansen, M, Mortensen, PB, Pedersen, CB, Børglum, AD, Bybjerg-Grauholm, J, Djurovic, S, Durmishi, N, Pedersen, MG, Golimbet, V, Grove, J & Hougaard, DM 2018, 'Common schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection', Nature Genetics. https://doi.org/10.1038/s41588-018-0059-2

TY - JOUR

T1 - Common schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection

AU - GERAD1 Consortium:

AU - Pardiñas, Antonio F.

AU - Holmans, Peter A

AU - Pocklington, Andrew J

AU - Escott-Price, Valentina

AU - Ripke, Stephan

AU - Carrera, Noa

AU - Legge, Sophie E.

AU - Bishop, Sophie

AU - Cameron, Darren

AU - Hamshere, Marian L

AU - Han, Jun

AU - Hubbard, Leon

AU - Lynham, Amy

AU - Mantripragada, Kiran

AU - Rees, Elliott

AU - MacCabe, James H

AU - McCarroll, Steven A.

AU - Baune, Bernhard T.

AU - Breen, Gerome

AU - Byrne, Enda M

AU - Dannlowski, Udo

AU - Eley, Thalia C

AU - Hayward, Caroline

AU - Martin, Nicholas G

AU - McIntosh, Andrew M

AU - Plomin, Robert

AU - Porteous, David J

AU - Wray, Naomi R

AU - Caballero, Armando

AU - Geschwind, Daniel H

AU - Huckins, Laura M

AU - Ruderfer, Douglas M

AU - Santiago, Enrique

AU - Sklar, Pamela

AU - Stahl, Eli A

AU - Won, Hyejung

AU - Agerbo, Esben

AU - Als, Thomas D.

AU - Andreassen, Ole A

AU - Bækvad-Hansen, Marie

AU - Mortensen, Preben Bo

AU - Pedersen, Carsten Bøcker

AU - Børglum, Anders D

AU - Bybjerg-Grauholm, Jonas

AU - Djurovic, Srdjan

AU - Durmishi, Naser

AU - Pedersen, Marianne Giørtz

AU - Golimbet, Vera

AU - Grove, Jakob

AU - Hougaard, David M

PY - 2018/2/26

Y1 - 2018/2/26

N2 - 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.

AB - 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.

KW - Journal Article

U2 - 10.1038/s41588-018-0059-2

DO - 10.1038/s41588-018-0059-2

M3 - Article

C2 - 29483656

SN - 1061-4036

JO - Nature Genetics

JF - Nature Genetics

ER -

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

Abstract / Description of output

Keywords / Materials (for Non-textual outputs)

Access to Document

Fingerprint

Projects

Stratifying Resilience and Depression Longitudinally

Generation Scotland

Genetic Health 21st Century

Cite this