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

Antonio F Pardiñas; Peter 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; Manuel Mattheisen; Espen Molden; Ole Mors; Merete Nordentoft; Milica Pejovic-Milovancevic; Engilbert Sigurdsson; Teimuraz Silagadze; Christine Søholm Hansen; Kari Stefansson; Hreinn Stefansson; Stacy Steinberg; Sarah Tosato; Thomas Werge; GERAD1 Consortium:; CRESTAR Consortium; David A Collier; Dan Rujescu; George Kirov; Michael J Owen; Michael C O'Donovan; James T. R. Walters

doi:10.1038/s41588-018-0059-2

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

Antonio F Pardiñas, Peter 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 ByrneUdo 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, Manuel Mattheisen, Espen Molden, Ole Mors, Merete Nordentoft, Milica Pejovic-Milovancevic, Engilbert Sigurdsson, Teimuraz Silagadze, Christine Søholm Hansen, Kari Stefansson, Hreinn Stefansson, Stacy Steinberg, Sarah Tosato, Thomas Werge, GERAD1 Consortium:, CRESTAR Consortium, David A Collier, Dan Rujescu, George Kirov, Michael J Owen, Michael C O'Donovan, James T. R. Walters

Institut for Klinisk Medicin

432 Citationer (Scopus)

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.

Originalsprog	Engelsk
Tidsskrift	Nature Genetics
Vol/bind	50
Sider (fra-til)	381-389
ISSN	1061-4036
DOI	https://doi.org/10.1038/s41588-018-0059-2
Status	Udgivet - 1 mar. 2018

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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., ... Walters, J. T. R. (2018). Common schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection. Nature Genetics, 50, 381-389. https://doi.org/10.1038/s41588-018-0059-2

Pardiñas, AF, Holmans, P, 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, Mattheisen, M, Molden, E, Mors, O, Nordentoft, M, Pejovic-Milovancevic, M, Sigurdsson, E, Silagadze, T, Hansen, CS, Stefansson, K, Stefansson, H, Steinberg, S, Tosato, S, Werge, T, GERAD1 Consortium:, CRESTAR Consortium, Collier, DA, Rujescu, D, Kirov, G, Owen, MJ, O'Donovan, MC & Walters, JTR 2018, 'Common schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection', Nature Genetics, bind 50, s. 381-389. https://doi.org/10.1038/s41588-018-0059-2

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

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.",

author = "Pardi{\~n}as, {Antonio F} and Peter Holmans and Pocklington, {Andrew J} and Valentina Escott-Price and Stephan Ripke and Noa Carrera and Legge, {Sophie E} and Sophie Bishop and Darren Cameron and Hamshere, {Marian L} and Jun Han and Leon Hubbard and Amy Lynham and Kiran Mantripragada and Elliott Rees and MacCabe, {James H} and McCarroll, {Steven A} and Baune, {Bernhard T} and Gerome Breen and Byrne, {Enda M} and Udo Dannlowski and Eley, {Thalia C} and Caroline Hayward and Martin, {Nicholas G} and McIntosh, {Andrew M} and Robert Plomin and Porteous, {David J} and Wray, {Naomi R} and Armando Caballero and Geschwind, {Daniel H} and Huckins, {Laura M} and Ruderfer, {Douglas M} and Enrique Santiago and Pamela Sklar and Stahl, {Eli A} and Hyejung Won and Esben Agerbo and Als, {Thomas D} and Andreassen, {Ole A} and Marie B{\ae}kvad-Hansen and Mortensen, {Preben Bo} and Pedersen, {Carsten B{\o}cker} and B{\o}rglum, {Anders D} and Jonas Bybjerg-Grauholm and Srdjan Djurovic and Naser Durmishi and Pedersen, {Marianne Gi{\o}rtz} and Vera Golimbet and Jakob Grove and Hougaard, {David M} and Manuel Mattheisen and Espen Molden and Ole Mors and Merete Nordentoft and Milica Pejovic-Milovancevic and Engilbert Sigurdsson and Teimuraz Silagadze and Hansen, {Christine S{\o}holm} and Kari Stefansson and Hreinn Stefansson and Stacy Steinberg and Sarah Tosato and Thomas Werge and {GERAD1 Consortium:} and {CRESTAR Consortium} and Collier, {David A} and Dan Rujescu and George Kirov and Owen, {Michael J} and O'Donovan, {Michael C} and Walters, {James T. R.}",

note = "Publisher correction: Common schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection (Nature Genetics, (2018), 50, 3, (381-389), DOI: 10.1038/s41588-019-0450-7",

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

AU - Pardiñas, Antonio F

AU - Holmans, Peter

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

AU - Mattheisen, Manuel

AU - Molden, Espen

AU - Mors, Ole

AU - Nordentoft, Merete

AU - Pejovic-Milovancevic, Milica

AU - Sigurdsson, Engilbert

AU - Silagadze, Teimuraz

AU - Hansen, Christine Søholm

AU - Stefansson, Kari

AU - Stefansson, Hreinn

AU - Steinberg, Stacy

AU - Tosato, Sarah

AU - Werge, Thomas

AU - GERAD1 Consortium:

AU - CRESTAR Consortium

AU - Collier, David A

AU - Rujescu, Dan

AU - Kirov, George

AU - Owen, Michael J

AU - O'Donovan, Michael C

AU - Walters, James T. R.

N1 - Publisher correction: Common schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection (Nature Genetics, (2018), 50, 3, (381-389), DOI: 10.1038/s41588-019-0450-7

PY - 2018/3/1

Y1 - 2018/3/1

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.

U2 - 10.1038/s41588-018-0059-2

DO - 10.1038/s41588-018-0059-2

M3 - Journal article

C2 - 29483656

SN - 1061-4036

VL - 50

SP - 381

EP - 389

JO - Nature Genetics

JF - Nature Genetics

ER -

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

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