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; Denise Harold; Rebecca Sims; Amy Gerrish; Jade Chapman; Richard Abraham; Paul Hollingworth; Jaspreet Pahwa; Nicola Denning; Charlene Thomas; Sarah Taylor; John Powell; Petroula Proitsi; Michelle Lupton; Simon Lovestone; Peter Passmore; David Craig; Bernadette McGuinness; Janet Johnston; Stephen Todd; Wolfgang Maier; Frank Jessen; Reiner Heun; Britta Schurmann; Alfredo Ramirez; Tim Becker; Christine Herold; André Lacour; Dmitriy Drichel; Markus Nothen; Alison Goate; Carlos Cruchaga; Petra Nowotny; John C. Morris; Kevin Mayo; Michael C. O'Donovan; Michael J. Owen; Julie Williams; Evanthia Achilla; Cathy L. Barr; Theresa Wimberly Böttger; Dan Cohen; Sarah Curran; Emma Dempster; Danai Dima; Ramon Sabes-Figuera; Robert J. Flanagan; Sophia Frangou; Josef Frank; Christiane Gasse; Fiona Gaughran; Ina Giegling; Eilis Hannon; Annette M. Hartmann; Barbara Heißerer; Marinka Helthuis; Henriette Thisted Horsdal; Oddur Ingimarsson; Karel Jollie; James L. Kennedy; Ole Köhler; Bettina Konte; Maren Lang; Cathryn Lewis; James MacCaba; Anil K. Malhotra; Paul McCrone; Sandra M. Meier; Jonathan Mill; Markus M. Nöthen; Carsten B. Pedersen; Marcella Rietschel; Dan Rujescu; Ameli Schwalber; Holger J. Sørensen; Benjamin Spencer; Henrik Støvring; Jana Strohmaier; Patrick Sullivan; Evangelos Vassos; Moira Verbelen; David A. Collier; George Kirov; 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, Denise Harold, Rebecca Sims, Amy Gerrish, Jade Chapman, Richard Abraham, Paul Hollingworth, Jaspreet Pahwa, Nicola Denning, Charlene Thomas, Sarah Taylor, John Powell, Petroula Proitsi, Michelle Lupton, Simon Lovestone, Peter Passmore, David Craig, Bernadette McGuinness, Janet Johnston, Stephen Todd, Wolfgang Maier, Frank Jessen, Reiner Heun, Britta Schurmann, Alfredo Ramirez, Tim Becker, Christine Herold, André Lacour, Dmitriy Drichel, Markus Nothen, Alison Goate, Carlos Cruchaga, Petra Nowotny, John C. Morris, Kevin Mayo, Michael C. O'Donovan, Michael J. Owen, Julie Williams, Evanthia Achilla, Cathy L. Barr, Theresa Wimberly Böttger, Dan Cohen, Sarah Curran, Emma Dempster, Danai Dima, Ramon Sabes-Figuera, Robert J. Flanagan, Sophia Frangou, Josef Frank, Christiane Gasse, Fiona Gaughran, Ina Giegling, Eilis Hannon, Annette M. Hartmann, Barbara Heißerer, Marinka Helthuis, Henriette Thisted Horsdal, Oddur Ingimarsson, Karel Jollie, James L. Kennedy, Ole Köhler, Bettina Konte, Maren Lang, Cathryn Lewis, James MacCaba, Anil K. Malhotra, Paul McCrone, Sandra M. Meier, Jonathan Mill, Markus M. Nöthen, Carsten B. Pedersen, Marcella Rietschel, Dan Rujescu, Ameli Schwalber, Holger J. Sørensen, Benjamin Spencer, Henrik Støvring, Jana Strohmaier, Patrick Sullivan, Evangelos Vassos, Moira Verbelen, David A. Collier, George Kirov, James T.R. Walters

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

996 Scopus citations

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.

Original language	English
Pages (from-to)	381-389
Number of pages	9
Journal	Nature Genetics
Volume	50
Issue number	3
DOIs	https://doi.org/10.1038/s41588-018-0059-2
State	Published - Mar 1 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(3), 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 Denise Harold and Rebecca Sims and Amy Gerrish and Jade Chapman and Richard Abraham and Paul Hollingworth and Jaspreet Pahwa and Nicola Denning and Charlene Thomas and Sarah Taylor and John Powell and Petroula Proitsi and Michelle Lupton and Simon Lovestone and Peter Passmore and David Craig and Bernadette McGuinness and Janet Johnston and Stephen Todd and Wolfgang Maier and Frank Jessen and Reiner Heun and Britta Schurmann and Alfredo Ramirez and Tim Becker and Christine Herold and Andr{\'e} Lacour and Dmitriy Drichel and Markus Nothen and Alison Goate and Carlos Cruchaga and Petra Nowotny and Morris, {John C.} and Kevin Mayo and O'Donovan, {Michael C.} and Owen, {Michael J.} and Julie Williams and Evanthia Achilla and Barr, {Cathy L.} and B{\"o}ttger, {Theresa Wimberly} and Dan Cohen and Sarah Curran and Emma Dempster and Danai Dima and Ramon Sabes-Figuera and Flanagan, {Robert J.} and Sophia Frangou and Josef Frank and Christiane Gasse and Fiona Gaughran and Ina Giegling and Eilis Hannon and Hartmann, {Annette M.} and Barbara Hei{\ss}erer and Marinka Helthuis and Horsdal, {Henriette Thisted} and Oddur Ingimarsson and Karel Jollie and Kennedy, {James L.} and Ole K{\"o}hler and Bettina Konte and Maren Lang and Cathryn Lewis and James MacCaba and Malhotra, {Anil K.} and Paul McCrone and Meier, {Sandra M.} and Jonathan Mill and N{\"o}then, {Markus M.} and Pedersen, {Carsten B.} and Marcella Rietschel and Dan Rujescu and Ameli Schwalber and S{\o}rensen, {Holger J.} and Benjamin Spencer and Henrik St{\o}vring and Jana Strohmaier and Patrick Sullivan and Evangelos Vassos and Moira Verbelen and Collier, {David A.} and George Kirov and Walters, {James T.R.}",

note = "Publisher Copyright: {\textcopyright} 2018 The Author(s).",

year = "2018",

month = mar,

day = "1",

doi = "10.1038/s41588-018-0059-2",

language = "English",

volume = "50",

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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, Harold, D, Sims, R, Gerrish, A, Chapman, J, 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, Herold, C, Lacour, A, Drichel, D, Nothen, M, Goate, A, Cruchaga, C, Nowotny, P, Morris, JC, Mayo, K, O'Donovan, MC, Owen, MJ, Williams, J, Achilla, E, Barr, CL, Böttger, TW, Cohen, D, Curran, S, Dempster, E, Dima, D, Sabes-Figuera, R, Flanagan, RJ, Frangou, S, Frank, J, Gasse, C, Gaughran, F, Giegling, I, Hannon, E, Hartmann, AM, Heißerer, B, Helthuis, M, Horsdal, HT, Ingimarsson, O, Jollie, K, Kennedy, JL, Köhler, O, Konte, B, Lang, M, Lewis, C, MacCaba, J, Malhotra, AK, McCrone, P, Meier, SM, Mill, J, Nöthen, MM, Pedersen, CB, Rietschel, M, Rujescu, D, Schwalber, A, Sørensen, HJ, Spencer, B, Støvring, H, Strohmaier, J, Sullivan, P, Vassos, E, Verbelen, M, Collier, DA, Kirov, G & Walters, JTR 2018, 'Common schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection', Nature Genetics, vol. 50, no. 3, pp. 381-389. 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 - 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 - Harold, Denise

AU - Sims, Rebecca

AU - Gerrish, Amy

AU - Chapman, Jade

AU - Abraham, Richard

AU - Hollingworth, Paul

AU - Pahwa, Jaspreet

AU - Denning, Nicola

AU - Thomas, Charlene

AU - Taylor, Sarah

AU - Powell, John

AU - Proitsi, Petroula

AU - Lupton, Michelle

AU - Lovestone, Simon

AU - Passmore, Peter

AU - Craig, David

AU - McGuinness, Bernadette

AU - Johnston, Janet

AU - Todd, Stephen

AU - Maier, Wolfgang

AU - Jessen, Frank

AU - Heun, Reiner

AU - Schurmann, Britta

AU - Ramirez, Alfredo

AU - Becker, Tim

AU - Herold, Christine

AU - Lacour, André

AU - Drichel, Dmitriy

AU - Nothen, Markus

AU - Goate, Alison

AU - Cruchaga, Carlos

AU - Nowotny, Petra

AU - Morris, John C.

AU - Mayo, Kevin

AU - O'Donovan, Michael C.

AU - Owen, Michael J.

AU - Williams, Julie

AU - Achilla, Evanthia

AU - Barr, Cathy L.

AU - Böttger, Theresa Wimberly

AU - Cohen, Dan

AU - Curran, Sarah

AU - Dempster, Emma

AU - Dima, Danai

AU - Sabes-Figuera, Ramon

AU - Flanagan, Robert J.

AU - Frangou, Sophia

AU - Frank, Josef

AU - Gasse, Christiane

AU - Gaughran, Fiona

AU - Giegling, Ina

AU - Hannon, Eilis

AU - Hartmann, Annette M.

AU - Heißerer, Barbara

AU - Helthuis, Marinka

AU - Horsdal, Henriette Thisted

AU - Ingimarsson, Oddur

AU - Jollie, Karel

AU - Kennedy, James L.

AU - Köhler, Ole

AU - Konte, Bettina

AU - Lang, Maren

AU - Lewis, Cathryn

AU - MacCaba, James

AU - Malhotra, Anil K.

AU - McCrone, Paul

AU - Meier, Sandra M.

AU - Mill, Jonathan

AU - Nöthen, Markus M.

AU - Pedersen, Carsten B.

AU - Rietschel, Marcella

AU - Rujescu, Dan

AU - Schwalber, Ameli

AU - Sørensen, Holger J.

AU - Spencer, Benjamin

AU - Støvring, Henrik

AU - Strohmaier, Jana

AU - Sullivan, Patrick

AU - Vassos, Evangelos

AU - Verbelen, Moira

AU - Collier, David A.

AU - Kirov, George

AU - Walters, James T.R.

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.

UR - http://www.scopus.com/inward/record.url?scp=85042546549&partnerID=8YFLogxK

U2 - 10.1038/s41588-018-0059-2

DO - 10.1038/s41588-018-0059-2

M3 - Article

C2 - 29483656

AN - SCOPUS:85042546549

SN - 1061-4036

VL - 50

SP - 381

EP - 389

JO - Nature Genetics

JF - Nature Genetics

IS - 3

ER -

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

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