A polygenic burden of rare disruptive mutations in schizophrenia

Shaun M. Purcell; Jennifer L. Moran; Menachem Fromer; Douglas Ruderfer; Nadia Solovieff; Panos Roussos; Colm O'Dushlaine; Kimberly Chambert; Sarah E. Bergen; Anna Kähler; Laramie Duncan; Eli Stahl; Giulio Genovese; Esperanza Fernández; Mark O. Collins; Noboru H. Komiyama; Jyoti S. Choudhary; Patrik K.E. Magnusson; Eric Banks; Khalid Shakir; Kiran Garimella; Tim Fennell; Mark Depristo; Seth G.N. Grant; Stephen J. Haggarty; Stacey Gabriel; Edward M. Scolnick; Eric S. Lander; Christina M. Hultman; Patrick F. Sullivan; Steven A. McCarroll; Pamela Sklar

doi:10.1038/nature12975

A polygenic burden of rare disruptive mutations in schizophrenia

Shaun M. Purcell, Jennifer L. Moran, Menachem Fromer, Douglas Ruderfer, Nadia Solovieff, Panos Roussos, Colm O'Dushlaine, Kimberly Chambert, Sarah E. Bergen, Anna Kähler, Laramie Duncan, Eli Stahl, Giulio Genovese, Esperanza Fernández, Mark O. Collins, Noboru H. Komiyama, Jyoti S. Choudhary, Patrik K.E. Magnusson, Eric Banks, Khalid ShakirKiran Garimella, Tim Fennell, Mark Depristo, Seth G.N. Grant, Stephen J. Haggarty, Stacey Gabriel, Edward M. Scolnick, Eric S. Lander, Christina M. Hultman, Patrick F. Sullivan, Steven A. McCarroll, Pamela Sklar

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Abstract

Schizophrenia is a common disease with a complex aetiology, probably involving multiple and heterogeneous genetic factors. Here, by analysing the exome sequences of 2,536 schizophrenia cases and 2,543 controls, we demonstrate a polygenic burden primarily arising from rare (less than 1 in 10,000), disruptive mutations distributed across many genes. Particularly enriched gene sets include the voltage-gated calcium ion channel and the signalling complex formed by the activity-regulated cytoskeleton-associated scaffold protein (ARC) of the postsynaptic density, sets previously implicated by genome-wide association and copy-number variation studies. Similar to reports in autism, targets of the fragile X mental retardation protein (FMRP, product of FMR1) are enriched for case mutations. No individual gene-based test achieves significance after correction for multiple testing and we do not detect any alleles of moderately low frequency (approximately 0.5 to 1 per cent) and moderately large effect. Taken together, these data suggest that population-based exome sequencing can discover risk alleles and complements established gene-mapping paradigms in neuropsychiatric disease.

Original language	English
Pages (from-to)	185-190
Number of pages	6
Journal	Nature
Volume	506
Issue number	7487
DOIs	https://doi.org/10.1038/nature12975
State	Published - 2014

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Purcell, S. M., Moran, J. L., Fromer, M., Ruderfer, D., Solovieff, N., Roussos, P., O'Dushlaine, C., Chambert, K., Bergen, S. E., Kähler, A., Duncan, L., Stahl, E., Genovese, G., Fernández, E., Collins, M. O., Komiyama, N. H., Choudhary, J. S., Magnusson, P. K. E., Banks, E., ... Sklar, P. (2014). A polygenic burden of rare disruptive mutations in schizophrenia. Nature, 506(7487), 185-190. https://doi.org/10.1038/nature12975

@article{4b4bbc718454486bab544b41d711870d,

title = "A polygenic burden of rare disruptive mutations in schizophrenia",

abstract = "Schizophrenia is a common disease with a complex aetiology, probably involving multiple and heterogeneous genetic factors. Here, by analysing the exome sequences of 2,536 schizophrenia cases and 2,543 controls, we demonstrate a polygenic burden primarily arising from rare (less than 1 in 10,000), disruptive mutations distributed across many genes. Particularly enriched gene sets include the voltage-gated calcium ion channel and the signalling complex formed by the activity-regulated cytoskeleton-associated scaffold protein (ARC) of the postsynaptic density, sets previously implicated by genome-wide association and copy-number variation studies. Similar to reports in autism, targets of the fragile X mental retardation protein (FMRP, product of FMR1) are enriched for case mutations. No individual gene-based test achieves significance after correction for multiple testing and we do not detect any alleles of moderately low frequency (approximately 0.5 to 1 per cent) and moderately large effect. Taken together, these data suggest that population-based exome sequencing can discover risk alleles and complements established gene-mapping paradigms in neuropsychiatric disease.",

author = "Purcell, {Shaun M.} and Moran, {Jennifer L.} and Menachem Fromer and Douglas Ruderfer and Nadia Solovieff and Panos Roussos and Colm O'Dushlaine and Kimberly Chambert and Bergen, {Sarah E.} and Anna K{\"a}hler and Laramie Duncan and Eli Stahl and Giulio Genovese and Esperanza Fern{\'a}ndez and Collins, {Mark O.} and Komiyama, {Noboru H.} and Choudhary, {Jyoti S.} and Magnusson, {Patrik K.E.} and Eric Banks and Khalid Shakir and Kiran Garimella and Tim Fennell and Mark Depristo and Grant, {Seth G.N.} and Haggarty, {Stephen J.} and Stacey Gabriel and Scolnick, {Edward M.} and Lander, {Eric S.} and Hultman, {Christina M.} and Sullivan, {Patrick F.} and McCarroll, {Steven A.} and Pamela Sklar",

note = "Funding Information: Acknowledgements We are grateful for the participation of all subjects contributing to this research, and to the collection team that worked to recruit them: E. Flordal-Thelander, A.-B. Holmgren, M. Hallin, M. Lundin, A.-K. Sundberg, C. Pettersson, R. Satgunanthan-Dawoud, S. Hassellund, M. R{\aa}dstrom, B. Ohlander, L. Nyr{\'e}n and I. Kizling. We acknowledge funding support from National Institutes of Health (NIH)/National Institute of Mental Health (NIMH) ARRA Grand Opportunity grant NIMH RC2 MH089905 (S.M.P., P.S.), the Sylvan Herman Foundation, the Stanley Center for Psychiatric Research, the Stanley Medical Research Institute, NIH/National Human Genome Research Institute (NHGRI) grant U54HG003067 (E.S.L.), NIH/NIMH grant R01 MH095088 (S.J.H.), NIH/NIMH grant R01 MH091115 (S.J.H.), the Tau Consortium (S.J.H.), NIH/NIMH grant R01 MH099126 (S.M.P.), NIH/NHGRI grant R01 HG005827 (S.M.P.), NIH/NIMH grant R01 MH077139 (P.F.S.), NIH/NIMH grant R01 MH095034 (P.S.),NIH/NIMHgrantT32 MH017119(L.D.),the FriedmanBrain Institute at Mount Sinai School of Medicine, the Karolinska Institutet, Karolinska University Hospital, the Swedish Research Council, an ALF grant from Swedish County Council, the S{\"o}derstr{\"o}m K{\"o}nigska Foundation, the Netherlands Scientific Organization (NWO 645-000-003), the Wellcome Trust, Genes to Cognition Program, The Medical Research Council and European Union projects GENCODYS no. 241995, EUROSPIN no. 242498 and SYNSYS no. 242167 (E.F., M.O.C., N.H.K., J.S.C., S.G.N.G.). Work at the Icahn School of Medicine at Mount Sinai was also supported by the Institute for Genomics and Multiscale Biology (including computational resources and staff expertise provided by the Department of Scientific Computing). The funders had no role in study design, execution, analysis or manuscript preparation.",

year = "2014",

doi = "10.1038/nature12975",

language = "English",

volume = "506",

pages = "185--190",

journal = "Nature",

issn = "0028-0836",

publisher = "Nature Research",

number = "7487",

}

Purcell, SM, Moran, JL, Fromer, M, Ruderfer, D, Solovieff, N, Roussos, P, O'Dushlaine, C, Chambert, K, Bergen, SE, Kähler, A, Duncan, L, Stahl, E, Genovese, G, Fernández, E, Collins, MO, Komiyama, NH, Choudhary, JS, Magnusson, PKE, Banks, E, Shakir, K, Garimella, K, Fennell, T, Depristo, M, Grant, SGN, Haggarty, SJ, Gabriel, S, Scolnick, EM, Lander, ES, Hultman, CM, Sullivan, PF, McCarroll, SA & Sklar, P 2014, 'A polygenic burden of rare disruptive mutations in schizophrenia', Nature, vol. 506, no. 7487, pp. 185-190. https://doi.org/10.1038/nature12975

TY - JOUR

T1 - A polygenic burden of rare disruptive mutations in schizophrenia

AU - Purcell, Shaun M.

AU - Moran, Jennifer L.

AU - Fromer, Menachem

AU - Ruderfer, Douglas

AU - Solovieff, Nadia

AU - Roussos, Panos

AU - O'Dushlaine, Colm

AU - Chambert, Kimberly

AU - Bergen, Sarah E.

AU - Kähler, Anna

AU - Duncan, Laramie

AU - Stahl, Eli

AU - Genovese, Giulio

AU - Fernández, Esperanza

AU - Collins, Mark O.

AU - Komiyama, Noboru H.

AU - Choudhary, Jyoti S.

AU - Magnusson, Patrik K.E.

AU - Banks, Eric

AU - Shakir, Khalid

AU - Garimella, Kiran

AU - Fennell, Tim

AU - Depristo, Mark

AU - Grant, Seth G.N.

AU - Haggarty, Stephen J.

AU - Gabriel, Stacey

AU - Scolnick, Edward M.

AU - Lander, Eric S.

AU - Hultman, Christina M.

AU - Sullivan, Patrick F.

AU - McCarroll, Steven A.

AU - Sklar, Pamela

N1 - Funding Information: Acknowledgements We are grateful for the participation of all subjects contributing to this research, and to the collection team that worked to recruit them: E. Flordal-Thelander, A.-B. Holmgren, M. Hallin, M. Lundin, A.-K. Sundberg, C. Pettersson, R. Satgunanthan-Dawoud, S. Hassellund, M. Rådstrom, B. Ohlander, L. Nyrén and I. Kizling. We acknowledge funding support from National Institutes of Health (NIH)/National Institute of Mental Health (NIMH) ARRA Grand Opportunity grant NIMH RC2 MH089905 (S.M.P., P.S.), the Sylvan Herman Foundation, the Stanley Center for Psychiatric Research, the Stanley Medical Research Institute, NIH/National Human Genome Research Institute (NHGRI) grant U54HG003067 (E.S.L.), NIH/NIMH grant R01 MH095088 (S.J.H.), NIH/NIMH grant R01 MH091115 (S.J.H.), the Tau Consortium (S.J.H.), NIH/NIMH grant R01 MH099126 (S.M.P.), NIH/NHGRI grant R01 HG005827 (S.M.P.), NIH/NIMH grant R01 MH077139 (P.F.S.), NIH/NIMH grant R01 MH095034 (P.S.),NIH/NIMHgrantT32 MH017119(L.D.),the FriedmanBrain Institute at Mount Sinai School of Medicine, the Karolinska Institutet, Karolinska University Hospital, the Swedish Research Council, an ALF grant from Swedish County Council, the Söderström Königska Foundation, the Netherlands Scientific Organization (NWO 645-000-003), the Wellcome Trust, Genes to Cognition Program, The Medical Research Council and European Union projects GENCODYS no. 241995, EUROSPIN no. 242498 and SYNSYS no. 242167 (E.F., M.O.C., N.H.K., J.S.C., S.G.N.G.). Work at the Icahn School of Medicine at Mount Sinai was also supported by the Institute for Genomics and Multiscale Biology (including computational resources and staff expertise provided by the Department of Scientific Computing). The funders had no role in study design, execution, analysis or manuscript preparation.

PY - 2014

Y1 - 2014

N2 - Schizophrenia is a common disease with a complex aetiology, probably involving multiple and heterogeneous genetic factors. Here, by analysing the exome sequences of 2,536 schizophrenia cases and 2,543 controls, we demonstrate a polygenic burden primarily arising from rare (less than 1 in 10,000), disruptive mutations distributed across many genes. Particularly enriched gene sets include the voltage-gated calcium ion channel and the signalling complex formed by the activity-regulated cytoskeleton-associated scaffold protein (ARC) of the postsynaptic density, sets previously implicated by genome-wide association and copy-number variation studies. Similar to reports in autism, targets of the fragile X mental retardation protein (FMRP, product of FMR1) are enriched for case mutations. No individual gene-based test achieves significance after correction for multiple testing and we do not detect any alleles of moderately low frequency (approximately 0.5 to 1 per cent) and moderately large effect. Taken together, these data suggest that population-based exome sequencing can discover risk alleles and complements established gene-mapping paradigms in neuropsychiatric disease.

AB - Schizophrenia is a common disease with a complex aetiology, probably involving multiple and heterogeneous genetic factors. Here, by analysing the exome sequences of 2,536 schizophrenia cases and 2,543 controls, we demonstrate a polygenic burden primarily arising from rare (less than 1 in 10,000), disruptive mutations distributed across many genes. Particularly enriched gene sets include the voltage-gated calcium ion channel and the signalling complex formed by the activity-regulated cytoskeleton-associated scaffold protein (ARC) of the postsynaptic density, sets previously implicated by genome-wide association and copy-number variation studies. Similar to reports in autism, targets of the fragile X mental retardation protein (FMRP, product of FMR1) are enriched for case mutations. No individual gene-based test achieves significance after correction for multiple testing and we do not detect any alleles of moderately low frequency (approximately 0.5 to 1 per cent) and moderately large effect. Taken together, these data suggest that population-based exome sequencing can discover risk alleles and complements established gene-mapping paradigms in neuropsychiatric disease.

UR - http://www.scopus.com/inward/record.url?scp=84893904007&partnerID=8YFLogxK

U2 - 10.1038/nature12975

DO - 10.1038/nature12975

M3 - Article

AN - SCOPUS:84893904007

SN - 0028-0836

VL - 506

SP - 185

EP - 190

JO - Nature

JF - Nature

IS - 7487

ER -

A polygenic burden of rare disruptive mutations in schizophrenia

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