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 Kahler; Laramie Duncan; Eli Stahl; Giulio Genovese; Esperanza Fernandez; 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 Kahler, Laramie Duncan, Eli Stahl, Giulio Genovese, Esperanza Fernandez, 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

^*Corresponding author for this work

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

Abstract / Description of output

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
Early online date	22 Jan 2014
DOIs	https://doi.org/10.1038/nature12975
Publication status	Published - 13 Feb 2014

Keywords / Materials (for Non-textual outputs)

DE-NOVO MUTATIONS
INTELLECTUAL DISABILITY
MESSENGER-RNA
POSTSYNAPTIC DENSITY-95
PSYCHIATRIC-DISORDERS
ASSOCIATION ANALYSIS
SEQUENCING DATA
NMDA RECEPTOR
RISK LOCI
AUTISM

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10.1038/nature12975Licence: All Rights Reserved

GENCODYS - Genetic and Epigenetic Networks in Cognitive Dysfunction
Grant, S.
EU government bodies
1/09/11 → 30/04/15
Project: Research
SynSys - Synaptic systems: dissecting brain function in health and disease
Grant, S. & Armstrong, D.
EU government bodies
1/07/10 → 31/12/14
Project: Research

Noboru Komiyama
- Deanery of Clinical Sciences - Senior Lecturer
- Centre for Clinical Brain Sciences
- Edinburgh Neuroscience
Person: Academic: Research Active

Cite this

Purcell, S. M., Moran, J. L., Fromer, M., Ruderfer, D., Solovieff, N., Roussos, P., O'Dushlaine, C., Chambert, K., Bergen, S. E., Kahler, A., Duncan, L., Stahl, E., Genovese, G., Fernandez, 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{1530f62582a94e47b60c50ba62beacc6,

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.",

keywords = "DE-NOVO MUTATIONS, INTELLECTUAL DISABILITY, MESSENGER-RNA, POSTSYNAPTIC DENSITY-95, PSYCHIATRIC-DISORDERS, ASSOCIATION ANALYSIS, SEQUENCING DATA, NMDA RECEPTOR, RISK LOCI, AUTISM",

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 Kahler and Laramie Duncan and Eli Stahl and Giulio Genovese and Esperanza Fernandez 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",

year = "2014",

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day = "13",

doi = "10.1038/nature12975",

language = "English",

volume = "506",

pages = "185--190",

journal = "Nature",

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Purcell, SM, Moran, JL, Fromer, M, Ruderfer, D, Solovieff, N, Roussos, P, O'Dushlaine, C, Chambert, K, Bergen, SE, Kahler, A, Duncan, L, Stahl, E, Genovese, G, Fernandez, 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 - Kahler, Anna

AU - Duncan, Laramie

AU - Stahl, Eli

AU - Genovese, Giulio

AU - Fernandez, 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

PY - 2014/2/13

Y1 - 2014/2/13

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.

KW - DE-NOVO MUTATIONS

KW - INTELLECTUAL DISABILITY

KW - MESSENGER-RNA

KW - POSTSYNAPTIC DENSITY-95

KW - PSYCHIATRIC-DISORDERS

KW - ASSOCIATION ANALYSIS

KW - SEQUENCING DATA

KW - NMDA RECEPTOR

KW - RISK LOCI

KW - AUTISM

U2 - 10.1038/nature12975

DO - 10.1038/nature12975

M3 - Article

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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Keywords / Materials (for Non-textual outputs)

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Projects

GENCODYS - Genetic and Epigenetic Networks in Cognitive Dysfunction

SynSys - Synaptic systems: dissecting brain function in health and disease

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Noboru Komiyama

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