A polygenic burden of rare disruptive mutations in schizophrenia.
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.
1] Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA [2] Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA [3] Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA [4] Analytic and Translational Genetics Unit, Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA [5] Medical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
Shaun M
SM
Purcell
1] Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA [2].
Jennifer L
JL
Moran
1] Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA [2] Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA [3] Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA [4] Analytic and Translational Genetics Unit, Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA [5].
Menachem
M
Fromer
1] Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA [2] Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA [3].
Douglas
D
Ruderfer
Analytic and Translational Genetics Unit, Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
Nadia
N
Solovieff
1] Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA [2] Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
Panos
P
Roussos
Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
Colm
C
O'Dushlaine
Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
Kimberly
K
Chambert
1] Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA [2] Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm SE-171 77, Sweden.
Sarah E
SE
Bergen
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm SE-171 77, Sweden.
Anna
A
Kähler
1] Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA [2] Analytic and Translational Genetics Unit, Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA [3] Medical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
Laramie
L
Duncan
1] Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA [2] Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
Eli
E
Stahl
Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
Giulio
G
Genovese
1] Center for Human Genetics, KU Leuven, 3000 Leuven, Belgium [2] VIB Center for Biology of Disease, 3000 Leuven, Belgium.
Esperanza
E
Fernández
Proteomic Mass Spectrometry, The Wellcome Trust Sanger Institute, Cambridge CB10 1SA, UK.
Mark O
MO
Collins
Proteomic Mass Spectrometry, The Wellcome Trust Sanger Institute, Cambridge CB10 1SA, UK.
Noboru H
NH
Komiyama
Proteomic Mass Spectrometry, The Wellcome Trust Sanger Institute, Cambridge CB10 1SA, UK.
Jyoti S
JS
Choudhary
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm SE-171 77, Sweden.
Patrik K E
PK
Magnusson
Medical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
Eric
E
Banks
Medical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
Khalid
K
Shakir
Medical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
Kiran
K
Garimella
Medical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
Tim
T
Fennell
Medical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
Mark
M
DePristo
Genes to Cognition Programme, Centre for Clinical Brain Sciences and Centre for Neuroregeneration, The University of Edinburgh, Edinburgh EH16 4SB, UK.
Seth G N
SG
Grant
1] Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA [2] Analytic and Translational Genetics Unit, Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA [3] Department of Neurology, Harvard Medical School, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
Stephen J
SJ
Haggarty
Medical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
Stacey
S
Gabriel
Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
Edward M
EM
Scolnick
Medical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
Eric S
ES
Lander
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm SE-171 77, Sweden.
Christina M
CM
Hultman
Departments of Genetics and Psychiatry, University of North Carolina, Chapel Hill, North Carolina 27599-7264, USA.
Patrick F
PF
Sullivan
1] Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA [2] Medical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA [3] Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.
Steven A
SA
McCarroll
1] Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA [2] Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA [3] Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
Pamela
P
Sklar
D001321:Autistic Disorder / Q000235:genetics; D015220:Calcium Channels / Q000235:genetics; D003598:Cytoskeletal Proteins / Q000235:genetics; D056915:DNA Copy Number Variations / Q000235:genetics; D000076122:Disks Large Homolog 4 Protein; D005260:Female; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000378:metabolism; D055106:Genome-Wide Association Study; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D020412:Multifactorial Inheritance / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics; D012559:Schizophrenia / Q000235:genetics*
D015220:Calcium Channels; D003598:Cytoskeletal Proteins; D000076122:Disks Large Homolog 4 Protein; D051860:Fragile X Messenger Ribonucleoprotein 1; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D016194:Receptors, N-Methyl-D-Aspartate; C501444:DLG4 protein, human; C497683:FMR1 protein, human; C092069:activity regulated cytoskeletal-associated protein