Increased burden of ultra-rare protein-altering variants among 4,877 individuals with schizophrenia.
By analyzing the exomes of 12,332 unrelated Swedish individuals, including 4,877 individuals affected with schizophrenia, in ways informed by exome sequences from 45,376 other individuals, we identified 244,246 coding-sequence and splice-site ultra-rare variants (URVs) that were unique to individual Swedes. We found that gene-disruptive and putatively protein-damaging URVs (but not synonymous URVs) were more abundant among individuals with schizophrenia than among controls (P = 1.3 × 10-10). This elevation of protein-compromising URVs was several times larger than an analogously elevated rate for de novo mutations, suggesting that most rare-variant effects on schizophrenia risk are inherited. Among individuals with schizophrenia, the elevated frequency of protein-compromising URVs was concentrated in brain-expressed genes, particularly in neuronally expressed genes; most of this elevation arose from large sets of genes whose RNAs have been found to interact with synaptically localized proteins. Our results suggest that synaptic dysfunction may mediate a large fraction of strong, individually rare genetic influences on schizophrenia risk.
Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.|Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.|Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.
Giulio
G
Genovese
Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York, USA.|Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Menachem
M
Fromer
Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York, USA.|Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Eli A
EA
Stahl
Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York, USA.|Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Douglas M
DM
Ruderfer
Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
Kimberly
K
Chambert
Department of Psychiatry and Neurochemistry, Institute of Neuroscience a Physiology at Sahlgrenska Academy at University of Gothenburg, Göteborg, Sweden.
Mikael
M
Landén
Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
Jennifer L
JL
Moran
Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York, USA.|Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Shaun M
SM
Purcell
Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York, USA.|Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Pamela
P
Sklar
Departments of Genetics and Psychiatry, University of North Carolina, Chapel Hill, North Carolina, USA.|Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
Patrick F
0000-0002-6619-873X
PF
Sullivan
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
Christina M
CM
Hultman
Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.|Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.|Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.
Steven A
SA
McCarroll
D059472:Exome / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics; D012306:Risk; D012559:Schizophrenia / Q000235:genetics*; D013548:Sweden
D009419:Nerve Tissue Proteins
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