publication . Other literature type . Article . 2016

Increased burden of ultra-rare protein-altering variants among 4,877 individuals with schizophrenia

Giulio Genovese; Menachem Fromer; Eli A Stahl; Douglas M Ruderfer; Kimberly Chambert; Mikael Landén; Jennifer L Moran; Shaun M Purcell; Pamela Sklar; Patrick F Sullivan; ...
  • Published: 03 Oct 2016
  • Publisher: Springer Science and Business Media LLC
  • Country: United States
Abstract
By analyzing the exomes of 12,332 unrelated Swedish individuals – including 4,877 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 in schizophrenia cases than 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...
Subjects
free text keywords: Article, Biology, Schizophrenia, medicine.disease, medicine, Synapse, Mutation, medicine.disease_cause, Gene, Genetics, Genome-wide association study, Exome
Funded by
NIH| 1/2 A Large-Scale Schizophrenia Association Study in Sweden
Project
  • Funder: National Institutes of Health (NIH)
  • Project Code: 5R01MH077139-05
  • Funding stream: NATIONAL INSTITUTE OF MENTAL HEALTH
,
NIH| Multi-allelic copy number variation of the human genome
Project
  • Funder: National Institutes of Health (NIH)
  • Project Code: 5R01HG006855-02
  • Funding stream: NATIONAL HUMAN GENOME RESEARCH INSTITUTE
,
NIH| Large Scale Sequencing and Analysis of Genomes
Project
  • Funder: National Institutes of Health (NIH)
  • Project Code: 3U54HG003067-07S1
  • Funding stream: NATIONAL HUMAN GENOME RESEARCH INSTITUTE
,
NIH| Whole genome sequencing of bipolar disorder and schizophrenia
Project
  • Funder: National Institutes of Health (NIH)
  • Project Code: 1RC2MH089905-01
  • Funding stream: NATIONAL INSTITUTE OF MENTAL HEALTH
109 references, page 1 of 8

McGrath, J, Saha, S, Chant, D, Welham, J. Schizophrenia: a concise overview of incidence, prevalence, and mortality. Epidemiol. Rev. 2008; 30: 67-76 [PubMed]

Sullivan, PF, Kendler, KS, Neale, MC. Schizophrenia as a complex trait: evidence from a meta-analysis of twin studies. Arch. Gen. Psychiatry. 2003; 60: 1187-1192 [PubMed]

Lichtenstein, P. Common genetic determinants of schizophrenia and bipolar disorder in Swedish families: a population-based study. Lancet Lond. Engl. 2009; 373: 234-239

Bundy, H, Stahl, D, MacCabe, JH. A systematic review and meta-analysis of the fertility of patients with schizophrenia and their unaffected relatives. Acta Psychiatr. Scand. 2011; 123: 98-106 [OpenAIRE] [PubMed]

Power, RA. Fecundity of patients with schizophrenia, autism, bipolar disorder, depression, anorexia nervosa, or substance abuse vs their unaffected siblings. JAMA Psychiatry. 2013; 70: 22-30 [PubMed]

Zuk, O. Searching for missing heritability: designing rare variant association studies. Proc. Natl. Acad. Sci. U. S. A. 2014; 111: E455-464 [OpenAIRE] [PubMed]

Stefansson, H. CNVs conferring risk of autism or schizophrenia affect cognition in controls. Nature. 2014; 505: 361-366 [OpenAIRE] [PubMed]

Lek, M. Analysis of protein-coding genetic variation in 60,706 humans. Nature. 2016; 536: 285-291 [OpenAIRE] [PubMed]

Purcell, SM. A polygenic burden of rare disruptive mutations in schizophrenia. Nature. 2014; 506: 185-190 [OpenAIRE] [PubMed]

MacArthur, DG. A systematic survey of loss-of-function variants in human protein-coding genes. Science. 2012; 335: 823-828 [OpenAIRE] [PubMed]

Maquat, LE. Nonsense-mediated mRNA decay: splicing, translation and mRNP dynamics. Nat. Rev. Mol. Cell Biol. 2004; 5: 89-99 [OpenAIRE] [PubMed]

Fromer, M. De novo mutations in schizophrenia implicate synaptic networks. Nature. 2014; 506: 179-184 [OpenAIRE] [PubMed]

Iossifov, I. The contribution of de novo coding mutations to autism spectrum disorder. Nature. 2014; 515: 216-221 [OpenAIRE] [PubMed]

Ionita-Laza, I, Lee, S, Makarov, V, Buxbaum, JD, Lin, X. Sequence kernel association tests for the combined effect of rare and common variants. Am. J. Hum. Genet. 2013; 92: 841-853 [OpenAIRE] [PubMed]

Purcell, S, Cherny, SS, Sham, PC. Genetic Power Calculator: design of linkage and association genetic mapping studies of complex traits. Bioinforma. Oxf. Engl. 2003; 19: 149-150 [OpenAIRE]

109 references, page 1 of 8
Abstract
By analyzing the exomes of 12,332 unrelated Swedish individuals – including 4,877 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 in schizophrenia cases than 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...
Subjects
free text keywords: Article, Biology, Schizophrenia, medicine.disease, medicine, Synapse, Mutation, medicine.disease_cause, Gene, Genetics, Genome-wide association study, Exome
Funded by
NIH| 1/2 A Large-Scale Schizophrenia Association Study in Sweden
Project
  • Funder: National Institutes of Health (NIH)
  • Project Code: 5R01MH077139-05
  • Funding stream: NATIONAL INSTITUTE OF MENTAL HEALTH
,
NIH| Multi-allelic copy number variation of the human genome
Project
  • Funder: National Institutes of Health (NIH)
  • Project Code: 5R01HG006855-02
  • Funding stream: NATIONAL HUMAN GENOME RESEARCH INSTITUTE
,
NIH| Large Scale Sequencing and Analysis of Genomes
Project
  • Funder: National Institutes of Health (NIH)
  • Project Code: 3U54HG003067-07S1
  • Funding stream: NATIONAL HUMAN GENOME RESEARCH INSTITUTE
,
NIH| Whole genome sequencing of bipolar disorder and schizophrenia
Project
  • Funder: National Institutes of Health (NIH)
  • Project Code: 1RC2MH089905-01
  • Funding stream: NATIONAL INSTITUTE OF MENTAL HEALTH
109 references, page 1 of 8

McGrath, J, Saha, S, Chant, D, Welham, J. Schizophrenia: a concise overview of incidence, prevalence, and mortality. Epidemiol. Rev. 2008; 30: 67-76 [PubMed]

Sullivan, PF, Kendler, KS, Neale, MC. Schizophrenia as a complex trait: evidence from a meta-analysis of twin studies. Arch. Gen. Psychiatry. 2003; 60: 1187-1192 [PubMed]

Lichtenstein, P. Common genetic determinants of schizophrenia and bipolar disorder in Swedish families: a population-based study. Lancet Lond. Engl. 2009; 373: 234-239

Bundy, H, Stahl, D, MacCabe, JH. A systematic review and meta-analysis of the fertility of patients with schizophrenia and their unaffected relatives. Acta Psychiatr. Scand. 2011; 123: 98-106 [OpenAIRE] [PubMed]

Power, RA. Fecundity of patients with schizophrenia, autism, bipolar disorder, depression, anorexia nervosa, or substance abuse vs their unaffected siblings. JAMA Psychiatry. 2013; 70: 22-30 [PubMed]

Zuk, O. Searching for missing heritability: designing rare variant association studies. Proc. Natl. Acad. Sci. U. S. A. 2014; 111: E455-464 [OpenAIRE] [PubMed]

Stefansson, H. CNVs conferring risk of autism or schizophrenia affect cognition in controls. Nature. 2014; 505: 361-366 [OpenAIRE] [PubMed]

Lek, M. Analysis of protein-coding genetic variation in 60,706 humans. Nature. 2016; 536: 285-291 [OpenAIRE] [PubMed]

Purcell, SM. A polygenic burden of rare disruptive mutations in schizophrenia. Nature. 2014; 506: 185-190 [OpenAIRE] [PubMed]

MacArthur, DG. A systematic survey of loss-of-function variants in human protein-coding genes. Science. 2012; 335: 823-828 [OpenAIRE] [PubMed]

Maquat, LE. Nonsense-mediated mRNA decay: splicing, translation and mRNP dynamics. Nat. Rev. Mol. Cell Biol. 2004; 5: 89-99 [OpenAIRE] [PubMed]

Fromer, M. De novo mutations in schizophrenia implicate synaptic networks. Nature. 2014; 506: 179-184 [OpenAIRE] [PubMed]

Iossifov, I. The contribution of de novo coding mutations to autism spectrum disorder. Nature. 2014; 515: 216-221 [OpenAIRE] [PubMed]

Ionita-Laza, I, Lee, S, Makarov, V, Buxbaum, JD, Lin, X. Sequence kernel association tests for the combined effect of rare and common variants. Am. J. Hum. Genet. 2013; 92: 841-853 [OpenAIRE] [PubMed]

Purcell, S, Cherny, SS, Sham, PC. Genetic Power Calculator: design of linkage and association genetic mapping studies of complex traits. Bioinforma. Oxf. Engl. 2003; 19: 149-150 [OpenAIRE]

109 references, page 1 of 8
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