publication . Preprint . Article . Other literature type . 2018

Weighted Burden Analysis of Exome-Sequenced Case-Control Sample Implicates Synaptic Genes in Schizophrenia Aetiology.

Curtis, David; Coelewij, Leda; Liu, Shou-Hwa; Humphrey, Jack; Mott, Richard;
Open Access English
  • Published: 21 Mar 2018
  • Publisher: Cold Spring Harbor Laboratory
Abstract
A previous study of exome-sequenced schizophrenia cases and controls reported an excess of singleton, gene-disruptive variants among cases, concentrated in particular gene sets. The dataset included a number of subjects with a substantial Finnish contribution to ancestry. We have reanalysed the same dataset after removal of these subjects and we have also included non-singleton variants of all types using a weighted burden test which assigns higher weights to variants predicted to have a greater effect on protein function. We investigated the same 31 gene sets as previously and also 1454 GO gene sets. The reduced dataset consisted of 4225 cases and 5834 controls...
Subjects
free text keywords: Genetics(clinical), Genetics, Ecology, Evolution, Behavior and Systematics, Exome, Exome sequencing, Biology, Candidate gene, GRIN2B, biology.protein, GRIN1, Genome-wide association study, Gene, Bonferroni correction, symbols.namesake, symbols, FYN, Original Research, Schizophrenia, Weighted burden test, FYN, FMRP target
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
,
NHMRC| Uncoupled Research Fellowship
Project
  • Funder: National Health and Medical Research Council (NHMRC) (NHMRC)
  • Project Code: 516702
  • Funding stream: NHMRC Research Fellowships
53 references, page 1 of 4

Adzhubei, I, Jordan, DM, Sunyaev, SR. Predicting functional effect of human missense mutations using PolyPhen-2. Curr Protoc Hum Genet. 2013 [OpenAIRE] [PubMed]

Ali, DW, Salter, MW. NMDA receptor regulation by Src kinase signalling in excitatory synaptic transmission and plasticity. Curr Opin Neurobiol. 2001; 11: 336-342 [OpenAIRE] [PubMed] [DOI]

Bayés, A, van de Lagemaat, LN, Collins, MO, Croning, MDR, Whittle, IR, Choudhary, JS, Grant, SGN. Characterization of the proteome, diseases and evolution of the human postsynaptic density. Nat Neurosci. 2011; 14: 19-21 [OpenAIRE] [PubMed] [DOI]

Blake, JA, Eppig, JT, Kadin, JA, Richardson, JE, Smith, CL, Bult, CJ. Mouse genome database (MGD)-2017: community knowledge resource for the laboratory mouse. Nucleic Acids Res. 2017; 45: D723-D729 [OpenAIRE] [PubMed] [DOI]

Boyle, EA, Li, YI, Pritchard, JK, Gordon, S, Henders, AK, Nyholt, DR, Madden, PA, Heath, AC, Martin, NG, Montgomery, GW, Al, E, Consortium, M, Consortium, P, Study, LC, Al, E, Consortium, GLGG, Investigators, M, Al, E, Consortium, M, Consortium, P, Consortium, R, Consortium, GLGG, Consortium, IE. Al an expanded view of complex traits: from polygenic to omnigenic. Cell. 2017; 169: 1177-1186 [OpenAIRE] [PubMed] [DOI]

Cahoy, JD, Emery, B, Kaushal, A, Foo, LC, Zamanian, JL, Christopherson, KS, Xing, Y, Lubischer, JL, Krieg, PA, Krupenko, SA, Thompson, WJ, Barres, BA. A transcriptome database for astrocytes, neurons, and oligodendrocytes: a new resource for understanding brain development and function. J Neurosci. 2008; 28: 264-278 [OpenAIRE] [PubMed] [DOI]

Cotton, AM, Ge, B, Light, N, Adoue, V, Pastinen, T, Brown, CJ. Analysis of expressed SNPs identifies variable extents of expression from the human inactive X chromosome. Genome Biol. 2013; 14: R122 [OpenAIRE] [PubMed] [DOI]

Curtis, D. Assessing the contribution family data can make to case-control studies of rare variants. Ann Hum Genet. 2011; 75: 630-638 [OpenAIRE] [PubMed] [DOI]

Curtis, D. A rapid method for combined analysis of common and rare variants at the level of a region, gene, or pathway. Adv Appl Bioinform Chem. 2012; 5: 1-9 [OpenAIRE] [PubMed]

Curtis, D. Approaches to the detection of recessive effects using next generation sequencing data from outbred populations. Adv Appl Bioinform Chem. 2013; 6: 29 [OpenAIRE] [PubMed]

Curtis, D. Investigation of recessive effects in schizophrenia using next-generation exome sequence data. Ann Hum Genet. 2015

Curtis, D. Pathway analysis of whole exome sequence data provides further support for the involvement of histone modification in the aetiology of schizophrenia. Psychiatr Genet. 2016; 26: 223-227 [OpenAIRE] [PubMed] [DOI]

Curtis, D. Construction of an exome-wide risk score for schizophrenia based on a weighted burden test. Ann Hum Genet. 2017

Curtis, D, Emmett, W. Association study of schizophrenia with variants in miR-137 binding sites. Schizophr Res. 2017 [OpenAIRE] [PubMed]

Darnell, JC, Van Driesche, SJ, Zhang, C, Hung, KYS, Mele, A, Fraser, CE, Stone, EF, Chen, C, Fak, JJ, Chi, SW, Licatalosi, DD, Richter, JD, Darnell, RB. FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism. Cell. 2011; 146: 247-261 [OpenAIRE] [PubMed] [DOI]

53 references, page 1 of 4
Abstract
A previous study of exome-sequenced schizophrenia cases and controls reported an excess of singleton, gene-disruptive variants among cases, concentrated in particular gene sets. The dataset included a number of subjects with a substantial Finnish contribution to ancestry. We have reanalysed the same dataset after removal of these subjects and we have also included non-singleton variants of all types using a weighted burden test which assigns higher weights to variants predicted to have a greater effect on protein function. We investigated the same 31 gene sets as previously and also 1454 GO gene sets. The reduced dataset consisted of 4225 cases and 5834 controls...
Subjects
free text keywords: Genetics(clinical), Genetics, Ecology, Evolution, Behavior and Systematics, Exome, Exome sequencing, Biology, Candidate gene, GRIN2B, biology.protein, GRIN1, Genome-wide association study, Gene, Bonferroni correction, symbols.namesake, symbols, FYN, Original Research, Schizophrenia, Weighted burden test, FYN, FMRP target
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
,
NHMRC| Uncoupled Research Fellowship
Project
  • Funder: National Health and Medical Research Council (NHMRC) (NHMRC)
  • Project Code: 516702
  • Funding stream: NHMRC Research Fellowships
53 references, page 1 of 4

Adzhubei, I, Jordan, DM, Sunyaev, SR. Predicting functional effect of human missense mutations using PolyPhen-2. Curr Protoc Hum Genet. 2013 [OpenAIRE] [PubMed]

Ali, DW, Salter, MW. NMDA receptor regulation by Src kinase signalling in excitatory synaptic transmission and plasticity. Curr Opin Neurobiol. 2001; 11: 336-342 [OpenAIRE] [PubMed] [DOI]

Bayés, A, van de Lagemaat, LN, Collins, MO, Croning, MDR, Whittle, IR, Choudhary, JS, Grant, SGN. Characterization of the proteome, diseases and evolution of the human postsynaptic density. Nat Neurosci. 2011; 14: 19-21 [OpenAIRE] [PubMed] [DOI]

Blake, JA, Eppig, JT, Kadin, JA, Richardson, JE, Smith, CL, Bult, CJ. Mouse genome database (MGD)-2017: community knowledge resource for the laboratory mouse. Nucleic Acids Res. 2017; 45: D723-D729 [OpenAIRE] [PubMed] [DOI]

Boyle, EA, Li, YI, Pritchard, JK, Gordon, S, Henders, AK, Nyholt, DR, Madden, PA, Heath, AC, Martin, NG, Montgomery, GW, Al, E, Consortium, M, Consortium, P, Study, LC, Al, E, Consortium, GLGG, Investigators, M, Al, E, Consortium, M, Consortium, P, Consortium, R, Consortium, GLGG, Consortium, IE. Al an expanded view of complex traits: from polygenic to omnigenic. Cell. 2017; 169: 1177-1186 [OpenAIRE] [PubMed] [DOI]

Cahoy, JD, Emery, B, Kaushal, A, Foo, LC, Zamanian, JL, Christopherson, KS, Xing, Y, Lubischer, JL, Krieg, PA, Krupenko, SA, Thompson, WJ, Barres, BA. A transcriptome database for astrocytes, neurons, and oligodendrocytes: a new resource for understanding brain development and function. J Neurosci. 2008; 28: 264-278 [OpenAIRE] [PubMed] [DOI]

Cotton, AM, Ge, B, Light, N, Adoue, V, Pastinen, T, Brown, CJ. Analysis of expressed SNPs identifies variable extents of expression from the human inactive X chromosome. Genome Biol. 2013; 14: R122 [OpenAIRE] [PubMed] [DOI]

Curtis, D. Assessing the contribution family data can make to case-control studies of rare variants. Ann Hum Genet. 2011; 75: 630-638 [OpenAIRE] [PubMed] [DOI]

Curtis, D. A rapid method for combined analysis of common and rare variants at the level of a region, gene, or pathway. Adv Appl Bioinform Chem. 2012; 5: 1-9 [OpenAIRE] [PubMed]

Curtis, D. Approaches to the detection of recessive effects using next generation sequencing data from outbred populations. Adv Appl Bioinform Chem. 2013; 6: 29 [OpenAIRE] [PubMed]

Curtis, D. Investigation of recessive effects in schizophrenia using next-generation exome sequence data. Ann Hum Genet. 2015

Curtis, D. Pathway analysis of whole exome sequence data provides further support for the involvement of histone modification in the aetiology of schizophrenia. Psychiatr Genet. 2016; 26: 223-227 [OpenAIRE] [PubMed] [DOI]

Curtis, D. Construction of an exome-wide risk score for schizophrenia based on a weighted burden test. Ann Hum Genet. 2017

Curtis, D, Emmett, W. Association study of schizophrenia with variants in miR-137 binding sites. Schizophr Res. 2017 [OpenAIRE] [PubMed]

Darnell, JC, Van Driesche, SJ, Zhang, C, Hung, KYS, Mele, A, Fraser, CE, Stone, EF, Chen, C, Fak, JJ, Chi, SW, Licatalosi, DD, Richter, JD, Darnell, RB. FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism. Cell. 2011; 146: 247-261 [OpenAIRE] [PubMed] [DOI]

53 references, page 1 of 4
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