. 2015 Jul 21;5(7):e607.

doi: 10.1038/tp.2015.99.

Analysis of exome sequence in 604 trios for recessive genotypes in schizophrenia

E Rees¹, G Kirov¹, J T Walters¹, A L Richards¹, D Howrigan², D H Kavanagh³, A J Pocklington¹, M Fromer⁴, D M Ruderfer³, L Georgieva¹, N Carrera¹, P Gormley⁵, P Palta⁶, H Williams⁷, S Dwyer⁸, J S Johnson³, P Roussos³, D D Barker⁹, E Banks⁵, V Milanova¹⁰, S A Rose³, K Chambert⁹, M Mahajan³, E M Scolnick⁹, J L Moran⁹, M T Tsuang¹¹, S J Glatt¹², W J Chen¹³, H-G Hwu¹⁴; Taiwanese Trios Exome Sequencing Consortium; B M Neale¹⁵, A Palotie⁵, P Sklar³, S M Purcell⁴, S A McCarroll¹⁶, P Holmans¹, M J Owen¹⁷, M C O'Donovan¹

Collaborators, Affiliations

Collaborators

Taiwanese Trios Exome Sequencing Consortium:
Stephen V Faraone, Cheri A Roe, Sharon D Chandler, Chih-Min Liu, Chen-Chung Liu, Ling-Ling Yeh, Wen-Chen Ouyang, Hung-Yu Chan, Chun-Ying Chen

Affiliations

¹ Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK.
² Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
³ Division of Psychiatric Genomics, Department of Psychiatry, Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁴ 1] Division of Psychiatric Genomics, Department of Psychiatry, Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA [2] Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁵ Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁶ Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.
⁷ GOSgene,ICH Genetics and Genomic Medicine Program, Institute of Child Health, Faculty of Population Health Sciences, University College London, London, UK.
⁸ Molecular Genetics and Genomics, National Heart and Lung Institute, Imperial College London, London, UK.
⁹ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
¹⁰ Department of Psychiatry, Medical University, Sofia, Bulgaria.
¹¹ 1] Center for Behavioral Genomics and Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA, USA [2] Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA [3] Harvard Institute of Psychiatric Epidemiology and Genetics, Boston, MA, USA.
¹² Psychiatric Genetic Epidemiology and Neurobiology Laboratory (PsychGENe Lab); Department of Psychiatry and Behavioral Sciences, SUNY Upstate Medical University, Syracuse, NY, USA.
¹³ Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan.
¹⁴ 1] Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan [2] Department of Psychiatry, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan.
¹⁵ 1] Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA [2] Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
¹⁶ 1] Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA [2] Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA [3] Department of Genetics, Harvard Medical School, Boston, MA, USA.
¹⁷ Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Neuroscience and Mental Health Research Institute, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK.

PMID: 26196440
PMCID: PMC5068730
DOI: 10.1038/tp.2015.99

Analysis of exome sequence in 604 trios for recessive genotypes in schizophrenia

E Rees et al. Transl Psychiatry. 2015.

. 2015 Jul 21;5(7):e607.

doi: 10.1038/tp.2015.99.

Authors

Collaborators

Taiwanese Trios Exome Sequencing Consortium:
Stephen V Faraone, Cheri A Roe, Sharon D Chandler, Chih-Min Liu, Chen-Chung Liu, Ling-Ling Yeh, Wen-Chen Ouyang, Hung-Yu Chan, Chun-Ying Chen

Affiliations

¹ Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK.
² Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
³ Division of Psychiatric Genomics, Department of Psychiatry, Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁴ 1] Division of Psychiatric Genomics, Department of Psychiatry, Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA [2] Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁵ Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁶ Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.
⁷ GOSgene,ICH Genetics and Genomic Medicine Program, Institute of Child Health, Faculty of Population Health Sciences, University College London, London, UK.
⁸ Molecular Genetics and Genomics, National Heart and Lung Institute, Imperial College London, London, UK.
⁹ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
¹⁰ Department of Psychiatry, Medical University, Sofia, Bulgaria.
¹¹ 1] Center for Behavioral Genomics and Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA, USA [2] Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA [3] Harvard Institute of Psychiatric Epidemiology and Genetics, Boston, MA, USA.
¹² Psychiatric Genetic Epidemiology and Neurobiology Laboratory (PsychGENe Lab); Department of Psychiatry and Behavioral Sciences, SUNY Upstate Medical University, Syracuse, NY, USA.
¹³ Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan.
¹⁴ 1] Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan [2] Department of Psychiatry, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan.
¹⁵ 1] Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA [2] Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
¹⁶ 1] Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA [2] Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA [3] Department of Genetics, Harvard Medical School, Boston, MA, USA.
¹⁷ Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Neuroscience and Mental Health Research Institute, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK.

PMID: 26196440
PMCID: PMC5068730
DOI: 10.1038/tp.2015.99

Abstract

Genetic associations involving both rare and common alleles have been reported for schizophrenia but there have been no systematic scans for rare recessive genotypes using fully phased trio data. Here, we use exome sequencing in 604 schizophrenia proband-parent trios to investigate the role of recessive (homozygous or compound heterozygous) nonsynonymous genotypes in the disorder. The burden of recessive genotypes was not significantly increased in probands at either a genome-wide level or in any individual gene after adjustment for multiple testing. At a system level, probands had an excess of nonsynonymous compound heterozygous genotypes (minor allele frequency, MAF ⩽ 1%) in voltage-gated sodium channels (VGSCs; eight in probands and none in parents, P = 1.5 × 10(-)(4)). Previous findings of multiple de novo loss-of-function mutations in this gene family, particularly SCN2A, in autism and intellectual disability provide biological and genetic plausibility for this finding. Pointing further to the involvement of VGSCs in schizophrenia, we found that these genes were enriched for nonsynonymous mutations (MAF ⩽ 0.1%) in cases genotyped using an exome array, (5585 schizophrenia cases and 8103 controls), and that in the trios data, synaptic proteins interacting with VGSCs were also enriched for both compound heterozygosity (P = 0.018) and de novo mutations (P = 0.04). However, we were unable to replicate the specific association with compound heterozygosity at VGSCs in an independent sample of Taiwanese schizophrenia trios (N = 614). We conclude that recessive genotypes do not appear to make a substantial contribution to schizophrenia at a genome-wide level. Although multiple lines of evidence, including several from this study, suggest that rare mutations in VGSCs contribute to the disorder, in the absence of replication of the original findings regarding compound heterozygosity, this conclusion requires evaluation in a larger sample of trios.

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References

1. Fromer M, Pocklington AJ, Kavanagh DH, Williams HJ, Dwyer S, Gormley P et al. De novo mutations in schizophrenia implicate synaptic networks. Nature 2014; 506: 179–184. - PMC - PubMed
1. Purcell SM, Moran JL, Fromer M, Ruderfer D, Solovieff N, Roussos P et al. A polygenic burden of rare disruptive mutations in schizophrenia. Nature 2014; 506: 185–190. - PMC - PubMed
1. Rees E, Walters JTR, Georgieva L, Isles AR, Chambert KD, Richards AL et al. Analysis of copy number variations at 15 schizophrenia-associated loci. Br J Psychiatry 2014; 204: 108–114. - PMC - PubMed
1. International Schizophrenia Consortium, Purcell SM, Wray NR, Stone JL, Visscher PM, O'Donovan MC et al. Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature 2009; 460: 748–752. - PMC - PubMed
1. Stefansson H, Ophoff RA, Steinberg S, Andreassen OA, Cichon S, Rujescu D et al. Common variants conferring risk of schizophrenia. Nature 2009; 460: 744–747. - PMC - PubMed

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Analysis of exome sequence in 604 trios for recessive genotypes in schizophrenia

Collaborators

Affiliations

Analysis of exome sequence in 604 trios for recessive genotypes in schizophrenia

Authors

Collaborators

Affiliations

Abstract

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical

Molecular Biology Databases