title: Analysis of exome sequence in 604 trios for recessive genotypes in schizophrenia.
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.
authors.affiliation: Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK.
authors.forename: E
authors.initials: E
authors.lastname: Rees
authors.affiliation: Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK.
authors.forename: G
authors.initials: G
authors.lastname: Kirov
authors.affiliation: Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK.
authors.forename: J T
authors.initials: JT
authors.lastname: Walters
authors.affiliation: Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK.
authors.forename: A L
authors.initials: AL
authors.lastname: Richards
authors.affiliation: Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: D
authors.initials: D
authors.lastname: Howrigan
authors.affiliation: Division of Psychiatric Genomics, Department of Psychiatry, Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: D H
authors.initials: DH
authors.lastname: Kavanagh
authors.affiliation: Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK.
authors.forename: A J
authors.initials: AJ
authors.lastname: Pocklington
authors.affiliation: 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.
authors.forename: M
authors.initials: M
authors.lastname: Fromer
authors.affiliation: Division of Psychiatric Genomics, Department of Psychiatry, Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: D M
authors.initials: DM
authors.lastname: Ruderfer
authors.affiliation: Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK.
authors.forename: L
authors.initials: L
authors.lastname: Georgieva
authors.affiliation: Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK.
authors.forename: N
authors.initials: N
authors.lastname: Carrera
authors.affiliation: Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
authors.forename: P
authors.initials: P
authors.lastname: Gormley
authors.affiliation: Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.
authors.forename: P
authors.identifier: 0000000193207008
authors.initials: P
authors.lastname: Palta
authors.affiliation: GOSgene,ICH Genetics and Genomic Medicine Program, Institute of Child Health, Faculty of Population Health Sciences, University College London, London, UK.
authors.forename: H
authors.initials: H
authors.lastname: Williams
authors.affiliation: Molecular Genetics and Genomics, National Heart and Lung Institute, Imperial College London, London, UK.
authors.forename: S
authors.initials: S
authors.lastname: Dwyer
authors.affiliation: Division of Psychiatric Genomics, Department of Psychiatry, Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: J S
authors.initials: JS
authors.lastname: Johnson
authors.affiliation: Division of Psychiatric Genomics, Department of Psychiatry, Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: P
authors.initials: P
authors.lastname: Roussos
authors.affiliation: Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
authors.forename: D D
authors.initials: DD
authors.lastname: Barker
authors.affiliation: Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
authors.forename: E
authors.initials: E
authors.lastname: Banks
authors.affiliation: Department of Psychiatry, Medical University, Sofia, Bulgaria.
authors.forename: V
authors.initials: V
authors.lastname: Milanova
authors.affiliation: Division of Psychiatric Genomics, Department of Psychiatry, Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: S A
authors.initials: SA
authors.lastname: Rose
authors.affiliation: Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
authors.forename: K
authors.initials: K
authors.lastname: Chambert
authors.affiliation: Division of Psychiatric Genomics, Department of Psychiatry, Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: M
authors.initials: M
authors.lastname: Mahajan
authors.affiliation: Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
authors.forename: E M
authors.initials: EM
authors.lastname: Scolnick
authors.affiliation: Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
authors.forename: J L
authors.initials: JL
authors.lastname: Moran
authors.affiliation: 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.
authors.forename: M T
authors.initials: MT
authors.lastname: Tsuang
authors.affiliation: Psychiatric Genetic Epidemiology and Neurobiology Laboratory (PsychGENe Lab); Department of Psychiatry and Behavioral Sciences, SUNY Upstate Medical University, Syracuse, NY, USA.
authors.forename: S J
authors.initials: SJ
authors.lastname: Glatt
authors.affiliation: Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan.
authors.forename: W J
authors.initials: WJ
authors.lastname: Chen
authors.affiliation: 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.
authors.forename: H-G
authors.initials: HG
authors.lastname: Hwu
authors.affiliation: 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.
authors.forename: B M
authors.initials: BM
authors.lastname: Neale
authors.affiliation: Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Palotie
authors.affiliation: Division of Psychiatric Genomics, Department of Psychiatry, Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: P
authors.initials: P
authors.lastname: Sklar
authors.affiliation: 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.
authors.forename: S M
authors.initials: SM
authors.lastname: Purcell
authors.affiliation: 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.
authors.forename: S A
authors.initials: SA
authors.lastname: McCarroll
authors.affiliation: Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK.
authors.forename: P
authors.initials: P
authors.lastname: Holmans
authors.affiliation: 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.
authors.forename: M J
authors.initials: MJ
authors.lastname: Owen
authors.affiliation: Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK.
authors.forename: M C
authors.initials: MC
authors.lastname: O'Donovan
mesh_terms: D016022:Case-Control Studies; D059472:Exome / Q000235:genetics*; D005190:Family; D005260:Female; D005787:Gene Frequency; D005808:Genes, Recessive / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008297:Male; D012559:Schizophrenia / Q000235:genetics*; D061566:Voltage-Gated Sodium Channels / Q000235:genetics
chemical_list: D061566:Voltage-Gated Sodium Channels