Department of Economics and Business Economics

Population-based identity-by-descent mapping combined with exome sequencing to detect rare risk variants for schizophrenia

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DOI

  • Denise Harold, Bioinformatics and Molecular Evolution Group, School of Biotechnology, Dublin City University, Glasnevin, Dublin 9, Ireland.
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  • Siobhan Connolly, Neuropsychiatric Genetics Research Group, Institute of Molecular Medicine and Discipline of Psychiatry, Trinity College Dublin, Dublin, Ireland.
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  • Brien P Riley, Departments of Psychiatry and Human Genetics, Virginia Institute of Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, Virginia.
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  • Kenneth S Kendler, Departments of Psychiatry and Human Genetics, Virginia Institute of Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, Virginia.
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  • Shane E McCarthy, The Stanley Institute for Cognitive Genomics, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York.
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  • William R McCombie, The Stanley Institute for Cognitive Genomics, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York.
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  • Alex Richards, MRC Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University, Heath Park, Cardiff, United Kingdom.
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  • Michael J Owen, MRC Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University, Heath Park, Cardiff, United Kingdom.
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  • Michael C O'Donovan, MRC Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University, Heath Park, Cardiff, United Kingdom.
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  • James Walters, MRC Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University, Heath Park, Cardiff, United Kingdom.
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  • Wellcome Trust Case Control Consortium 2
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  • The Schizophrenia Working Group of the Psychiatric Genomics Consortium
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  • Gary Donohoe, Cognitive Genetics and Cognitive Therapy Group, Neuroimaging, Cognition and Genomics Centre (NICOG) and NCBES Galway Neuroscience Centre, School of Psychology and Discipline of Biochemistry, National University of Ireland Galway, Galway, Ireland.
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  • Michael Gill, Neuropsychiatric Genetics Research Group, Institute of Molecular Medicine and Discipline of Psychiatry, Trinity College Dublin, Dublin, Ireland.
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  • Aiden Corvin, Neuropsychiatric Genetics Research Group, Institute of Molecular Medicine and Discipline of Psychiatry, Trinity College Dublin, Dublin, Ireland.
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  • Derek W Morris, Cognitive Genetics and Cognitive Therapy Group, Neuroimaging, Cognition and Genomics Centre (NICOG) and NCBES Galway Neuroscience Centre, School of Psychology and Discipline of Biochemistry, National University of Ireland Galway, Galway, Ireland.

Genome-wide association studies (GWASs) are highly effective at identifying common risk variants for schizophrenia. Rare risk variants are also important contributors to schizophrenia etiology but, with the exception of large copy number variants, are difficult to detect with GWAS. Exome and genome sequencing, which have accelerated the study of rare variants, are expensive so alternative methods are needed to aid detection of rare variants. Here we re-analyze an Irish schizophrenia GWAS dataset (n = 3,473) by performing identity-by-descent (IBD) mapping followed by exome sequencing of individuals identified as sharing risk haplotypes to search for rare risk variants in coding regions. We identified 45 rare haplotypes (>1 cM) that were significantly more common in cases than controls. By exome sequencing 105 haplotype carriers, we investigated these haplotypes for functional coding variants that could be tested for association in independent GWAS samples. We identified one rare missense variant in PCNT but did not find statistical support for an association with schizophrenia in a replication analysis. However, IBD mapping can prioritize both individual samples and genomic regions for follow-up analysis but genome rather than exome sequencing may be more effective at detecting risk variants on rare haplotypes.

Original languageEnglish
JournalAmerican Journal of Medical Genetics. Part B: Neuropsychiatric Genetics
Volume180
Issue3
Pages (from-to)223-231
Number of pages9
ISSN1552-4841
DOIs
Publication statusPublished - Apr 2019

    Research areas

  • GWAS, IBD mapping, rare variants

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