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

Wellcome Trust Case Control Consortium 2, Schizophrenia Working Group of the Psychiatric Genomics Consortium

Research output: Contribution to journalArticle

Abstract

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
Pages (from-to)223-231
Number of pages9
JournalAmerican Journal of Medical Genetics, Part B: Neuropsychiatric Genetics
Volume180
Issue number3
DOIs
Publication statusPublished - 01-04-2019

Fingerprint

Exome
Haplotypes
Genome-Wide Association Study
Schizophrenia
Population
Genome

All Science Journal Classification (ASJC) codes

  • Genetics(clinical)
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience

Cite this

Wellcome Trust Case Control Consortium 2 ; Schizophrenia Working Group of the Psychiatric Genomics Consortium. / Population-based identity-by-descent mapping combined with exome sequencing to detect rare risk variants for schizophrenia. In: American Journal of Medical Genetics, Part B: Neuropsychiatric Genetics. 2019 ; Vol. 180, No. 3. pp. 223-231.
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abstract = "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.",
author = "{Wellcome Trust Case Control Consortium 2} and {Schizophrenia Working Group of the Psychiatric Genomics Consortium} and Denise Harold and Siobhan Connolly and Riley, {Brien P.} and Kendler, {Kenneth S.} and McCarthy, {Shane E.} and McCombie, {William R.} and Alex Richards and Owen, {Michael J.} and O'Donovan, {Michael C.} and James Walters and Peter Donnelly and Lesley Bates and Ines Barroso and Blackwell, {Jenefer M.} and Elvira Bramon and Brown, {Matthew A.} and Casas, {Juan P.} and Aiden Corvin and Panos Deloukas and Audrey Duncanson and Janusz Jankowski and Markus, {Hugh S.} and Mathew, {Christopher G.} and Palmer, {Colin N.A.} and Robert Plomin and Anna Rautanen and Sawcer, {Stephen J.} and Trembath, {Richard C.} and Viswanathan, {Ananth C.} and Wood, {Nicholas W.} and Spencer, {Chris C.A.} and Gavin Band and C{\'e}line Bellenguez and Colin Freeman and Garrett Hellenthal and Eleni Giannoulatou and Lucinda Hopkins and Matti Pirinen and Richard Pearson and Amy Strange and Zhan Su and Damjan Vukcevic and Cordelia Langford and Hunt, {Sarah E.} and Sarah Edkins and Rhian Gwilliam and Hannah Blackburn and Bumpstead, {Suzannah J.} and Masashi Ikeda and Nakao Iwata",
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Population-based identity-by-descent mapping combined with exome sequencing to detect rare risk variants for schizophrenia. / Wellcome Trust Case Control Consortium 2; Schizophrenia Working Group of the Psychiatric Genomics Consortium.

In: American Journal of Medical Genetics, Part B: Neuropsychiatric Genetics, Vol. 180, No. 3, 01.04.2019, p. 223-231.

Research output: Contribution to journalArticle

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AU - Wellcome Trust Case Control Consortium 2

AU - Schizophrenia Working Group of the Psychiatric Genomics Consortium

AU - Harold, Denise

AU - Connolly, Siobhan

AU - Riley, Brien P.

AU - Kendler, Kenneth S.

AU - McCarthy, Shane E.

AU - McCombie, William R.

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AU - Markus, Hugh S.

AU - Mathew, Christopher G.

AU - Palmer, Colin N.A.

AU - Plomin, Robert

AU - Rautanen, Anna

AU - Sawcer, Stephen J.

AU - Trembath, Richard C.

AU - Viswanathan, Ananth C.

AU - Wood, Nicholas W.

AU - Spencer, Chris C.A.

AU - Band, Gavin

AU - Bellenguez, Céline

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AU - Hellenthal, Garrett

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AU - Su, Zhan

AU - Vukcevic, Damjan

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AU - Hunt, Sarah E.

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AU - Bumpstead, Suzannah J.

AU - Ikeda, Masashi

AU - Iwata, Nakao

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