TY - JOUR
T1 - Population-based identity-by-descent mapping combined with exome sequencing to detect rare risk variants for schizophrenia
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.
AU - Richards, Alex
AU - Owen, Michael J.
AU - O'Donovan, Michael C.
AU - Walters, James T.R.
AU - Donnelly, Peter
AU - Bates, Lesley
AU - Barroso, Ines
AU - Blackwell, Jenefer M.
AU - Bramon, Elvira
AU - Brown, Matthew A.
AU - Casas, Juan P.
AU - Corvin, Aiden
AU - Deloukas, Panos
AU - Duncanson, Audrey
AU - Jankowski, Janusz
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
AU - Freeman, Colin
AU - Hellenthal, Garrett
AU - Giannoulatou, Eleni
AU - Hopkins, Lucinda
AU - Pirinen, Matti
AU - Pearson, Richard
AU - Strange, Amy
AU - Su, Zhan
AU - Vukcevic, Damjan
AU - Langford, Cordelia
AU - Hunt, Sarah E.
AU - Edkins, Sarah
AU - Gwilliam, Rhian
AU - Blackburn, Hannah
AU - Bumpstead, Suzannah J.
AU - Sigurdsson, Engilbert
AU - Stefansson, Kari
N1 - Publisher Copyright:
© 2019 Wiley Periodicals, Inc.
PY - 2019/4/1
Y1 - 2019/4/1
N2 - 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.
AB - 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.
KW - GWAS
KW - IBD mapping
KW - rare variants
UR - http://www.scopus.com/inward/record.url?scp=85061993948&partnerID=8YFLogxK
U2 - 10.1002/ajmg.b.32716
DO - 10.1002/ajmg.b.32716
M3 - Article
C2 - 30801977
AN - SCOPUS:85061993948
SN - 1552-4841
VL - 180
SP - 223
EP - 231
JO - American Journal of Medical Genetics, Part B: Neuropsychiatric Genetics
JF - American Journal of Medical Genetics, Part B: Neuropsychiatric Genetics
IS - 3
ER -