TY - JOUR
T1 - Population-based identity-by-descent mapping combined with exome sequencing to detect rare risk variants for schizophrenia
AU - Trust Case Control Consortium
AU - Psychiatric Genomics Consortium
AU - Schizophrenia Working Group of the Psychiatric Genomics Consortium, SWE-SCZ 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
A2 - Donnelly, Peter
A2 - Bates, Lesley
A2 - Barroso, Ines
A2 - Blackwell, Jenefer M.
A2 - Bramon, Elvira
A2 - Brown, Matthew A.
A2 - Casas, Juan P.
A2 - Corvin, Aiden
A2 - Deloukas, Panos
A2 - Duncanson, Audrey
A2 - Jankowski, Janusz
A2 - Markus, Hugh S.
A2 - Mathew, Christopher G.
A2 - Palmer, Colin N.A.
A2 - Plomin, Robert
A2 - Rautanen, Anna
A2 - Sawcer, Stephen J.
A2 - Trembath, Richard C.
A2 - Viswanathan, Ananth C.
A2 - Wood, Nicholas W.
A2 - Spencer, Chris C.A.
A2 - Band, Gavin
A2 - Bellenguez, Céline
A2 - Freeman, Colin
A2 - Hellenthal, Garrett
A2 - Giannoulatou, Eleni
A2 - Hopkins, Lucinda
A2 - Pirinen, Matti
A2 - Pearson, Richard
A2 - Strange, Amy
A2 - Su, Zhan
A2 - Vukcevic, Damjan
A2 - Langford, Cordelia
A2 - Hunt, Sarah E.
A2 - Edkins, Sarah
A2 - Gwilliam, Rhian
A2 - Blackburn, Hannah
A2 - Bumpstead, Suzannah J.
A2 - Dronov, Serge
A2 - Nikitina-Zake, Liene
N1 - Funding Information:
We wish to thank all patients and their support staff, and all healthy volunteers for participating in the data collection on which this manuscript is based. Recruitment, genotyping, and analysis were supported by Science Foundation Ireland grants (12/IP/1670, 12/IP/1359, and 08/IN.1/B1916), US National Institutes of Health grants (R01-MH083094 and R01-MH041953) and the Wellcome Trust Case Control Consortium 2 project grant (085475/B/08/Z). We thank EMI author Yu Qian for providing a script to convert EMI cluster files to plink format. CSHL funding was from a generous gift of The Stanley Family. We acknowledge the support of the Trinity Biobank in providing control samples for this analysis.
Funding Information:
National Institutes of Health, Grant/Award Numbers: R01-MH041953, R01-MH083094; Science Foundation Ireland, Grant/Award Numbers: 08/IN.1/B1916, 12/IP/1359, 12/ IP/1670; Wellcome Trust, Grant/Award Number: 085475/B/08/Z
Funding Information:
We wish to thank all patients and their support staff, and all healthy volunteers for participating in the data collection on which this manuscript is based. Recruitment, genotyping, and analysis were supported by Science Foundation Ireland grants (12/IP/1670, 12/IP/1359, and 08/IN.1/ B1916), US National Institutes of Health grants (R01-MH083094 and R01-MH041953) and the Wellcome Trust Case Control Consortium 2 project grant (085475/B/08/Z). We thank EMI author Yu Qian for providing a script to convert EMI cluster files to plink format. CSHL funding was from a generous gift of The Stanley Family. We acknowledge the support of the Trinity Biobank in providing control samples for this analysis.
Publisher Copyright:
© 2019 Wiley Periodicals, Inc.
PY - 2019/4
Y1 - 2019/4
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 -