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

Harold, Denise and Connolly, Siobhan and Riley, Brien P and Kendler, Kenneth S and McCarthy, Shane E and McCombie, William R and Richards, Alex and Owen, Michael J and O'Donovan, Michael C and Walters, James and Donohoe, Gary and Gill, Michael and Corvin, Aiden and Morris, Derek W and Knight, Jo (2019) Population-based identity-by-descent mapping combined with exome sequencing to detect rare risk variants for schizophrenia. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 180 (3). pp. 223-231. ISSN 1552-4841

[img]
Text (jok2)
jok2.pdf - Accepted Version
Available under License Creative Commons Attribution-NonCommercial.

Download (424kB)

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.

Item Type:
Journal Article
Journal or Publication Title:
American Journal of Medical Genetics Part B: Neuropsychiatric Genetics
Additional Information:
This is the peer reviewed version of the following article:Harold, D, Connolly, S, Riley, BP, et al. Population‐based identity‐by‐descent mapping combined with exome sequencing to detect rare risk variants for schizophrenia. Am J Med Genet Part B. 2019; 180B: 223– 231. https://doi.org/10.1002/ajmg.b.32716 which has been published in final form at https://onlinelibrary.wiley.com/doi/full/10.1002/ajmg.b.32716 This article may be used for non-commercial purposes in accordance With Wiley Terms and Conditions for self-archiving.
Uncontrolled Keywords:
/dk/atira/pure/subjectarea/asjc/2700/2738
Subjects:
ID Code:
135896
Deposited By:
Deposited On:
06 Aug 2019 13:05
Refereed?:
Yes
Published?:
Published
Last Modified:
27 Sep 2020 05:23