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

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@article{13f6a2b502674683ab9fab6f1e70973d,
title = "Population-based identity-by-descent mapping combined with exome sequencing to detect rare risk variants for schizophrenia",
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 = "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 Gary Donohoe and Michael Gill and Aiden Corvin and Morris, {Derek W} and {Wellcome Trust Case Control Consortium 2} and Werge, {Thomas Mears}",
note = "{\circledC} 2019 Wiley Periodicals, Inc.",
year = "2019",
month = "4",
doi = "10.1002/ajmg.b.32716",
language = "English",
volume = "180",
pages = "223--231",
journal = "American Journal of Medical Genetics, Part B: Neuropsychiatric Genetics",
issn = "1552-4841",
publisher = "JohnWiley & Sons, Inc",
number = "3",

}

RIS

TY - JOUR

T1 - Population-based identity-by-descent mapping combined with exome sequencing to detect rare risk variants for schizophrenia

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

AU - Donohoe, Gary

AU - Gill, Michael

AU - Corvin, Aiden

AU - Morris, Derek W

AU - Wellcome Trust Case Control Consortium 2

A2 - Werge, Thomas Mears

N1 - © 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.

U2 - 10.1002/ajmg.b.32716

DO - 10.1002/ajmg.b.32716

M3 - Journal article

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

SN - 1552-4841

IS - 3

ER -

ID: 59085578