Sequencing and imputation in GWAS: Cost-effective strategies to increase power and genomic coverage across diverse populations.
GWAS
WGS
genotype imputation
genotyping
rare variants
sequencing
study design
Journal
Genetic epidemiology
ISSN: 1098-2272
Titre abrégé: Genet Epidemiol
Pays: United States
ID NLM: 8411723
Informations de publication
Date de publication:
09 2020
09 2020
Historique:
received:
07
10
2019
revised:
02
04
2020
accepted:
22
05
2020
pubmed:
11
6
2020
medline:
22
5
2021
entrez:
11
6
2020
Statut:
ppublish
Résumé
A key aim for current genome-wide association studies (GWAS) is to interrogate the full spectrum of genetic variation underlying human traits, including rare variants, across populations. Deep whole-genome sequencing is the gold standard to fully capture genetic variation, but remains prohibitively expensive for large sample sizes. Array genotyping interrogates a sparser set of variants, which can be used as a scaffold for genotype imputation to capture a wider set of variants. However, imputation quality depends crucially on reference panel size and genetic distance from the target population. Here, we consider sequencing a subset of GWAS participants and imputing the rest using a reference panel that includes both sequenced GWAS participants and an external reference panel. We investigate how imputation quality and GWAS power are affected by the number of participants sequenced for admixed populations (African and Latino Americans) and European population isolates (Sardinians and Finns), and identify powerful, cost-effective GWAS designs given current sequencing and array costs. For populations that are well-represented in existing reference panels, we find that array genotyping alone is cost-effective and well-powered to detect common- and rare-variant associations. For poorly represented populations, sequencing a subset of participants is often most cost-effective, and can substantially increase imputation quality and GWAS power.
Identifiants
pubmed: 32519380
doi: 10.1002/gepi.22326
pmc: PMC7449570
mid: NIHMS1615007
doi:
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
537-549Subventions
Organisme : NHLBI NIH HHS
ID : K01 HL140218
Pays : United States
Organisme : NHGRI NIH HHS
ID : T32 HG000040
Pays : United States
Organisme : NHGRI NIH HHS
ID : R56 HG000376
Pays : United States
Organisme : NIH HHS
ID : N01-AG-1-2109
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK020572
Pays : United States
Organisme : NIGMS NIH HHS
ID : RL5 GM118984
Pays : United States
Organisme : NIDA NIH HHS
ID : HHSN271201100005C
Pays : United States
Organisme : NHGRI NIH HHS
ID : R01 HG009976
Pays : United States
Informations de copyright
© 2020 The Authors. Genetic Epidemiology Published by Wiley Periodicals LLC.
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