Accounting for age of onset and family history improves power in genome-wide association studies.
ADHD
LT-FH
LT-FH++
UKBB
age-of-onset
family history
genome-wide association study
iPSYCH
liability threshold model
mortality
Journal
American journal of human genetics
ISSN: 1537-6605
Titre abrégé: Am J Hum Genet
Pays: United States
ID NLM: 0370475
Informations de publication
Date de publication:
03 03 2022
03 03 2022
Historique:
received:
16
07
2021
accepted:
07
01
2022
pubmed:
10
2
2022
medline:
3
5
2022
entrez:
9
2
2022
Statut:
ppublish
Résumé
Genome-wide association studies (GWASs) have revolutionized human genetics, allowing researchers to identify thousands of disease-related genes and possible drug targets. However, case-control status does not account for the fact that not all controls may have lived through their period of risk for the disorder of interest. This can be quantified by examining the age-of-onset distribution and the age of the controls or the age of onset for cases. The age-of-onset distribution may also depend on information such as sex and birth year. In addition, family history is not routinely included in the assessment of control status. Here, we present LT-FH++, an extension of the liability threshold model conditioned on family history (LT-FH), which jointly accounts for age of onset and sex as well as family history. Using simulations, we show that, when family history and the age-of-onset distribution are available, the proposed approach yields statistically significant power gains over LT-FH and large power gains over genome-wide association study by proxy (GWAX). We applied our method to four psychiatric disorders available in the iPSYCH data and to mortality in the UK Biobank and found 20 genome-wide significant associations with LT-FH++, compared to ten for LT-FH and eight for a standard case-control GWAS. As more genetic data with linked electronic health records become available to researchers, we expect methods that account for additional health information, such as LT-FH++, to become even more beneficial.
Identifiants
pubmed: 35139346
pii: S0002-9297(22)00009-X
doi: 10.1016/j.ajhg.2022.01.009
pmc: PMC8948165
pii:
doi:
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
417-432Informations de copyright
Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests J.C. has received honoraria for serving on the Scientific Advisory Board of Union Chimique Belge (UCB) Nordic and Eisai AB and for giving lectures for UCB Nordic and Eisai as well as travel funds from UCB Nordic and funding by the Novo Nordisk Foundation (grant number: NNF16OC0019126), the Central Denmark Region, and the Danish Epilepsy Association.
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