ProxECAT: Proxy External Controls Association Test. A new case-control gene region association test using allele frequencies from public controls

A primary goal of the recent investment in sequencing is to detect novel genetic associations in health and disease improving the development of treatments and playing a critical role in precision medicine. While this investment has resulted in an enormous total number of sequenced genomes, individu...

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Vydáno v:PLoS genetics Ročník 14; číslo 10; s. e1007591
Hlavní autoři: Hendricks, Audrey E., Billups, Stephen C., Pike, Hamish N. C., Farooqi, I. Sadaf, Zeggini, Eleftheria, Santorico, Stephanie A., Barroso, Inês, Dupuis, Josée
Médium: Journal Article
Jazyk:angličtina
Vydáno: United States Public Library of Science 01.10.2018
Public Library of Science (PLoS)
Témata:
Alleles
Biology and Life Sciences
Biomedical research
Consortia
Disease
Gene frequency
Genetic resources
Genetics
Genomes
Genomics
Hypotheses
Informatics
Laboratories
Metabolism
Methods
Mutation
Obesity
Physical Sciences
Population genetics
Precision medicine
Public health
Research and Analysis Methods
Social Sciences
United Kingdom > UK
United States > US
Colorado
ISSN:1553-7404, 1553-7390, 1553-7404
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Popis
Shrnutí:A primary goal of the recent investment in sequencing is to detect novel genetic associations in health and disease improving the development of treatments and playing a critical role in precision medicine. While this investment has resulted in an enormous total number of sequenced genomes, individual studies of complex traits and diseases are often smaller and underpowered to detect rare variant genetic associations. Existing genetic resources such as the Exome Aggregation Consortium (>60,000 exomes) and the Genome Aggregation Database (~140,000 sequenced samples) have the potential to be used as controls in these studies. Fully utilizing these and other existing sequencing resources may increase power and could be especially useful in studies where resources to sequence additional samples are limited. However, to date, these large, publicly available genetic resources remain underutilized, or even misused, in large part due to the lack of statistical methods that can appropriately use this summary level data. Here, we present a new method to incorporate external controls in case-control analysis called ProxECAT (Proxy External Controls Association Test). ProxECAT estimates enrichment of rare variants within a gene region using internally sequenced cases and external controls. We evaluated ProxECAT in simulations and empirical analyses of obesity cases using both low-depth of coverage (7x) whole-genome sequenced controls and ExAC as controls. We find that ProxECAT maintains the expected type I error rate with increased power as the number of external controls increases. With an accompanying R package, ProxECAT enables the use of publicly available allele frequencies as external controls in case-control analysis.
Bibliografie:ObjectType-Article-1
SourceType-Scholarly Journals-1
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The authors have declared that no competing interests exist.
ISSN:1553-7404
1553-7390
1553-7404
DOI:10.1371/journal.pgen.1007591