Abstract
Fifty Years On: GWAS Confirms the Role of a Rare Variant in Lung Disease
Highlights
The approach used by Thun et al.—the sequencing of SERPINA1, fine mapping, and a conditional approach to statistical analysis in the regression model—does not depend on knowing the rare variants on which models need to be conditioned, and was able to reliably identify known variants with minor allele frequencies (MAF) 1%– 5%
Thun et al could use their analyses to begin to address the longstanding debate regarding the role of alpha one antitrypsin deficiency (AATD) in lung disease at the population level
Since rare variant analysis is a topic of great interest to genetic epidemiologists at present, it is worth reprising how understanding AATD has moved clinical medicine forward
Summary
The approach used by Thun et al.—the sequencing of SERPINA1, fine mapping, and a conditional approach to statistical analysis in the regression model—does not depend on knowing the rare variants on which models need to be conditioned, and was able to reliably identify known variants with MAF 1%– 5%. The clinical relevance of this work was demonstrated by looking at lung function as the outcome, this revealed a more complex scenario. Several ideas have been proposed to explain this ‘‘missing heritability,’’ including gene–environment interaction, reduced power of GWAS to detect functional variants due to low levels of linkage disequilibrium with causative SNPs, and undetected rare variants.
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