Accounting for population structure in genetic studies of cystic fibrosis

CFTR F508del (c.1521_1523delCTT, p.Phe508delPhe) is the most common pathogenic allele underlying cystic fibrosis (CF), and its frequency varies in a geographic cline across Europe. We hypothesized that genetic variation associated with this cline is overrepresented in a large cohort (N > 5,000) o...

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Published in:HGG advances Vol. 3; no. 3; p. 100117
Main Authors: Kingston, Hanley, Stilp, Adrienne M., Gordon, William, Broome, Jai, Gogarten, Stephanie M., Ling, Hua, Barnard, John, Dugan-Perez, Shannon, Ellinor, Patrick T., Gabriel, Stacey, Germer, Soren, Gibbs, Richard A., Gupta, Namrata, Rice, Kenneth, Smith, Albert V., Zody, Michael C., Blackman, Scott M., Cutting, Garry, Knowles, Michael R., Zhou, Yi-Hui, Rosenfeld, Margaret, Gibson, Ronald L., Bamshad, Michael, Fohner, Alison, Blue, Elizabeth E.
Format: Journal Article
Language:English
Published: United States Elsevier Inc 14.07.2022
Elsevier
Subjects:
CFTR F508del
Genetics
genome-wide association study
population structure
CFTR F508del
population structure
genome-wide association study
ISSN:2666-2477, 2666-2477
Online Access:Get full text
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Summary:CFTR F508del (c.1521_1523delCTT, p.Phe508delPhe) is the most common pathogenic allele underlying cystic fibrosis (CF), and its frequency varies in a geographic cline across Europe. We hypothesized that genetic variation associated with this cline is overrepresented in a large cohort (N > 5,000) of persons with CF who underwent whole-genome sequencing and that this pattern could result in spurious associations between variants correlated with both the F508del genotype and CF-related outcomes. Using principal-component (PC) analyses, we showed that variation in the CFTR region disproportionately contributes to a PC explaining a relatively high proportion of genetic variance. Variation near CFTR was correlated with population structure among persons with CF, and this correlation was driven by a subset of the sample inferred to have European ancestry. We performed genome-wide association studies comparing persons with CF with one versus two copies of the F508del allele; this allowed us to identify genetic variation associated with the F508del allele and to determine that standard PC-adjustment strategies eliminated the significant association signals. Our results suggest that PC adjustment can adequately prevent spurious associations between genetic variants and CF-related traits and are therefore effective tools to control for population structure even when population structure is confounded with disease severity and a common pathogenic variant.
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ISSN:2666-2477
2666-2477
DOI:10.1016/j.xhgg.2022.100117