Accounting for population structure in genetic studies of cystic fibrosis.

TitleAccounting for population structure in genetic studies of cystic fibrosis.
Publication TypeJournal Article
Year of Publication2022
AuthorsKingston, H, Stilp, AM, Gordon, W, Broome, J, Gogarten, SM, Ling, H, Barnard, J, Dugan-Perez, S, Ellinor, PT, Gabriel, S, Germer, S, Gibbs, RA, Gupta, N, Rice, K, Smith, AV, Zody, MC, Blackman, SM, Cutting, G, Knowles, MR, Zhou, Y-H, Rosenfeld, M, Gibson, RL, Bamshad, M, Fohner, A, Blue, EE
Corporate AuthorsCystic Fibrosis Genome Project, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium
JournalHGG Adv
Date Published2022 Jul 14

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 region disproportionately contributes to a PC explaining a relatively high proportion of genetic variance. Variation near 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.

Alternate JournalHGG Adv
PubMed ID35647563
PubMed Central IDPMC9136666
Grant ListT32 GM081062 / GM / NIGMS NIH HHS / United States