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.
HGG Advances Volume 3, Issue 3, 14 July 2022, 100117
HanleyKingston1Adrienne M.Stilp2WilliamGordon3JaiBroome4Stephanie M.Gogarten2HuaLing5JohnBarnard6ShannonDugan-Perez7Patrick T.Ellinor89StaceyGabriel10SorenGermer11Richard A.Gibbs7NamrataGupta10KennethRice2Albert V.Smith12Michael C.Zody11The Cystic Fibrosis Genome ProjectNHLBI Trans-Omics for Precision Medicine (TOPMed) ConsortiumScott M.Blackman13GarryCutting14Michael R.Knowles15Yi-HuiZhou16MargaretRosenfeld1718Ronald L.Gibson1718MichaelBamshad3171920AlisonFohner121Elizabeth E.Blue1420
1 Institute for Public Health Genetics, University of Washington, Seattle, WA 98195, USA
2 Department of Biostatistics, University of Washington, Seattle, WA 98195, USA
3 Department of Pediatrics, Division of Genetic Medicine, University of Washington, Seattle, WA 98195, USA
4 Department of Medicine, Division of Medical Genetics, University of Washington, Seattle, WA 98195, USA
5 Department of Genetic Medicine, Center for Inherited Disease Research, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
6 Department of Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
7 Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA
8 Cardiovascular Disease Initiative, The Broad Institute of MIT and Harvard, Cambridge, MA 02124, USA
9 Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA 02114, USA
10 Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
11 New York Genome Center, New York, NY 10013, USA
12 Department of Biostatistics, University of Michigan, Ann Arbor, MI 48109, USA
13 Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
14 McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
15 Marsico Lung Institute/UNC CF Research Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
16 Department of Biological Sciences, North Carolina State University, Raleigh, NC 27797, USA
17 Center for Clinical and Translational Research, Seattle Children’s Hospital, Seattle, WA 98105, USA
18 Department of Pediatrics, University of Washington, Seattle, WA 98195, USA
19 Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA
20 Brotman Baty Institute for Precision Medicine, Seattle, WA 98195, USA
21 Department of Epidemiology, University of Washington, Seattle, WA 98195, USA
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