Accounting for population structure in genetic studies of cystic fibrosis

Hanley Kingston¹, Adrienne M Stilp², William Gordon³, Jai Broome⁴, Stephanie M Gogarten², Hua Ling⁵, John Barnard⁶, Shannon Dugan-Perez⁷, Patrick T Ellinor^{8

9}, Stacey Gabriel¹⁰, Soren Germer¹¹, Richard A Gibbs⁷, Namrata Gupta¹⁰, Kenneth Rice², Albert V Smith¹², Michael C Zody¹¹; Cystic Fibrosis Genome Project; NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium; Scott M Blackman¹³, Garry Cutting¹⁴, Michael R Knowles¹⁵, Yi-Hui Zhou¹⁶, Margaret Rosenfeld^{17

18}, Ronald L Gibson^{17

18}, Michael Bamshad^{3

17

19

20}, Alison Fohner^{1

21}, Elizabeth E Blue^{1

4

20}

Affiliations

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.

PMID: 35647563
PMCID: PMC9136666
DOI: 10.1016/j.xhgg.2022.100117

Accounting for population structure in genetic studies of cystic fibrosis

Hanley Kingston et al. HGG Adv. 2022.

. 2022 May 12;3(3):100117.

doi: 10.1016/j.xhgg.2022.100117. eCollection 2022 Jul 14.

Authors

Affiliations

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.

PMID: 35647563
PMCID: PMC9136666
DOI: 10.1016/j.xhgg.2022.100117

Abstract

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.

Keywords: CFTR F508del; genome-wide association study; population structure.

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Conflict of interest statement

M.B. is the editor-in-chief and J.X.C. (member of the Cystic Fibrosis Genome Project) is the deputy editor of HGG Advances. The authors declare no other competing interests.

Figures

**Figure 1**
Population structure within the entire CFGP (n = 4,939) Pairwise principal-component (PC) plots are shown for PCs 1–4 with frequency distributions and percentage of variance explained by each PC on the diagonal. Ancestry estimates indicate the ancestry with the highest estimated proportion using Somalier. Abbreviations: AFR, sub-Saharan African; AMR, Native American; EAS, East Asian; EUR, European; SAS, South Asian.

**Figure 2**
Correlation between PCs and genomic position (A and B) The correlation between PCs (Y axis) and genomic position (X axis) are shown for the (A) CFGP (n = 4,939) and (B) CFGP participants with estimated European ancestry >80% (n = 4,567). The number of PCs shown is the number used to calculate the genetic relatedness matrix and, for the total CFGP dataset, used in the PC-adjusted GWAS analysis. Color-coded regions include 7q21.31 (*CFTR*, pink) and three regions that have previously shown evidence of long-range LD: 2q21.1-2q22.1 (*LCT*, teal), 6p22.3-6p21.2 (the major histocompatibility complex, orange), and the 8p23 inversion polymorphism (purple).

**Figure 3**
GWASs for *CFTR* F508del heterozygosity versus homozygosity (Top) The baseline model adjusted for site and relatedness. (Bottom) The PC-adjusted model. Association signals are measured as -log₁₀(p values). Plot is truncated at p = 1 × 10^-10, as the peak at *CFTR* on chr7 reaches p < 1 × 10^-300 under both models. The genome-wide significance level, p < 5 × 10^-8, is indicated by the horizontal line.

See this image and copyright information in PMC

References

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Accounting for population structure in genetic studies of cystic fibrosis

Affiliations

Accounting for population structure in genetic studies of cystic fibrosis

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

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Full Text Sources

Medical