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. 2022 Feb 21:2021:601-610.
eCollection 2021.

Gene-Based Analysis Reveals Sex-Specific Genetic Risk Factors of COPD

Jaehyun Joo  1 , Blanca Himes  1
Affiliations

Gene-Based Analysis Reveals Sex-Specific Genetic Risk Factors of COPD

Jaehyun Joo et al. AMIA Annu Symp Proc. .

Abstract

Sex-specific differences have been noted among people with chronic obstructive pulmonary disease (COPD), but whether these differences are attributable to genetic variation is poorly understood. The availability of large biobanks with deeply phenotyped subjects such as the UK Biobank enables the investigation of sex-specific genetic associations that may provide new insights into COPD risk factors. We performed sex-stratified genome-wide association studies (GWAS) of COPD (male: 12,958 cases and 95,631 controls; female: 11,311 cases and 123,714 controls) and found that while most associations were shared between sexes, several regions had sex-specific contributions, including respiratory viral infection-related loci in/near C5orf56 and PELI1. Using the newly developed R package 'snpsettest', we performed gene-based association tests and identified gene-level sex-specific associations, including C5orf56 on 5q31.1, CFDP1/TMEM170A/CHST6 on 16q23.1 and ASTN2/TRIM32 on 9q33.1. Our results identified promising genes to pursue in functional studies to better understand sexual dimorphism in COPD.

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Figures

Figure 1.
Figure 1.
Manhattan plots of sex-stratified COPD GWAS results for (A) male and (B) female subjects. Each locus was annotated with its nearest coding gene. The green horizontal dashed line indicates the genome-wide significance threshold of 5 × 10-8. Overlapping loci in the GWAS are shown in blue. Sex-specific loci are shown in orange when genome-wide significant, with corresponding non-significant region shown in red in the alternate sex-specific plot.
Figure 2.
Figure 2.
Regional association plots for the loci in (A) HHIP as an example of a finding present in male and female GWAS and (B) C5orf56, the locus with the greatest sex-specific difference. Left panels display the results of the male GWAS and the right panels display the results of the female GWAS.
Figure 3.
Figure 3.
Comparison of -log10(P) obtained with the snpsettest package versus VEGAS using the summary statistics from GWAS of (A) male and (B) female subjects. The diagonal line indicates a 1:1 relationship.
Figure 4.
Figure 4.
Results of gene-based association tests. Sex-specific associations between genes and COPD are shown in a pairwise manner. Genes showing a significant sex-specific association are labeled. The vertical and horizontal dashed lines indicate the Bonferroni-corrected p-value = 0.05.
See this image and copyright information in PMC

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