• A multi-ethnic epigenome-wide association study of leukocyte DNA methylation and blood lipids

      Jhun, Mina-A; Mendelson, Michael; Wilson, Rory; Gondalia, Rahul; Joehanes, Roby; Salfati, Elias; Zhao, Xiaoping; Braun, Kim Valeska Emilie; Do, Anh Nguyet; Hedman, Åsa K; et al. (Springer Nature, 2021-06-28)
      Here we examine the association between DNA methylation in circulating leukocytes and blood lipids in a multi-ethnic sample of 16,265 subjects. We identify 148, 35, and 4 novel associations among Europeans, African Americans, and Hispanics, respectively, and an additional 186 novel associations through a trans-ethnic meta-analysis. We observe a high concordance in the direction of effects across racial/ethnic groups, a high correlation of effect sizes between high-density lipoprotein and triglycerides, a modest overlap of associations with epigenome-wide association studies of other cardio-metabolic traits, and a largely non-overlap with lipid loci identified to date through genome-wide association studies. Thirty CpGs reached significance in at least 2 racial/ethnic groups including 7 that showed association with the expression of an annotated gene. CpGs annotated to CPT1A showed evidence of being influenced by triglycerides levels. DNA methylation levels of circulating leukocytes show robust and consistent association with blood lipid levels across multiple racial/ethnic groups.
    • Multi-ethnic genome-wide and HLA association study of total serum IgE

      Daya, Michelle; Cox, Corey; Acevedo, Nathalie; Boorgula, Meher P; Campbell, Monica; Chavan, Sameer; Cho, Michael H; David, Gloria L; Kachroo, Priyadarshini; Lasky-Su, Jessica; et al. (Elsevier Inc., 2021-09-15)
      Background: Total serum IgE (tIgE) is an important intermediate phenotype of allergic disease. Whole genome genetic association studies across ancestries may identify important determinants of IgE. Objective: By leveraging data from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program, the Consortium on Asthma among African-ancestry Populations in the Americas (CAAPA) and the Atopic Dermatitis Research Network (ADRN), we aim to increase understanding of genetic variants affecting tIgE production across the ancestry and allergic disease spectrum (N=21,901). Methods: We performed genome-wide association within strata of study, disease, and ancestry groups, and combined results via a meta-regression approach that models heterogeneity attributable to ancestry. We also tested for association between HLA alleles called from whole genome sequence data and tIgE, assessing replication of associations in HLA alleles called from genotype array data. For details, please see the Methods section in this article's Online Repository at www.jacionline.org. Results: We identified six loci at genome-wide significance (P<5x10-9), including four loci previously reported as genome-wide significant for tIgE, as well as new regions in chr11q13.5 and chr15q22.2, also identified in prior GWAS of atopic dermatitis and asthma. In the HLA allele association study, HLA-A*02:01 was associated with decreased tIgE (discovery P = 2x10-4, replication P = 5x10-4, discovery+replication P=4x10-7) and HLA-DQB1*03:02 was strongly associated with decreased tIgE in Hispanic/Latino ancestry populations (Hispanic/Latino discovery+replication P=8x10-8). Conclusion: We performed the largest GWAS and HLA association study of tIgE focused on ancestrally diverse populations and found several known tIgE and allergic disease loci that are relevant in non-European ancestry populations.
    • Whole genome sequence analysis of pulmonary function and COPD in 19,996 multi-ethnic participants

      Zhao, Xutong; Qiao, Dandi; Yang, Chaojie; Kasela, Silva; Kim, Wonji; Ma, Yanlin; Shrine, Nick; Batini, Chiara; Sofer, Tamar; Taliun, Sarah A Gagliano; et al. (Springer Nature, 2020-10-14)
      Chronic obstructive pulmonary disease (COPD), diagnosed by reduced lung function, is a leading cause of morbidity and mortality. We performed whole genome sequence (WGS) analysis of lung function and COPD in a multi-ethnic sample of 11,497 participants from population- and family-based studies, and 8499 individuals from COPD-enriched studies in the NHLBI Trans-Omics for Precision Medicine (TOPMed) Program. We identify at genome-wide significance 10 known GWAS loci and 22 distinct, previously unreported loci, including two common variant signals from stratified analysis of African Americans. Four novel common variants within the regions of PIAS1, RGN (two variants) and FTO show evidence of replication in the UK Biobank (European ancestry n ~ 320,000), while colocalization analyses leveraging multi-omic data from GTEx and TOPMed identify potential molecular mechanisms underlying four of the 22 novel loci. Our study demonstrates the value of performing WGS analyses and multi-omic follow-up in cohorts of diverse ancestry.