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Admixture mapping and fine-mapping of type 2 diabetes susceptibility loci in African American women

Abstract

African American women are disproportionately affected by type 2 diabetes. Genetic factors may explain part of the excess risk. More than 100 genetic variants have been associated with risk of type 2 diabetes, but most studies have been conducted in white populations. Two genome-wide association studies (GWAS) in African Americans have identified three novel genetic variants only. We conducted admixture mapping using 2918 ancestral informative markers in 2632 cases of type 2 diabetes, and 2596 controls nested in the ongoing Black Women’s Health Study cohort, with the goal of identifying genomic loci with local African ancestry associated with type 2 diabetes. In addition, we performed replication analysis of 71 previously identified index SNPs, and fine-mapped those genetic loci to identify better or new genetic variants associated with type 2 diabetes in African Americans. We found that individual African ancestry was associated with higher risk of type 2 diabetes. In addition, we identified two genomic regions, 3q26 and 12q23, with excess of African ancestry associated with higher risk of type 2 diabetes. Lastly, we replicated 8 out of 71 index SNPs from previous GWAS, including, for the first time in African Americans, the X-linked rs5945326 SNP near the DUSP9 gene. In addition, our fine-mapping efforts suggest independent signals at five loci. Our detailed analysis identified two genomic regions associated with risk of type 2 diabetes, and showed that many genetic risk variants are shared across ancestries.

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Acknowledgements

We thank the Black Women’s Health Study participants for their continuing participation in this research effort.

Funding

This work was supported by grants R01MD007015 (to EARN) from the National Institute on Minority Health and Health Disparities (http://www.nimhd.nih.gov/); R01CA058420 (to L.R.), R01CA098663 (to J.R.P.), and UM1CA164974 (to L.R.) from the National Cancer Institute (http://www.cancer.gov/); and 11SDG7390014 (to E.A.R.N.) from the American Heart Association (http://www.heart.org/HEARTORG/).

Disclaimer

The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute on Minority Health and Health Disparities, the National Cancer Institute, the National Institutes of Health, or the American Heart Association. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Correspondence to Edward A. Ruiz-Narváez.

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The authors declare that they have no conflict of interest.

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The BWHS was approved by the institutional review board of Boston University (Boston, MA).

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All study subjects provided written informed consent for use of their saliva samples.

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Uribe-Salazar, J.M., Palmer, J.R., Haddad, S.A. et al. Admixture mapping and fine-mapping of type 2 diabetes susceptibility loci in African American women. J Hum Genet 63, 1109–1117 (2018). https://doi.org/10.1038/s10038-018-0503-2

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