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Cross-ancestry analyses identify new genetic loci associated with 25-hydroxyvitamin D

Vitamin D status–a complex trait influenced by environmental and genetic factors–is tightly associated with skin colour and ancestry. Yet very few studies have investigated the genetic underpinnings of vitamin D levels across diverse ancestries, and the ones that have, relied on small sample sizes,...

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Autores principales: Wang, Xiaotong, Hivert, Valentin, Groot, Shiane, Wang, Ying, Yengo, Loic, McGrath, John J., Kemper, Kathryn E., Visscher, Peter M., Wray, Naomi R., Revez, Joana A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10684098/
https://www.ncbi.nlm.nih.gov/pubmed/37963177
http://dx.doi.org/10.1371/journal.pgen.1011033
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author Wang, Xiaotong
Hivert, Valentin
Groot, Shiane
Wang, Ying
Yengo, Loic
McGrath, John J.
Kemper, Kathryn E.
Visscher, Peter M.
Wray, Naomi R.
Revez, Joana A.
author_facet Wang, Xiaotong
Hivert, Valentin
Groot, Shiane
Wang, Ying
Yengo, Loic
McGrath, John J.
Kemper, Kathryn E.
Visscher, Peter M.
Wray, Naomi R.
Revez, Joana A.
author_sort Wang, Xiaotong
collection PubMed
description Vitamin D status–a complex trait influenced by environmental and genetic factors–is tightly associated with skin colour and ancestry. Yet very few studies have investigated the genetic underpinnings of vitamin D levels across diverse ancestries, and the ones that have, relied on small sample sizes, resulting in inconclusive results. Here, we conduct genome-wide association studies (GWAS) of 25 hydroxyvitamin D (25OHD)–the main circulating form of vitamin D–in 442,435 individuals from four broad genetically-determined ancestry groups represented in the UK Biobank: European (N = 421,867), South Asian (N = 9,983), African (N = 8,306) and East Asian (N = 2,279). We identify a new genetic determinant of 25OHD (rs146759773) in individuals of African ancestry, which was not detected in previous analysis of much larger European cohorts due to low minor allele frequency. We show genome-wide significant evidence of dominance effects in 25OHD that protect against vitamin D deficiency. Given that key events in the synthesis of 25OHD occur in the skin and are affected by pigmentation levels, we conduct GWAS of 25OHD stratified by skin colour and identify new associations. Lastly, we test the interaction between skin colour and variants associated with variance in 25OHD levels and identify two loci (rs10832254 and rs1352846) whose association with 25OHD differs in individuals of distinct complexions. Collectively, our results provide new insights into the complex relationship between 25OHD and skin colour and highlight the importance of diversity in genomic studies. Despite the much larger rates of vitamin D deficiency that we and others report for ancestry groups with dark skin (e.g., South Asian), our study highlights the importance of considering ancestral background and/or skin colour when assessing the implications of low vitamin D.
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spelling pubmed-106840982023-11-30 Cross-ancestry analyses identify new genetic loci associated with 25-hydroxyvitamin D Wang, Xiaotong Hivert, Valentin Groot, Shiane Wang, Ying Yengo, Loic McGrath, John J. Kemper, Kathryn E. Visscher, Peter M. Wray, Naomi R. Revez, Joana A. PLoS Genet Research Article Vitamin D status–a complex trait influenced by environmental and genetic factors–is tightly associated with skin colour and ancestry. Yet very few studies have investigated the genetic underpinnings of vitamin D levels across diverse ancestries, and the ones that have, relied on small sample sizes, resulting in inconclusive results. Here, we conduct genome-wide association studies (GWAS) of 25 hydroxyvitamin D (25OHD)–the main circulating form of vitamin D–in 442,435 individuals from four broad genetically-determined ancestry groups represented in the UK Biobank: European (N = 421,867), South Asian (N = 9,983), African (N = 8,306) and East Asian (N = 2,279). We identify a new genetic determinant of 25OHD (rs146759773) in individuals of African ancestry, which was not detected in previous analysis of much larger European cohorts due to low minor allele frequency. We show genome-wide significant evidence of dominance effects in 25OHD that protect against vitamin D deficiency. Given that key events in the synthesis of 25OHD occur in the skin and are affected by pigmentation levels, we conduct GWAS of 25OHD stratified by skin colour and identify new associations. Lastly, we test the interaction between skin colour and variants associated with variance in 25OHD levels and identify two loci (rs10832254 and rs1352846) whose association with 25OHD differs in individuals of distinct complexions. Collectively, our results provide new insights into the complex relationship between 25OHD and skin colour and highlight the importance of diversity in genomic studies. Despite the much larger rates of vitamin D deficiency that we and others report for ancestry groups with dark skin (e.g., South Asian), our study highlights the importance of considering ancestral background and/or skin colour when assessing the implications of low vitamin D. Public Library of Science 2023-11-14 /pmc/articles/PMC10684098/ /pubmed/37963177 http://dx.doi.org/10.1371/journal.pgen.1011033 Text en © 2023 Wang et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Wang, Xiaotong
Hivert, Valentin
Groot, Shiane
Wang, Ying
Yengo, Loic
McGrath, John J.
Kemper, Kathryn E.
Visscher, Peter M.
Wray, Naomi R.
Revez, Joana A.
Cross-ancestry analyses identify new genetic loci associated with 25-hydroxyvitamin D
title Cross-ancestry analyses identify new genetic loci associated with 25-hydroxyvitamin D
title_full Cross-ancestry analyses identify new genetic loci associated with 25-hydroxyvitamin D
title_fullStr Cross-ancestry analyses identify new genetic loci associated with 25-hydroxyvitamin D
title_full_unstemmed Cross-ancestry analyses identify new genetic loci associated with 25-hydroxyvitamin D
title_short Cross-ancestry analyses identify new genetic loci associated with 25-hydroxyvitamin D
title_sort cross-ancestry analyses identify new genetic loci associated with 25-hydroxyvitamin d
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10684098/
https://www.ncbi.nlm.nih.gov/pubmed/37963177
http://dx.doi.org/10.1371/journal.pgen.1011033
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