GENOME-WIDE ASSOCIATION STUDY OF VITAMIN D STATUS IN KENYAN CHILDREN IN KILIFI AND GAMBIAN CHILDREN IN WEST KIANG

Abstract

Vitamin D deficiency is a major public health issue linked to autoimmune disorders, cancer, cardiovascular and musculoskeletal diseases among other medical conditions. The link between vitamin D status and these diseases has sparked a lot of interest in the factors that influence 25-hydroxyvitamin D (25(OH)D) levels, particularly the genetic components. There have been no. genome-wide association studies (GWAS) of vitamin D status of Africans living in Africa to date, and the genetic contribution to circulating 25(OH)D in the continent is not well understood. Africans have vast genetic differences compared to other ethnicities making it difficult to generalize their findings to Africans. The goal of the current study was to find single nucleotide polymorphisms (SNPs) that are linked to vitamin D status in Kenyan children in Kilifi and Gambian children in West Kiang. To achieve this objective, this study used two cohorts of children from Kilifi (n = 1,312), and West Kiang (n=574) whose samples were genotyped using the H3Africa genotyping chip array. Separate GWASs were conducted first to identify genomic regions linked to vitamin status in each of the study cohorts after which the summary statistics were meta-analyzed. Further, post-GWAS analyses were used to assess SNPs to uncover the biological mechanisms of vitamin D-associated genes among African participants. Population specific GWAS analysis for the Kenyan and Gambian cohorts revealed suggestive signals in chromosomes 1, 4, 5, 7, 8, 9, 11, 12, 16, 17, and 18 and in chromosomes 5, 7, 9, 10, 11 and 18, respectively. Meta-analysis GWAS revealed a new suggestive signal on chromosome 6 that was absent in the separate GWASs in addition to other suggestive signals on chromosomes 4, 5, 8, 9, 10, 11, 12, 16, and 17. Suggestive signals on chromosomes 1, 7 and 18 disappeared on the meta-analysis GWAS suggesting that they might have been false positive signals caused by artefacts. Post-GWAS analysis suggested that the majority of SNPs that attained a suggestive significance level of p value 1×10-5 were intronic. This result indicates that the identified SNPs could be in linkage disequilibrium with causal SNPs. Further visualization of eQTLs showed that these variants were majorly associated with NADSYN1 and DHCR7 traits. Overall, the findings of the current study contribute to the knowledge of the genetic factors determining 25(OH)D levels in Kenyan and Gambian children. The study acts as a baseline for future studies investigating the genetic components of vitamin D status among populations living in continental Africa. Keywords: GWAS, post-GWAS analyses, vitamin D, Kenya, The Gambia, Africa