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Koppelmaa_i6146826_BSc_Thesis_2019.pdf (6.27 MB)

From SNPs to Pathways: Functional Interpretation of Vitamin D GWAS Results

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thesis
posted on 2019-07-07, 11:34 authored by Kristin KoppelmaaKristin Koppelmaa

Abstract
Background: Vitamin D is an essential nutrient which influences many bodily functions. Serum levels are determined by both environmental factors and genetics. Several genetic loci which affect serum vitamin D levels have been identified by GWAS, but no further knowledge regarding the influence of these variants exists. With vitamin D deficiency becoming increasingly prevalent, understanding the genetic component in the development of conditions related to vitamin D deficiency could benefit millions. This study aims to utilise pathway- analysis to investigate the biological effects of the variation in vitamin D genetic determinants. Methods: Two vitamin D GWAS datasets were analysed using VEP and FUMA, which performed genetic mapping and functional annotation. A SNP-gene-pathway network was created in Cytoscape for each variant set. Biological pathways were linked from WikiPathways using CyTargetLinker. PathVisio was used to extend the amino acid metabolism pathway. Results: The two networks included a total of 53 different genes and 30 pathways. Variants in genes PDE3B, SEC23A, DHCR7 and NADSYN1 were linked to pathways involved in lipid metabolism and cholesterol synthesis (leptin signalling, SREBP signalling, and cholesterol biosynthesis). One variant in AMDHD1 and HAL influenced histidine catabolism. Conclusion: Pathway-based analysis was useful to gain more knowledge regarding the biological effect of genetic variants which influence vitamin D levels. These variants may disrupt normal function of genes of which the proteins regulate important biological processes. This may ultimately influence outcome of health conditions such as obesity, CVD, and T2D. However, these results and the exact role of genetic variants require confirmation and clarification, ideally by using data from larger studies with a more diverse study population. In the future, these variants could be utilised as biomarkers for diseases and/or used in genetic screening to improve personalized guidelines. This could ultimately help prevent the health consequences of vitamin D deficiency.

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