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Genome-wide Association Study for Vitamin D Levels Reveals 69 Independent Loci.

ABSTRACT: We aimed to increase our understanding of the genetic determinants of vitamin D levels by undertaking a large-scale genome-wide association study (GWAS) of serum 25 hydroxyvitamin D (25OHD). To do so, we used imputed genotypes from 401,460 white British UK Biobank participants with available 25OHD levels, retaining single-nucleotide polymorphisms (SNPs) with minor allele frequency (MAF) > 0.1% and imputation quality score > 0.3. We performed a linear mixed model GWAS on standardized log-transformed 25OHD, adjusting for age, sex, season of measurement, and vitamin D supplementation. These results were combined with those from a previous GWAS including 42,274 Europeans. In silico functional follow-up of the GWAS results was undertaken to identify enrichment in gene sets, pathways, and expression in tissues, and to investigate the partitioned heritability of 25OHD and its shared heritability with other traits. Using this approach, the SNP heritability of 25OHD was estimated to 16.1%. 138 conditionally independent SNPs were detected (p value < 6.6 × 10-9) among which 53 had MAF < 5%. Single variant association signals mapped to 69 distinct loci, among which 63 were previously unreported. We identified enrichment in hepatic and lipid metabolism gene pathways and enriched expression of the 25OHD genes in liver, skin, and gastrointestinal tissues. We observed partially shared heritability between 25OHD and socio-economic traits, a feature which may be mediated through time spent outdoors. Therefore, through a large 25OHD GWAS, we identified 63 loci that underline the contribution of genes outside the vitamin D canonical metabolic pathway to the genetic architecture of 25OHD.

SUBMITTER: Manousaki D

PROVIDER: S-EPMC7058824 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Genome-wide Association Study for Vitamin D Levels Reveals 69 Independent Loci.

Manousaki Despoina D Mitchell Ruth R Dudding Tom T Haworth Simon S Harroud Adil A Forgetta Vincenzo V Shah Rupal L RL Luan Jian'an J Langenberg Claudia C Timpson Nicholas J NJ Richards J Brent JB

American journal of human genetics 20200213 3

We aimed to increase our understanding of the genetic determinants of vitamin D levels by undertaking a large-scale genome-wide association study (GWAS) of serum 25 hydroxyvitamin D (25OHD). To do so, we used imputed genotypes from 401,460 white British UK Biobank participants with available 25OHD levels, retaining single-nucleotide polymorphisms (SNPs) with minor allele frequency (MAF) > 0.1% and imputation quality score > 0.3. We performed a linear mixed model GWAS on standardized log-transfor ...[more]

PMID: 32059762

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Project description:Recently, many genome-wide association studies (GWAS) have been conducted to understand the genetic architecture of economic important traits in farm animals. Pig is widely used as a biomedical animal model for its similarity with humans in terms of organ formation and disease mechanisms. Moreover, understanding the mechanisms that underlie the development of internal organs will impact the productive potential of pigs. Our aim was to uncover new single nucleotide polymorphisms (SNPs) associated with the weight of internal organs and carcass and also potential candidate genes.We performed GWAS for the weight of heart, liver, spleen, kidney and carcass on five pig populations (White Duroc × Erhualian F2 intercross, Sutai population, Laiwu population, Erhualian population and commercial population, for a total of 2650 individuals). Genotype data was produced using the PorcineSNP60 Beadchip array. After quality control, the data was used for association tests under a general linear mixed model. Population stratification was adjusted by including a random polygenic effect based on a matrix of genotypic relationships. A meta-analysis of our GWAS datasets was conducted by summing up the Chi square values across breeds, with the degrees of freedom of the Chi square distribution equal to the effective number of breeds.Thirty-nine quantitative trait loci (QTL) located on 15 chromosomes were identified by the single-population GWAS at the suggestive level. Among these, nine QTL surpassed the 5 % genome-wide significance threshold, including four for heart weight on SSC (Sus scrofa chromosome) 2, 4, 7 and 10, two for liver weight on SSC7, two for spleen weight on SSC5 and SSC7 and one for carcass weight on SSC11. The QTL on SSC7 showed pleiotropic effects for heart, liver and spleen weights in the F2 population. In addition, two QTL were detected in several populations, including one on SSC2 for heart weight in the F2 and Sutai populations and one on SSC7 for liver weight in the F2 and Laiwu populations. The meta-analysis detected four novel QTL on SSC1, 3, 8 and 16 for carcass weight.

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Genome-wide Association Study for Vitamin D Levels Reveals 69 Independent Loci.

Publications

Genome-wide Association Study for Vitamin D Levels Reveals 69 Independent Loci.

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