Genome-wide association study identifies 143 loci associated with 25 hydroxyvitamin D concentration

Abstract

Vitamin D deficiency is a candidate risk factor for a range of adverse health outcomes. In a genome-wide association study of 25 hydroxyvitamin D (25OHD) concentration in 417,580 Europeans we identify 143 independent loci in 112 1-Mb regions, providing insights into the physiology of vitamin D and implicating genes involved in lipid and lipoprotein metabolism, dermal tissue properties, and the sulphonation and glucuronidation of 25OHD. Mendelian randomization models find no robust evidence that 25OHD concentration has causal effects on candidate phenotypes (e.g. BMI, psychiatric disorders), but many phenotypes have (direct or indirect) causal effects on 25OHD concentration, clarifying the epidemiological relationship between 25OHD status and the health outcomes examined in this study.

A comprehensive genetic and epidemiological association analysis of vitamin D with common diseases/traits in the UK Biobank

“…Summary statistics for the effect sizes of the 25(OH)D‐associated single nucleotide polymorphisms (SNPs) were extracted from a recent GWAS study in the UKBB population (Revez et al, 2020) where 417,580 Europeans were analyzed. Specifically, the SNP‐based heritability estimate was 0.13 (SE = 0.01) and 143 independent loci were identified to be associated with 25(OH)D. In our MR analysis, the 143 leading SNPs were selected as instrumental variables (Table S2).…”

“…A recent GWAS (Revez et al, 2020) of vitamin D involving 417,580 Europeans from the UK Biobank (UKBB) has identified 143 independent variants, which accounted for ~13% of the variation of serum concentration of 25‐hydroxyvitamin D (25(OH)D), primary circulating form of vitamin D. Based on this set of genetic variants and the broad scope of UKBB, we set out to comprehensively re‐evaluate the associations of 25(OH)D with 106 diseases/traits (88 common diseases and 18 nondisease traits) using both epidemiological and two‐sample MR analyses.…”

A mendelian randomization study on causal effects of 25(OH)vitamin D levels on attention deficit/hyperactivity disorder

“…Actually, while this paper was under review, two GWAS on 25(OH)D concentrations, each with more than 400,000 European study participants, were published. These GWAS revealed 143 and 138 genome-wide significant SNPs, respectively [23,24]. Sensitivity MR analyses considering these findings for the definition of the IV also showed no significant association between genetically predicted 25(OH)D concentrations and ADHD.…”

“…During the review process of this paper, two additional GWAS on the impact of genetic variation on 25(OH) D concentrations revealed substantial larger numbers of genome-wide significant loci. Revez and colleagues used data from 417,580 European participants from UK Biobank and observed 143 independent loci [23]. Manousaki et al combined data from 401,460 UK Biobank participants with data from 42,274 Europeans from a previous GWAS and observed 138 conditional independent SNPs in 69 independent loci [24].…”

“…We conducted additional sensitivity MR analyses using alternative genetic instruments considering results from two recent GWAS on 25(OH)D [23,24]. Both of these additional MR analyses confirmed the results from our main analysis since the overall estimates, calculated by IVW or MR-Egger, Table 1 Genome-wide significant single nucleotide polymorphisms (SNPs) for natural log-transformed 25(OH)D levels and their association with ADHD Eaf effect allele frequency, OR odds ratio, SE standard error, palindromic + ambiguous true this SNP is palindromic and ambiguous and will be excluded a rs209955 is the proxy for rs17216707: distance = − 9491, D′ = 0.7908, r 2 = 0.4115; A1: Allele 1; A2: (Tables S1 and S2, Figures S4 and S5).…”