Elsevier

The Lancet

Volume 376, Issue 9736, 17–23 July 2010, Pages 180-188
The Lancet

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Common genetic determinants of vitamin D insufficiency: a genome-wide association study

https://doi.org/10.1016/S0140-6736(10)60588-0Get rights and content

Summary

Background

Vitamin D is crucial for maintenance of musculoskeletal health, and might also have a role in extraskeletal tissues. Determinants of circulating 25-hydroxyvitamin D concentrations include sun exposure and diet, but high heritability suggests that genetic factors could also play a part. We aimed to identify common genetic variants affecting vitamin D concentrations and risk of insufficiency.

Methods

We undertook a genome-wide association study of 25-hydroxyvitamin D concentrations in 33 996 individuals of European descent from 15 cohorts. Five epidemiological cohorts were designated as discovery cohorts (n=16 125), five as in-silico replication cohorts (n=9367), and five as de-novo replication cohorts (n=8504). 25-hydroxyvitamin D concentrations were measured by radioimmunoassay, chemiluminescent assay, ELISA, or mass spectrometry. Vitamin D insufficiency was defined as concentrations lower than 75 nmol/L or 50 nmol/L. We combined results of genome-wide analyses across cohorts using Z-score-weighted meta-analysis. Genotype scores were constructed for confirmed variants.

Findings

Variants at three loci reached genome-wide significance in discovery cohorts for association with 25-hydroxyvitamin D concentrations, and were confirmed in replication cohorts: 4p12 (overall p=1·9×10−109 for rs2282679, in GC); 11q12 (p=2·1×10−27 for rs12785878, near DHCR7); and 11p15 (p=3·3×10−20 for rs10741657, near CYP2R1). Variants at an additional locus (20q13, CYP24A1) were genome-wide significant in the pooled sample (p=6·0×10−10 for rs6013897). Participants with a genotype score (combining the three confirmed variants) in the highest quartile were at increased risk of having 25-hydroxyvitamin D concentrations lower than 75 nmol/L (OR 2·47, 95% CI 2·20–2·78, p=2·3×10−48) or lower than 50 nmol/L (1·92, 1·70–2·16, p=1·0×10−26) compared with those in the lowest quartile.

Interpretation

Variants near genes involved in cholesterol synthesis, hydroxylation, and vitamin D transport affect vitamin D status. Genetic variation at these loci identifies individuals who have substantially raised risk of vitamin D insufficiency.

Funding

Full funding sources listed at end of paper (see Acknowledgments).

Introduction

Vitamin D insufficiency affects as many as half of otherwise healthy adults in developed countries.1 The musculoskeletal consequences of inadequate vitamin D concentrations are well established, and include childhood rickets, osteomalacia, and fractures.2 A growing number of other disorders have also been linked to vitamin D insufficiency, although causal associations have not yet been established in randomised trials. These extraskeletal disorders include type 1 and type 2 diabetes,2, 3, 4 cardiovascular disease,5, 6 increased risk of falls,7 and cancers of the breast, colon, and prostate.8, 9, 10 Results of a 2007 meta-analysis suggested that vitamin D supplementation substantially reduced mortality.11

Personal, social, and cultural factors are important determinants of vitamin D availability via their effects on sun exposure and diet. Sufficient exposure to ultraviolet light or adequate intake from diet or supplements is needed to maintain vitamin D status. Concentrations of the widely accepted biomarker for vitamin D, 25-hydroxyvitamin D, are highest in the summer and lowest in the winter in northern latitudes. However, only about a quarter of the interindividual variability in 25-hydroxyvitamin D concentration is attributable to season of measurement, geographical latitude, or reported vitamin D intake.12, 13 Results of previous twin and family studies suggest that genetic factors contribute substantially to this variability,13, 14 with estimates of heritability as high as 53%. Although several rare mendelian disorders cause functional vitamin D insufficiency, data for the effect of common genetic variation on vitamin D status are scarce. Candidate gene studies have been done to examine the effect of specific vitamin D pathway genes, but these studies have been limited by small sample sizes and the small numbers of variants examined.15, 16, 17, 18

The SUNLIGHT consortium (Study of Underlying Genetic Determinants of Vitamin D and Highly Related Traits) was formed in 2008. It represents a collaboration of cohorts from the UK, USA, Canada, Netherlands, Sweden, and Finland. We aimed to identify common genetic variants affecting vitamin D concentrations and risk of vitamin D insufficiency.

Section snippets

Participants

We undertook a large, multicentre, genome-wide association study of 15 cohorts in Europe, Canada, and the USA. The discovery sample consisted of 16 125 individuals of European descent drawn from five epidemiological cohorts: the Framingham Heart Study, TwinsUK, the Rotterdam Study, the 1958 British Birth Cohort (1958BC), and the Amish Family Osteoporosis Study (AFOS). Five additional cohorts (n=9367) with genome-wide association data were used for in-silico replication: the Cardiovascular

Results

Characteristics of the study cohorts are summarised in the webappendix (pp 15–17). Table 1 shows the results of genome-wide association analyses. In analysis of data from the five discovery samples, single nucleotide polymorphisms at three unique loci met the prespecified threshold for genome-wide significance: 4p12, 11q12, and 11p15. The 4p12 polymorphisms were within or near the GC gene, and the results included a non-synonymous polymorphism in this gene, rs7041. The 11q12 polymorphisms were

Discussion

Vitamin D insufficiency has been implicated in many musculoskeletal and extraskeletal diseases,1, 2 which has led to substantial interest in the determinants of vitamin D status. Our findings establish a role for common genetic variants in regulation of circulating 25-hydroxyvitamin D concentrations. The presence of harmful alleles at the three confirmed loci more than doubled the risk of vitamin D insufficiency. These findings improve our understanding of vitamin D homoeostasis and could

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    *

    Authors contributed equally

    Prof Peltonen died in March, 2010

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