Background-Vitamin D is crucial for maintaining musculoskeletal health. Recently, vitamin D insufficiency has been linked to a number of extraskeletal disorders, including diabetes, cancer, and cardiovascular disease. Determinants of circulating 25-hydroxyvitamin D (25-OH D) include sun exposure and dietary intake, but its high heritability suggests that genetic determinants may also play a role.

Serum metabolite concentrations provide a direct readout of biological processes in the human body, and are associated with disorders such as cardiovascular and metabolic diseases. Here we present a genome-wide association study with 163 metabolic traits using 1809 participants from the KORA population, followed up in the TwinsUK cohort with 422 participants. In eight out of nine replicated loci (FADS1, ELOVL2, ACADS, ACADM, ACADL, SPTLC3, ETFDH, SLC16A9) the genetic variant is located in or near enzyme or solute carrier coding genes, where the associating metabolic traits match the proteins’ function. Many of these loci are located in rate limiting steps of important enzymatic reactions. Use of metabolite concentration ratios as proxies for enzymatic reaction rates reduces the variance and yields robust statistical associations with p-values between 3×10−24 and 6.5×10−179. These loci explained 5.6% to 36.3% of the observed variance. For several loci, associations with clinically relevant parameters have previously been reported.

SummaryBackgroundOsteoporosis is diagnosed by the measurement of bone mineral density, which is a highly heritable and multifactorial trait. We aimed to identify genetic loci that are associated with bone mineral density.MethodsIn this genome-wide association study, we identified the most promising of 314 075 single nucleotide polymorphisms (SNPs) in 2094 women in a UK study. We then tested these SNPs for replication in 6463 people from three other cohorts in western Europe. We also investigated allelic expression in lymphoblast cell lines. We tested the association between the replicated SNPs and osteoporotic fractures with data from two studies.FindingsWe identified genome-wide evidence for an association between bone mineral density and two SNPs (p<5×10−8). The SNPs were rs4355801, on chromosome 8, near to the TNFRSF11B (osteoprotegerin) gene, and rs3736228, on chromosome 11 in the LRP5 (lipoprotein-receptor-related protein) gene. A non-synonymous SNP in the LRP5 gene was associated with decreased bone mineral density (rs3736228, p=6·3×10−12 for lumbar spine and p=1·9×10−4 for femoral neck) and an increased risk of both osteoporotic fractures (odds ratio [OR] 1·3, 95% CI 1·09–1·52, p=0·002) and osteoporosis (OR 1·3, 1·08–1·63, p=0·008). Three SNPs near the TNFRSF11B gene were associated with decreased bone mineral density (top SNP, rs4355801: p=7·6×10−10 for lumbar spine and p=3·3×10−8 for femoral neck) and increased risk of osteoporosis (OR 1·2, 95% CI 1·01–1·42, p=0·038). For carriers of the risk allele at rs4355801, expression of TNFRSF11B in lymphoblast cell lines was halved (p=3·0×10−6). 1883 (22%) of 8557 people were at least heterozygous for these risk alleles, and these alleles had a cumulative association with bone mineral density (trend p=2·3×10−17). The presence of both risk alleles increased the risk of osteoporotic fractures (OR 1·3, 1·08–1·63, p=0·006) and this effect was independent of bone mineral density.InterpretationTwo gene variants of key biological proteins increase the risk of osteoporosis and osteoporotic fracture. The combined effect of these risk alleles on fractures is similar to that of most well-replicated environmental risk factors, and they are present in more than one in five white people, suggesting a potential role in screening.FundingWellcome Trust, European Commission, NWO Investments, Arthritis Research Campaign, Chronic Disease Research Foundation, Canadian Institutes of Health Research, European Society for Clinical and Economic Aspects of Osteoporosis, Genome Canada, Genome Quebéc, Canada Research Chairs, National Health and Medical Research Council of Australia, and European Union.

A sedentary lifestyle (in addition to smoking, high body mass index, and low socioeconomic status) has an effect on LTL and may accelerate the aging process. This provides a powerful message that could be used by clinicians to promote the potentially antiaging effect of regular exercise.

Background-Vitamin D is crucial for maintaining musculoskeletal health. Recently, vitamin D insufficiency has been linked to a number of extraskeletal disorders, including diabetes, cancer, and cardiovascular disease. Determinants of circulating 25-hydroxyvitamin D (25-OH D) include sun exposure and dietary intake, but its high heritability suggests that genetic determinants may also play a role.Methods-We performed a genome-wide association study of 25-OH D among ∼30,000 individuals of European descent from 15 cohorts. Five cohorts were designated as discovery cohorts (n=16,125), five as in silico replication cohorts (n=9,366), and five as de novo replication * rs2282679 in Framingham, rs4588 in 1958 Birth Cohort (r 2 between SNPs >0.99).