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.

中文翻译：

---

维生素 D 水平的全基因组关联研究揭示了 69 个独立基因座。


我们旨在通过对血清 25 羟基维生素 D (25OHD) 进行大规模全基因组关联研究 (GWAS)，加深对维生素 D 水平遗传决定因素的了解。为此，我们使用了来自 401,460 名英国白人生物银行参与者的估算基因型（具有可用的 25OHD 水平），保留了次要等位基因频率 (MAF) > 0.1% 且估算质量得分 > 0.3 的单核苷酸多态性 (SNP)。我们对标准化对数转换的 25OHD 进行了线性混合模型 GWAS，并根据年龄、性别、测量季节和维生素 D 补充情况进行了调整。这些结果与先前 GWAS 的结果相结合，其中包括 42,274 名欧洲人。对 GWAS 结果进行计算机功能跟踪，以确定组织中基因集、途径和表达的富集，并研究 25OHD 的分区遗传力及其与其他性状的共享遗传力。使用这种方法，25OHD 的 SNP 遗传力估计为 16.1%。检测到 138 个条件独立的 SNP（p 值 < 6.6 × 10-9），其中 53 个 MAF < 5%。单变体关联信号映射到 69 个不同的位点，其中 63 个以前未报告。我们确定了肝脏和脂质代谢基因途径的富集以及肝脏、皮肤和胃肠组织中 25OHD 基因的富集表达。我们观察到 25OHD 和社会经济特征之间存在部分共享的遗传性，这一特征可能通过户外活动时间来调节。因此，通过大型 25OHD GWAS，我们确定了 63 个位点，这些位点强调了维生素 D 规范代谢途径之外的基因对 25OHD 遗传结构的贡献。