Department of Human Genetics, McGill University, Montreal, QC H3A 1B1, Canada; Centre for Clinical Epidemiology, Department of Epidemiology, Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, QC H3T 1E2, Canada.
MRC Integrative Epidemiology Unit, Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol BS8 2BN, UK.
Am J Hum Genet. 2020 Mar 5;106(3):327-337. doi: 10.1016/j.ajhg.2020.01.017. Epub 2020 Feb 13.
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) 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.
我们旨在通过开展大规模的血清 25 羟维生素 D（25OHD）全基因组关联研究（GWAS）来增加对维生素 D 水平遗传决定因素的了解。为此，我们使用了来自 401,460 名具有可用 25OHD 水平的白种英国 UK Biobank 参与者的经推断基因型，保留了次要等位基因频率（MAF）> 0.1%和推断质量评分> 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，调整了年龄、性别、测量季节和维生素 D 补充。将这些结果与包括 42,274 名欧洲人在内的先前 GWAS 的结果进行了组合。对 GWAS 结果进行了计算机功能随访，以确定基因集、途径和组织表达的富集情况，并研究 25OHD 的分区遗传率及其与其他特征的共享遗传率。通过这种方法，估计 25OHD 的 SNP 遗传率为 16.1%。在条件独立 SNP 中检测到 138 个（p 值<6.6×10），其中 53 个 MAF<5%。单变体关联信号映射到 69 个不同的基因座，其中 63 个是以前未报道过的。我们发现肝和脂质代谢基因途径富集，以及 25OHD 基因在肝脏、皮肤和胃肠道组织中的富集表达。我们观察到 25OHD 与社会经济特征之间存在部分共享遗传率，这一特征可能是通过户外活动时间来介导的。因此，通过大规模的 25OHD GWAS，我们确定了 63 个基因座，这些基因座强调了维生素 D 经典代谢途径之外的基因对 25OHD 遗传结构的贡献。
