Division of Population Health & Genomics, School of Medicine, Ninewells Hospital & Medical School, University of Dundee, Dundee DD1 9SY, UK.
Department of Endocrinology and Diabetes, Ninewells Hospital & Medical School, University of Dundee, Dundee DD1 9SY, UK.
J Clin Endocrinol Metab. 2022 Nov 25;107(12):3302-3308. doi: 10.1210/clinem/dgac527.
A hypothesis-free genetic association analysis has not been reported for patients with primary hyperparathyroidism (PHPT).
We aimed to investigate genetic associations with PHPT using both genome-wide association study (GWAS) and candidate gene approaches.
A cross-sectional study was conducted among patients of European White ethnicity recruited in Tayside (Scotland, UK). Electronic medical records were used to identify PHPT cases and controls, and linked to genetic biobank data. Genetic associations were performed by logistic regression models and odds ratios (ORs). The combined effect of the genotypes was researched by genetic risk score (GRS) analysis.
We identified 15 622 individuals for the GWAS that yielded 34 top single-nucleotide variations (formerly single-nucleotide polymorphisms), and LPAR3-rs147672681 reached genome-wide statistical significance (P = 1.2e-08). Using a more restricted PHPT definition, 8722 individuals with data on the GWAS-identified loci were found. Age- and sex-adjusted ORs for the effect alleles of SOX9-rs11656269, SLITRK5-rs185436526, and BCDIN3D-AS1-rs2045094 showed statistically significant increased risks (P < 1.5e-03). GRS analysis of 5482 individuals showed an OR of 2.51 (P = 1.6e-04), 3.78 (P = 4.0e-08), and 7.71 (P = 5.3e-17) for the second, third, and fourth quartiles, respectively, compared to the first, and there was a statistically significant linear trend across quartiles (P < 1.0e-04). Results were similar when stratifying by sex.
Using genetic loci discovered in a GWAS of PHPT carried out in a Scottish population, this study suggests new evidence for the involvement of genetic variants at SOX9, SLITRK5, LPAR3, and BCDIN3D-AS1. It also suggests that male and female carriers of greater numbers of PHPT-risk alleles both have a statistically significant increased risk of PHPT.
原发性甲状旁腺功能亢进症（PHPT）患者的无假设遗传关联分析尚未报道。
我们旨在使用全基因组关联研究（GWAS）和候选基因方法研究 PHPT 的遗传关联。
在苏格兰泰赛德（Tayside）的欧洲白人患者中进行了一项横断面研究。电子病历用于识别 PHPT 病例和对照，并与遗传生物库数据相关联。通过逻辑回归模型和比值比（OR）进行遗传关联分析。通过遗传风险评分（GRS）分析研究基因型的综合效应。
我们确定了 15622 名个体进行 GWAS，产生了 34 个顶级单核苷酸变异（以前称为单核苷酸多态性），LPAR3-rs147672681 达到了全基因组统计学意义（P = 1.2e-08）。使用更严格的 PHPT 定义，发现了 8722 名具有 GWAS 确定基因座数据的个体。SOX9-rs11656269、SLITRK5-rs185436526 和 BCDIN3D-AS1-rs2045094 的效应等位基因的年龄和性别调整 OR 显示出统计学上显著的风险增加（P < 1.5e-03）。对 5482 名个体的 GRS 分析显示，与第一四分位相比，第二、第三和第四四分位的 OR 分别为 2.51（P = 1.6e-04）、3.78（P = 4.0e-08）和 7.71（P = 5.3e-17），并且四分位数之间存在统计学上显著的线性趋势（P < 1.0e-04）。按性别分层时，结果相似。
使用在苏格兰人群中进行的 PHPT GWAS 发现的遗传基因座，本研究提示了新的证据表明 SOX9、SLITRK5、LPAR3 和 BCDIN3D-AS1 中的遗传变异参与了 PHPT。它还表明，携带更多 PHPT 风险等位基因的男性和女性携带者均具有统计学上显著增加的 PHPT 风险。
