Heng Teng Hiang, Walter Klaudia, Huang Qin Qin, Karjalainen Juha, Daly Mark J, Heyne Henrike O, Malawsky Daniel S, Kalantzis Georgios, Finer Sarah, van Heel David A, Martin Hilary C
Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton CB10 1SA, UK.
Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton CB10 1SA, UK.
Am J Hum Genet. 2025 Jun 5;112(6):1316-1329. doi: 10.1016/j.ajhg.2025.03.020. Epub 2025 Apr 29.
Genetic association studies have focused on testing additive models in cohorts with European ancestry. Little is known about recessive effects on common diseases, specifically for non-European ancestry. Genes & Health is a cohort of British Pakistani and Bangladeshi individuals with elevated rates of consanguinity and endogamy, making it suitable to study recessive effects. We imputed variants into a genotyped dataset (n = 44,190) by using two reference panels: a set of 4,982 whole-exome sequences from within the cohort and the Trans-Omics for Precision Medicine (TOPMed-r2) panel. We performed association testing with 898 diseases from electronic health records. 185 independent loci reached genome-wide significance (p < 5 × 10) under the recessive model, with p values lower than under the additive model, and >40% of these were novel. 140 loci demonstrated nominally significant (p < 0.05) dominance deviation p values, confirming a recessive association pattern. Sixteen loci in three clusters were significant at a Bonferroni threshold, accounting for multiple phenotypes tested (p < 5.4 × 10). In FinnGen, we replicated 44% of the expected number of Bonferroni-significant loci we were powered to replicate, at least one from each cluster, including an intronic variant in patatin-like phospholipase domain-containing protein 3 (PNPLA3; rs66812091) and non-alcoholic fatty liver disease, a previously reported additive association. We present evidence suggesting that the association is recessive instead (odds ratio [OR] = 1.3, recessive p = 2 × 10, additive p = 2 × 10, dominance deviation p = 3 × 10, and FinnGen recessive OR = 1.3 and p = 6 × 10). We identified a novel protective recessive association between a missense variant in SGLT4 (rs61746559), a sodium-glucose transporter with a possible role in the renin-angiotensin-aldosterone system, and hypertension (OR = 0.2, p = 3 × 10, dominance deviation p = 7 × 10). These results motivate interrogating recessive effects on common diseases more widely.
基因关联研究主要集中在对欧洲血统队列中的加性模型进行测试。对于常见疾病的隐性效应，尤其是非欧洲血统人群的隐性效应，我们了解甚少。“基因与健康”研究项目涵盖了英国的巴基斯坦裔和孟加拉裔个体，这些人群中近亲结婚和族内通婚的比例较高，因此适合用于研究隐性效应。我们通过使用两个参考面板，将变异位点推算到一个基因分型数据集（n = 44,190）中：一个是该队列内部的4982个全外显子序列集合，另一个是精准医学全基因组关联研究（TOPMed-r2）面板。我们对电子健康记录中的898种疾病进行了关联测试。在隐性模型下，185个独立位点达到全基因组显著性水平（p < 5×10），其p值低于加性模型下的p值，且其中超过40%是新发现的。140个位点显示出名义上显著的（p < 0.05）显性偏差p值，证实了隐性关联模式。三个聚类中的16个位点在考虑了多个测试表型的Bonferroni阈值下具有显著性（p < 5.4×10）。在芬兰基因研究项目（FinnGen）中，我们复制了我们有能力复制的预期Bonferroni显著位点数的44%，每个聚类至少有一个，包括含帕他丁样磷脂酶结构域蛋白3（PNPLA3；rs66812091）中的一个内含子变异与非酒精性脂肪性肝病的关联，这是之前报道的加性关联。我们提供的证据表明该关联实际上是隐性的（优势比[OR] = 1.3，隐性p = 2×10，加性p = 2×10，显性偏差p = 3×10，芬兰基因研究项目隐性OR = 1.3且p = 6×10）。我们发现钠葡萄糖转运蛋白4（SGLT4；rs61746559）中的一个错义变异与高血压之间存在一种新的保护性隐性关联，SGLT4在肾素 - 血管紧张素 - 醛固酮系统中可能发挥作用（OR = 0.2，p = 3×10，显性偏差p = 7×10）。这些结果促使我们更广泛地研究常见疾病的隐性效应。
