Khajouei Ehsan, Ghisays Valentina, Piras Ignazio S, Martinez Kiana L, Naymik Marcus, Ngo Preston, Tran Tam C, Denny Joshua C, Wheeler Travis J, Huentelman Matthew J, Reiman Eric M, Karnes Jason H
Department of Pharmacy Practice and Science, R. Ken Coit College of Pharmacy, University of Arizona, Tucson, AZ, USA.
Banner Alzheimer's Institute, Phoenix, AZ, USA.
medRxiv. 2024 Sep 4:2024.09.04.24313010. doi: 10.1101/2024.09.04.24313010.
Genetic variation in is associated with altered lipid metabolism, as well as cardiovascular and neurodegenerative disease risk. However, prior studies are largely limited to European ancestry populations and differential risk by sex and ancestry has not been widely evaluated. We utilized a phenome-wide association study (PheWAS) approach to explore -associated phenotypes in the Research Program.
We determined alleles for 181,880 participants with whole genome sequencing and electronic health record (EHR) data, representing seven gnomAD ancestry groups. We tested association of variants, ordered based on Alzheimer's disease risk hierarchy (ε2/ε2<ε2/ε3<ε3/ε3<ε2/ε4<ε3/ε4<ε4/ε4), with 2,318 EHR-derived phenotypes. Bonferroni-adjusted analyses were performed overall, by ancestry, by sex, and with adjustment for social determinants of health (SDOH).
In the overall cohort, PheWAS identified 17 significant associations, including an increased odds of hyperlipidemia (OR 1.15 [1.14-1.16] per genotype group; =1.8×10), dementia, and Alzheimer's disease (OR 1.55 [1.40-1.70]; =5×10), and a reduced odds of fatty liver disease (OR 0.93 [0.90-0.95]; =1.6×10) and chronic liver disease. ORs were similar after SDOH adjustment and by sex, except for an increased number of cardiovascular associations in males, and decreased odds of noninflammatory disorders of vulva and perineum in females (OR 0.89 [0.84-0.94]; =1.1×10). Significant heterogeneity was observed for hyperlipidemia and mild cognitive impairment across ancestry. Unique associations by ancestry included transient retinal arterial occlusion in the European ancestry group, and first-degree atrioventricular block in the American Admixed/Latino ancestry group.
We replicate extensive phenotypic associations with alleles in a large, diverse cohort, despite limitations in accuracy for EHR-derived phenotypes. We provide a comprehensive catalog of -associated phenotypes and present evidence of unique phenotypic associations by sex and ancestry, as well as heterogeneity in effect size across ancestry.
[基因名称]的基因变异与脂质代谢改变以及心血管疾病和神经退行性疾病风险相关。然而，先前的研究主要局限于欧洲血统人群，性别和血统的差异风险尚未得到广泛评估。我们利用全表型组关联研究（PheWAS）方法在[研究项目名称]中探索与[基因名称]相关的表型。
我们对181,880名参与者进行全基因组测序和电子健康记录（EHR）数据，确定[基因名称]的等位基因，这些参与者代表七个gnomAD血统组。我们根据阿尔茨海默病风险等级（ε2/ε2<ε2/ε3<ε3/ε3<ε2/ε4<ε3/ε4<ε4/ε4）对[基因名称]变异进行排序，并测试其与2318种源自EHR的表型的关联。总体上、按血统、按性别以及对健康的社会决定因素（SDOH）进行调整后进行Bonferroni校正分析。
在整个队列中，PheWAS确定了17种显著关联，包括高脂血症的几率增加（每[基因名称]基因型组的优势比[OR]为1.15[1.14 - 1.16]；P = 1.8×10⁻¹²）、痴呆和阿尔茨海默病（OR 1.55[1.40 - 1.70]；P = 5×10⁻⁸），以及脂肪肝疾病（OR 0.93[0.90 - 0.95]；P = 1.6×10⁻⁶）和慢性肝病的几率降低。在调整SDOH后以及按性别分析时，OR相似，但男性的心血管关联数量增加，女性外阴和会阴非炎性疾病的几率降低（OR 0.89[0.84 - 0.94]；P = 1.1×10⁻⁵）。在高脂血症和轻度认知障碍方面，不同血统之间观察到显著的异质性。按血统的独特关联包括欧洲血统组中的短暂性视网膜动脉阻塞，以及美国混血/拉丁裔血统组中的一度房室传导阻滞。
尽管源自EHR的表型准确性存在局限性，但我们在一个大型、多样化的队列中重复了与[基因名称]等位基因广泛的表型关联。我们提供了与[基因名称]相关表型的综合目录，并展示了按性别和血统的独特表型关联证据，以及不同血统间效应大小的异质性。
