Division of Endocrinology, Diabetes and Nutrition and Program for Personalized and Genomic Medicine, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.
Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL, USA.
Commun Biol. 2022 Apr 7;5(1):334. doi: 10.1038/s42003-022-03291-2.
Identifying the genetic determinants of inter-individual variation in lipid species (lipidome) may provide deeper understanding and additional insight into the mechanistic effect of complex lipidomic pathways in CVD risk and progression beyond simple traditional lipids. Previous studies have been largely population based and thus only powered to discover associations with common genetic variants. Founder populations represent a powerful resource to accelerate discovery of previously unknown biology associated with rare population alleles that have risen to higher frequency due to genetic drift. We performed a genome-wide association scan of 355 lipid species in 650 individuals from the Amish founder population including 127 lipid species not previously tested. To the best of our knowledge, we report for the first time the lipid species associated with two rare-population but Amish-enriched lipid variants: APOB_rs5742904 and APOC3_rs76353203. We also identified novel associations for 3 rare-population Amish-enriched loci with several sphingolipids and with proposed potential functional/causal variant in each locus including GLTPD2_rs536055318, CERS5_rs771033566, and AKNA_rs531892793. We replicated 7 previously known common loci including novel associations with two sterols: androstenediol with UGT locus and estriol with SLC22A8/A24 locus. Our results show the double power of founder populations and detailed lipidome to discover novel trait-associated variants.
鉴定个体间脂质种类（脂质组）差异的遗传决定因素，可能会深入了解和提供更多的见解，认识到复杂的脂质组学途径在 CVD 风险和进展中的机械作用，超越简单的传统脂质。先前的研究主要基于人群，因此只能发现与常见遗传变异有关的关联。创始人群体是加速发现与罕见人群等位基因相关的未知生物学的有力资源，这些等位基因由于遗传漂变而上升到更高的频率。我们对来自阿米什创始人群体的 650 个人中的 355 种脂质进行了全基因组关联扫描，其中包括 127 种以前未测试过的脂质。据我们所知，我们首次报告了与两种罕见人群但阿米什丰富的脂质变体相关的脂质种类：APOB_rs5742904 和 APOC3_rs76353203。我们还确定了与几个鞘脂以及每个基因座中提议的潜在功能/因果变异体相关的 3 个罕见人群阿米什丰富的基因座的新型关联，包括 GLTPD2_rs536055318、CERS5_rs771033566 和 AKNA_rs531892793。我们复制了 7 个先前已知的常见基因座，包括与两种甾体醇的新关联：与 UGT 基因座的雄烯二酮和与 SLC22A8/A24 基因座的雌三醇。我们的研究结果显示了创始人群体和详细脂质组的双重力量，能够发现新的与特征相关的变异体。
