Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, 02114, USA.
Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, 02142, USA.
Nat Commun. 2022 Oct 11;13(1):5995. doi: 10.1038/s41467-022-33510-7.
Blood lipids are heritable modifiable causal factors for coronary artery disease. Despite well-described monogenic and polygenic bases of dyslipidemia, limitations remain in discovery of lipid-associated alleles using whole genome sequencing (WGS), partly due to limited sample sizes, ancestral diversity, and interpretation of clinical significance. Among 66,329 ancestrally diverse (56% non-European) participants, we associate 428M variants from deep-coverage WGS with lipid levels; ~400M variants were not assessed in prior lipids genetic analyses. We find multiple lipid-related genes strongly associated with blood lipids through analysis of common and rare coding variants. We discover several associated rare non-coding variants, largely at Mendelian lipid genes. Notably, we observe rare LDLR intronic variants associated with markedly increased LDL-C, similar to rare LDLR exonic variants. In conclusion, we conducted a systematic whole genome scan for blood lipids expanding the alleles linked to lipids for multiple ancestries and characterize a clinically-relevant rare non-coding variant model for lipids.
血脂是冠心病可遗传的可改变的因果因素。尽管已描述了血脂异常的单基因和多基因基础，但由于样本量有限、祖先多样性以及对临床意义的解释，使用全基因组测序（WGS）发现与脂质相关的等位基因仍然存在局限性。在 66329 名具有不同祖先（56%非欧洲人）的参与者中，我们将深度覆盖 WGS 的 4.28 亿个变体与血脂水平相关联；~4 亿个变体在先前的脂质遗传分析中未被评估。通过对常见和罕见编码变异体的分析，我们发现多个与血液脂质密切相关的脂质相关基因。我们发现了一些与罕见的非编码变异体相关的关联，这些关联主要发生在孟德尔脂质基因上。值得注意的是，我们观察到与 LDL-C 显著增加相关的 LDLR 内含子稀有变异体，类似于 LDLR 外显子稀有变异体。总之，我们进行了一项针对血脂的全基因组系统性扫描，扩大了与多种祖先相关的与脂质相关的等位基因，并对脂质的一种具有临床相关性的罕见非编码变异体模型进行了特征描述。
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