The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Nat Commun. 2024 Oct 9;15(1):8741. doi: 10.1038/s41467-024-52939-6.
Whole genome sequences (WGS) enable discovery of rare variants which may contribute to missing heritability of coronary artery disease (CAD). To measure their contribution, we apply the GREML-LDMS-I approach to WGS of 4949 cases and 17,494 controls of European ancestry from the NHLBI TOPMed program. We estimate CAD heritability at 34.3% assuming a prevalence of 8.2%. Ultra-rare (minor allele frequency ≤ 0.1%) variants with low linkage disequilibrium (LD) score contribute ~50% of the heritability. We also investigate CAD heritability enrichment using a diverse set of functional annotations: i) constraint; ii) predicted protein-altering impact; iii) cis-regulatory elements from a cell-specific chromatin atlas of the human coronary; and iv) annotation principal components representing a wide range of functional processes. We observe marked enrichment of CAD heritability for most functional annotations. These results reveal the predominant role of ultra-rare variants in low LD on the heritability of CAD. Moreover, they highlight several functional processes including cell type-specific regulatory mechanisms as key drivers of CAD genetic risk.
全基因组序列（WGS）能够发现可能导致冠状动脉疾病（CAD）遗传率缺失的罕见变异。为了衡量它们的贡献，我们应用 GREML-LDMS-I 方法对 NHLBI TOPMed 计划中 4949 例欧洲血统病例和 17494 例对照的 WGS 进行了分析。我们假设 CAD 的患病率为 8.2%，则 CAD 的遗传率为 34.3%。低连锁不平衡（LD）分数的超罕见（次要等位基因频率≤0.1%）变异体约占遗传率的 50%。我们还使用多种功能注释来研究 CAD 遗传率富集：i）约束；ii）预测蛋白质改变的影响；iii）来自人类冠状动脉特定细胞染色质图谱的顺式调控元件；以及 iv）代表广泛功能过程的注释主成分。我们观察到大多数功能注释的 CAD 遗传率明显富集。这些结果揭示了超罕见变异在低 LD 下对 CAD 遗传率的主要作用。此外，它们突出了包括细胞类型特异性调节机制在内的几个功能过程，这些过程是 CAD 遗传风险的关键驱动因素。
