遗传共定位与生理和药理扰动的整合确定了心脏代谢疾病基因。

Integration of genetic colocalizations with physiological and pharmacological perturbations identifies cardiometabolic disease genes.

机构信息

Biomedical Informatics Training Program, Stanford, CA, USA.

Department of Pathology, Stanford, CA, USA.

出版信息

Genome Med. 2022 Mar 15;14(1):31. doi: 10.1186/s13073-022-01036-8.

DOI:10.1186/s13073-022-01036-8

PMID:35292083

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8925074/

Abstract

BACKGROUND

Identification of causal genes for polygenic human diseases has been extremely challenging, and our understanding of how physiological and pharmacological stimuli modulate genetic risk at disease-associated loci is limited. Specifically, insulin resistance (IR), a common feature of cardiometabolic disease, including type 2 diabetes, obesity, and dyslipidemia, lacks well-powered genome-wide association studies (GWAS), and therefore, few associated loci and causal genes have been identified.

METHODS

Here, we perform and integrate linkage disequilibrium (LD)-adjusted colocalization analyses across nine cardiometabolic traits (fasting insulin, fasting glucose, insulin sensitivity, insulin sensitivity index, type 2 diabetes, triglycerides, high-density lipoprotein, body mass index, and waist-hip ratio) combined with expression and splicing quantitative trait loci (eQTLs and sQTLs) from five metabolically relevant human tissues (subcutaneous and visceral adipose, skeletal muscle, liver, and pancreas). To elucidate the upstream regulators and functional mechanisms for these genes, we integrate their transcriptional responses to 21 relevant physiological and pharmacological perturbations in human adipocytes, hepatocytes, and skeletal muscle cells and map their protein-protein interactions.

RESULTS

We identify 470 colocalized loci and prioritize 207 loci with a single colocalized gene. Patterns of shared colocalizations across traits and tissues highlight different potential roles for colocalized genes in cardiometabolic disease and distinguish several genes involved in pancreatic β-cell function from others with a more direct role in skeletal muscle, liver, and adipose tissues. At the loci with a single colocalized gene, 42 of these genes were regulated by insulin and 35 by glucose in perturbation experiments, including 17 regulated by both. Other metabolic perturbations regulated the expression of 30 more genes not regulated by glucose or insulin, pointing to other potential upstream regulators of candidate causal genes.

CONCLUSIONS

Our use of transcriptional responses under metabolic perturbations to contextualize genetic associations from our custom colocalization approach provides a list of likely causal genes and their upstream regulators in the context of IR-associated cardiometabolic risk.

摘要

背景

多基因人类疾病的因果基因鉴定极具挑战性，我们对生理和药理刺激如何调节与疾病相关基因座的遗传风险的理解也很有限。具体来说，胰岛素抵抗（IR）是代谢性心血管疾病（包括 2 型糖尿病、肥胖和血脂异常）的共同特征，但缺乏有力的全基因组关联研究（GWAS），因此，很少有相关基因座和因果基因被鉴定出来。

方法

在这里，我们进行并整合了九个代谢性心血管特征（空腹胰岛素、空腹血糖、胰岛素敏感性、胰岛素敏感性指数、2 型糖尿病、甘油三酯、高密度脂蛋白、体重指数和腰臀比）的连锁不平衡（LD）调整后的共定位分析，同时结合来自五个与代谢相关的人体组织（皮下和内脏脂肪、骨骼肌、肝脏和胰腺）的表达和剪接数量性状基因座（eQTL 和 sQTL）。为了阐明这些基因的上游调控因子和功能机制，我们整合了它们对人类脂肪细胞、肝细胞和骨骼肌细胞中 21 种相关生理和药理扰动的转录反应，并对它们的蛋白质-蛋白质相互作用进行了映射。

结果

我们鉴定出 470 个共定位基因座，并优先考虑了 207 个具有单个共定位基因的基因座。跨特征和组织的共享共定位模式突出了共定位基因在代谢性心血管疾病中的不同潜在作用，并区分了一些参与胰岛β细胞功能的基因与其他更直接作用于骨骼肌、肝脏和脂肪组织的基因。在具有单个共定位基因的基因座中，有 42 个基因受到胰岛素的调节，35 个基因受到葡萄糖的调节，其中 17 个基因受到两者的共同调节。其他代谢性扰动调节了 30 个不受葡萄糖或胰岛素调节的更多基因的表达，这表明候选因果基因的其他潜在上游调控因子。