将冠状动脉疾病和体重指数之间的多效性进行分区，揭示了低频变异和中枢神经系统特异性功能元件的重要性。

Partitioning the Pleiotropy Between Coronary Artery Disease and Body Mass Index Reveals the Importance of Low Frequency Variants and Central Nervous System-Specific Functional Elements.

机构信息

From the Ruddy Canadian Cardiovascular Genetics Centre, University of Ottawa, Heart Institute.

出版信息

Circ Genom Precis Med. 2018 Feb;11(2):e002050. doi: 10.1161/CIRCGEN.117.002050.

DOI:10.1161/CIRCGEN.117.002050

PMID:29444804

Abstract

BACKGROUND

The objective of this study is to investigate the extent and nature of pleiotropy between coronary artery disease (CAD) and body mass index (BMI).

METHODS

We examined the contribution of genome-wide single-nucleotide polymorphisms (minor allele frequency ≥0.01) to co-occurrence of CAD and BMI in a sample of genetically unrelated 8041 subjects (genetic resemblance ≤0.025) of European ancestry using mixed-linear-models. We further partitioned the estimated pleiotropy according to biological features to gain insight into the nature of pleiotropy between CAD and BMI.

RESULTS

We found significant (<0.0001) positive genetic correlation between CAD and BMI ( =0.60). The estimated pleiotropy explained 68% of phenotypic correlation, and it was not proportionally distributed across the chromosomes; notably, chromosome 10 contributed more; whereas, chromosomes 11 and 14 contributed less to pleiotropy than expected given their chromosomal length. We noted that a large proportion (63%; =0.002) of the pleiotropy is attributed to single-nucleotide polymorphisms with low allele frequency (minor allele frequency <0.05). Of note, pleiotropy was enriched among central nervous system genes and genes of metabolic pathways. Further analyses revealed that these effects are more pronounced in the proopiomelanocortin pathway and genes involved in carbohydrate metabolism. After genome-wide association study meta-analysis, only single-nucleotide polymorphisms downstream of the gene were found concordantly associated with (<5×10) BMI and CAD with lead single-nucleotide polymorphism being rs663129 (combined =2.7×10). Finally, partitioning the pleiotropy according to functional elements pointed to the importance of superenhancers and notably brain-specific superenhancers.

CONCLUSIONS

Genome-wide pleiotropy substantially contributes to co-occurrence of CAD and obesity, and it is highly enriched among low frequency variants and central nervous system-specific functional elements.

摘要

背景

本研究旨在探讨冠状动脉疾病（CAD）和体重指数（BMI）之间的表型多效性的程度和性质。

方法

我们使用混合线性模型，在一个具有欧洲血统的 8041 名无遗传关系的个体（遗传相似性≤0.025）样本中，检查了全基因组单核苷酸多态性（次要等位基因频率≥0.01）对 CAD 和 BMI 同时发生的贡献。我们进一步根据生物学特征对估计的多效性进行划分，以深入了解 CAD 和 BMI 之间的多效性的性质。

结果

我们发现 CAD 和 BMI 之间存在显著的（<0.0001）正遗传相关性（ =0.60）。估计的多效性解释了表型相关性的 68%，并且它不是按染色体比例分布的；值得注意的是，10 号染色体贡献更大；相比之下，11 号和 14 号染色体的多效性贡献低于根据其染色体长度预期的贡献。我们注意到，大部分（63%； =0.002）多效性归因于等位基因频率较低（次要等位基因频率<0.05）的单核苷酸多态性。值得注意的是，多效性在中枢神经系统基因和代谢途径基因中富集。进一步的分析表明，这些效应在 proopiomelanocortin 途径和参与碳水化合物代谢的基因中更为明显。全基因组关联研究荟萃分析后，仅在基因下游发现单核苷酸多态性与 BMI 和 CAD 一致相关（<5×10），其主要单核苷酸多态性为 rs663129（联合 =2.7×10）。最后，根据功能元件对多效性进行划分，指出了超级增强子的重要性，特别是大脑特异性超级增强子。