Molecular Basis of Gene-Gene Interaction: Cyclic Cross-Regulation of Gene Expression and Post-GWAS Gene-Gene Interaction Involved in Atrial Fibrillation.

Yufeng Huang,Sisi Li,Yuhua Liao,Yuan Huang,Xiaowei Yang,Yufeng Yao,Dan Wang,Jing Chen,Rongfeng Zhang,Meng Han,Jingjing Wang,Jia Li,Tie Ke,Yuanyuan Zhao,Zhenkun Hu,Fan Wang,Bo Yang,Shaoqi Rao,Shanshan Chen,Feifei Chen,Yanzong Yang,Li Wang,Yanxia Wu,Xin Xiong,Xiaoyu Zuo,Chuchu Wang,Qin Yang,Dan Yin,Xiang Cheng,Gang Wu,Xin Tu,Le Chang,Pengxia Wang,Chengqi Xu,Ying Liu,Wenxia Si,Xiaojing Wang,Hongfu Zhang,Xiuchun Li,Qiuyun Chen,Jian Ye,Qiulun Lu,Robert C Elston ,Chi-Wen Luo ,Cong Liu ,Long Wang ,Qingwei Song ,Qing Kenneth Wang

doi:10.1371/journal.pgen.1005393

Abstract

Atrial fibrillation (AF) is the most common cardiac arrhythmia at the clinic. Recent GWAS identified several variants associated with AF, but they account for <10% of heritability. Gene-gene interaction is assumed to account for a significant portion of missing heritability. Among GWAS loci for AF, only three were replicated in the Chinese Han population, including SNP rs2106261 (G/A substitution) in ZFHX3, rs2200733 (C/T substitution) near PITX2c, and rs3807989 (A/G substitution) in CAV1. Thus, we analyzed the interaction among these three AF loci. We demonstrated significant interaction between rs2106261 and rs2200733 in three independent populations and combined population with 2,020 cases/5,315 controls. Compared to non-risk genotype GGCC, two-locus risk genotype AATT showed the highest odds ratio in three independent populations and the combined population (OR=5.36 (95% CI 3.87-7.43), P=8.00×10-24). The OR of 5.36 for AATT was significantly higher than the combined OR of 3.31 for both GGTT and AACC, suggesting a synergistic interaction between rs2106261 and rs2200733. Relative excess risk due to interaction (RERI) analysis also revealed significant interaction between rs2106261 and rs2200733 when exposed two copies of risk alleles (RERI=2.87, P<1.00×10-4) or exposed to one additional copy of risk allele (RERI=1.29, P<1.00×10-4). The INTERSNP program identified significant genotypic interaction between rs2106261 and rs2200733 under an additive by additive model (OR=0.85, 95% CI: 0.74-0.97, P=0.02). Mechanistically, PITX2c negatively regulates expression of miR-1, which negatively regulates expression of ZFHX3, resulting in a positive regulation of ZFHX3 by PITX2c; ZFHX3 positively regulates expression of PITX2C, resulting in a cyclic loop of cross-regulation between ZFHX3 and PITX2c. Both ZFHX3 and PITX2c regulate expression of NPPA, TBX5 and NKX2.5. These results suggest that cyclic cross-regulation of gene expression is a molecular basis for gene-gene interactions involved in genetics of complex disease traits.

Highlights

Genome-wide association studies (GWAS) have been highly successful in identifying common genomic variants that are associated with complex human diseases or traits
We use atrial fibrillation (AF) as a model to demonstrate that gene-gene interaction plays an important role in disease pathogenesis
Three of the ten Atrial fibrillation (AF) loci identified by GWAS in European ancestry populations, including PITX2c, ZFHX3, and CAV1, were replicated in the Chinese population and selected for gene-gene interaction studies

Summary

Introduction

Genome-wide association studies (GWAS) have been highly successful in identifying common genomic variants that are associated with complex human diseases or traits. These common variants have small effects, and in aggregate explain only a small fraction of heritability for most diseases or traits. Genegene interaction has been proposed to be a contributor to the problem of missing heritability. It has been challenging to detect gene-gene interaction in human GWAS. Without doubt, studies of gene-gene interaction will contribute to the understanding of inheritance, inheritance of important diseases and traits, and provide insights into the biological pathways and molecular mechanisms of disease pathogenesis

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