PLoS Genetics (Aug 2015)

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

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

DOI
https://doi.org/10.1371/journal.pgen.1005393
Journal volume & issue
Vol. 11, no. 8
p. e1005393

Abstract

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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.