Molecular Basis of Gene-Gene Interaction: Cyclic Cross-Regulation of Gene Expression and Post-GWAS Gene-Gene Interaction Involved in Atrial Fibrillation.
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.
Key Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Center, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, China.
Yufeng
Y
Huang
Key Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Center, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, China.
Chuchu
C
Wang
Key Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Center, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, China.
Yufeng
Y
Yao
Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
Xiaoyu
X
Zuo
Key Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Center, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, China.
Shanshan
S
Chen
Key Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Center, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, China.
Chengqi
C
Xu
Key Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Center, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, China.
Hongfu
H
Zhang
Key Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Center, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, China.
Qiulun
Q
Lu
Key Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Center, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, China.
Le
L
Chang
Key Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Center, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, China.
Fan
F
Wang
Key Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Center, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, China.
Pengxia
P
Wang
Department of Cardiology, First Affiliated Hospital of Dalian Medical University, Dalian, China.
Rongfeng
R
Zhang
Key Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Center, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, China.
Zhenkun
Z
Hu
Key Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Center, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, China.
Qixue
Q
Song
Key Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Center, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, China.
Xiaowei
X
Yang
Key Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Center, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, China.
Cong
C
Li
Key Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Center, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, China.
Sisi
S
Li
Key Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Center, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, China.
Yuanyuan
Y
Zhao
Key Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Center, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, China.
Qin
Q
Yang
Key Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Center, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, China.
Dan
D
Yin
Key Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Center, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, China.
Xiaojing
X
Wang
Key Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Center, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, China.
Wenxia
W
Si
Key Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Center, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, China.
Xiuchun
X
Li
Key Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Center, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, China.
Xin
X
Xiong
Key Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Center, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, China.
Dan
D
Wang
Key Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Center, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, China.
Yuan
Y
Huang
Key Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Center, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, China.
Chunyan
C
Luo
Key Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Center, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, China.
Jia
J
Li
Key Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Center, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, China.
Jingjing
J
Wang
Key Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Center, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, China.
Jing
J
Chen
Key Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Center, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, China.
Longfei
L
Wang
Key Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Center, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, China.
Li
L
Wang
Key Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Center, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, China.
Meng
M
Han
Key Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Center, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, China.
Jian
J
Ye
Department of Cardiology, First Affiliated Hospital of Dalian Medical University, Dalian, China.
Feifei
F
Chen
Department of Cardiology, First Affiliated Hospital of Dalian Medical University, Dalian, China.
Jingqiu
J
Liu
Department of Cardiology, First Affiliated Hospital of Dalian Medical University, Dalian, China.
Ying
Y
Liu
Department of Cardiology, People's Hospital, Wuhan University, Wuhan, China.
Gang
G
Wu
Department of Cardiology, People's Hospital, Wuhan University, Wuhan, China.
Bo
B
Yang
Department of Cardiology, Union Hospital, Huazhong University of Science and Technology, Wuhan, China.
Xiang
X
Cheng
Department of Cardiology, Union Hospital, Huazhong University of Science and Technology, Wuhan, China.
Yuhua
Y
Liao
Department of Cardiology, the First Affiliated Hospital of Wuhan City, Wuhan, China.
Yanxia
Y
Wu
Key Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Center, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, China.
Tie
T
Ke
Center for Cardiovascular Genetics, Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, United States of America; Department of Molecular Medicine, Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, Ohio, United States of America.
Qiuyun
Q
Chen
Key Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Center, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, China.
Xin
X
Tu
Department of Epidemiology and Biostatistics, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States of America.
Robert
R
Elston
Institute of Medical Systems Biology and Department of Medical Statistics and Epidemiology, School of Public Health, Guangdong Medical College, Dongguan, China.
Shaoqi
S
Rao
Department of Cardiology, First Affiliated Hospital of Dalian Medical University, Dalian, China.
Yanzong
Y
Yang
Department of Cardiology, First Affiliated Hospital of Dalian Medical University, Dalian, China.
Yunlong
Y
Xia
Key Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Center, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, China; Center for Cardiovascular Genetics, Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, United States of America; Department of Molecular Medicine, Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, Ohio, United States of America.
Qing K
QK
Wang
D020413:3' Untranslated Regions; D001281:Atrial Fibrillation / Q000235:genetics* / Q000378:metabolism; D009320:Atrial Natriuretic Factor / Q000235:genetics / Q000378:metabolism; D001483:Base Sequence; D001665:Binding Sites; D016022:Case-Control Studies; D051242:Caveolin 1 / Q000235:genetics / Q000378:metabolism; D004843:Epistasis, Genetic; D015870:Gene Expression; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D035683:MicroRNAs / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D034622:RNA Interference; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D000097577:Homeobox Protein PITX2
D020413:3' Untranslated Regions; D009320:Atrial Natriuretic Factor; D051242:Caveolin 1; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins; D035683:MicroRNAs; D014157:Transcription Factors; D000097577:Homeobox Protein PITX2; C495540:CAV1 protein, human; C544547:MIRN1 microRNA, human; C095552:NKX2-5 protein, human; C472955:NPPA protein, human; C071660:ZFHX3 protein, human