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:10.1371/journal.pgen.1005393

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 YinXiaojing 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

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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.

Original language	English (US)
Article number	e1005393
Journal	PLoS genetics
Volume	11
Issue number	8
DOIs	https://doi.org/10.1371/journal.pgen.1005393
State	Published - Aug 1 2015
Externally published	Yes

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© 2015 Huang et al.

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Huang, Y., Wang, C., Yao, Y., Zuo, X., Chen, S., Xu, C., Zhang, H., Lu, Q., Chang, L., Wang, F., Wang, P., Zhang, R., Hu, Z., Song, Q., Yang, X., Li, C., Li, S., Zhao, Y., Yang, Q., ... Wang, Q. K. (2015). Molecular Basis of Gene-Gene Interaction: Cyclic Cross-Regulation of Gene Expression and Post-GWAS Gene-Gene Interaction Involved in Atrial Fibrillation. PLoS genetics, 11(8), Article e1005393. https://doi.org/10.1371/journal.pgen.1005393

Huang, Y, Wang, C, Yao, Y, Zuo, X, Chen, S, Xu, C, Zhang, H, Lu, Q, Chang, L, Wang, F, Wang, P, Zhang, R, Hu, Z, Song, Q, Yang, X, Li, C, Li, S, Zhao, Y, Yang, Q, Yin, D, Wang, X, Si, W, Li, X, Xiong, X, Wang, D, Huang, Y, Luo, C, Li, J, Wang, J, Chen, J, Wang, L, Wang, L, Han, M, Ye, J, Chen, F, Liu, J, Liu, Y, Wu, G, Yang, B, Cheng, X, Liao, Y, Wu, Y, Ke, T, Chen, Q, Tu, X, Elston, R, Rao, S, Yang, Y, Xia, Y & Wang, QK 2015, 'Molecular Basis of Gene-Gene Interaction: Cyclic Cross-Regulation of Gene Expression and Post-GWAS Gene-Gene Interaction Involved in Atrial Fibrillation', PLoS genetics, vol. 11, no. 8, e1005393. https://doi.org/10.1371/journal.pgen.1005393

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title = "Molecular Basis of Gene-Gene Interaction: Cyclic Cross-Regulation of Gene Expression and Post-GWAS Gene-Gene Interaction Involved in Atrial Fibrillation",

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.",

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

note = "Publisher Copyright: {\textcopyright} 2015 Huang et al.",

year = "2015",

month = aug,

day = "1",

doi = "10.1371/journal.pgen.1005393",

language = "English (US)",

volume = "11",

journal = "PLoS genetics",

issn = "1553-7390",

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T1 - Molecular Basis of Gene-Gene Interaction

T2 - Cyclic Cross-Regulation of Gene Expression and Post-GWAS Gene-Gene Interaction Involved in Atrial Fibrillation

AU - Huang, Yufeng

AU - Wang, Chuchu

AU - Yao, Yufeng

AU - Zuo, Xiaoyu

AU - Chen, Shanshan

AU - Xu, Chengqi

AU - Zhang, Hongfu

AU - Lu, Qiulun

AU - Chang, Le

AU - Wang, Fan

AU - Wang, Pengxia

AU - Zhang, Rongfeng

AU - Hu, Zhenkun

AU - Song, Qixue

AU - Yang, Xiaowei

AU - Li, Cong

AU - Li, Sisi

AU - Zhao, Yuanyuan

AU - Yang, Qin

AU - Yin, Dan

AU - Wang, Xiaojing

AU - Si, Wenxia

AU - Li, Xiuchun

AU - Xiong, Xin

AU - Wang, Dan

AU - Huang, Yuan

AU - Luo, Chunyan

AU - Li, Jia

AU - Wang, Jingjing

AU - Chen, Jing

AU - Wang, Longfei

AU - Wang, Li

AU - Han, Meng

AU - Ye, Jian

AU - Chen, Feifei

AU - Liu, Jingqiu

AU - Liu, Ying

AU - Wu, Gang

AU - Yang, Bo

AU - Cheng, Xiang

AU - Liao, Yuhua

AU - Wu, Yanxia

AU - Ke, Tie

AU - Chen, Qiuyun

AU - Tu, Xin

AU - Elston, Robert

AU - Rao, Shaoqi

AU - Yang, Yanzong

AU - Xia, Yunlong

AU - Wang, Qing K.

PY - 2015/8/1

Y1 - 2015/8/1

N2 - 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.

AB - 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.

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

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