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Integrative analysis of genetics, epigenetics and RNA expression data reveal three susceptibility loci for smoking behavior in Chinese Han population

Molecular Psychiatry volume 29, pages 3516–3526 (2024)Cite this article

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Abstract

Despite numerous studies demonstrate that genetics and epigenetics factors play important roles on smoking behavior, our understanding of their functional relevance and coordinated regulation remains largely unknown. Here we present a multiomics study on smoking behavior for Chinese smoker population with the goal of not only identifying smoking-associated functional variants but also deciphering the pathogenesis and mechanism underlying smoking behavior in this under-studied ethnic population. After whole-genome sequencing analysis of 1329 Chinese Han male samples in discovery phase and OpenArray analysis of 3744 samples in replication phase, we discovered that three novel variants located near FOXP1 (rs7635815), and between DGCR6 and PRODH (rs796774020), and in ARVCF (rs148582811) were significantly associated with smoking behavior. Subsequently cis-mQTL and cis-eQTL analysis indicated that these variants correlated significantly with the differential methylation regions (DMRs) or differential expressed genes (DEGs) located in the regions where these variants present. Finally, our in silico multiomics analysis revealed several hub genes, like DRD2, PTPRD, FOXP1, COMT, CTNNAP2, to be synergistic regulated each other in the etiology of smoking.

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Fig. 1: Sequencing quality for WGS and association analysis.
Fig. 2: Epigenetic landscape and DMRs analysis.
Fig. 3: Gene coexpression modules with smoking and expression changes in blood.
Fig. 4: Illustration of interaction of multiomics integration for smoking behavior.
Fig. 5: Schematic diagram of multiomics analysis results for rs7635815.

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Data availability

The sequencing data have been deposited in the Genome Sequence Archive (GSA) database with Accession numbers of CRA011029 and HRA007273. Additional information for this study is available from the corresponding author upon reasonable request.

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Acknowledgements

This study was supported in part by the National Natural Science Foundation of China (82271560), China Precision Medicine Initiative (2016YFC0906300), Open project of Joint Research Institute of Tobacco and Health of China (2021539200340045), and Research Center for Air Pollution and Health of Zhejiang University.

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  1. These authors contributed equally: Qiang Liu, Xiaoqiang Shi.

Authors and Affiliations

  1. State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

    Ming D. Li, Qiang Liu, Xiaoqiang Shi, Yan Wang, Jingmin He, Haijun Han, Ying Mao, Yunlong Ma, Wenji Yuan & Zhongli Yang

  2. Research Center for Air Pollution and Health, Zhejiang University, Hangzhou, China

    Ming D. Li

  3. Joint Institute of Tobacco and Health, Kunming, Yunnan, China

    Zhouhai Zhu, Ying Guan & Jianhua Yao

  4. College of Biological Sciences, Shanxi Agricultural University, Taigu, Shanxi, China

    Jingmin He

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Contributions

MDL, QL, XS, YM, YM, HH, WY and ZY participated sample collections; QL, XS, YM, ZZ, JH, YM and ZY participated in data analysis; WY, JY, YG and ZY managed the project; MDL, QL, XS and ZY participated in paper writing and editing; MDL and ZY conceived the study and was involved in every step of it. All authors approved the paper as submitted.

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Correspondence to Ming D. Li or Zhongli Yang.

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Li, M.D., Liu, Q., Shi, X. et al. Integrative analysis of genetics, epigenetics and RNA expression data reveal three susceptibility loci for smoking behavior in Chinese Han population. Mol Psychiatry 29, 3516–3526 (2024). https://doi.org/10.1038/s41380-024-02599-1

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