Analysis of blood methylation quantitative trait loci in East Asians reveals ancestry-specific impacts on complex traits

Qianqian Peng; Xinxuan Liu; Wenran Li; Han Jing; Jiarui Li; Xingjian Gao; Qi Luo; Charles E Breeze; Siyu Pan; Qiwen Zheng; Guochao Li; Jiaqiang Qian; Liyun Yuan; Na Yuan; Chenglong You; Siyuan Du; Yuanting Zheng; Ziyu Yuan; Jingze Tan; Peilin Jia; Jiucun Wang; Guoqing Zhang; Xianping Lu; Leming Shi; Shicheng Guo; Yun Liu; Ting Ni; Bo Wen; Changqing Zeng; Li Jin; Andrew E Teschendorff; Fan Liu; Sijia Wang

doi:10.1038/s41588-023-01494-9

Analysis of blood methylation quantitative trait loci in East Asians reveals ancestry-specific impacts on complex traits

Nat Genet. 2024 Apr 19. doi: 10.1038/s41588-023-01494-9. Online ahead of print.

Authors

Qianqian Peng^#¹, Xinxuan Liu^#^{2

3}, Wenran Li^#¹, Han Jing^#¹, Jiarui Li¹, Xingjian Gao², Qi Luo¹, Charles E Breeze⁴, Siyu Pan², Qiwen Zheng², Guochao Li², Jiaqiang Qian¹, Liyun Yuan¹, Na Yuan², Chenglong You¹, Siyuan Du¹, Yuanting Zheng^{5

6}, Ziyu Yuan⁷, Jingze Tan⁶, Peilin Jia², Jiucun Wang^{5

7

8}, Guoqing Zhang^{1

7}, Xianping Lu⁹, Leming Shi^{5

6

7}, Shicheng Guo^{10

11}, Yun Liu¹², Ting Ni¹³, Bo Wen^{5

14}, Changqing Zeng², Li Jin^{5

7

8}, Andrew E Teschendorff¹⁵, Fan Liu^{16

17

18}, Sijia Wang^{19

20

21}

Affiliations

¹ CAS Key Laboratory of Computational Biology, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
² CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing, China.
³ School of Future Technology, University of Chinese Academy of Sciences, Beijing, China.
⁴ Altius Institute for Biomedical Sciences, Seattle, WA, USA.
⁵ State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, and Human Phenome Institute, Fudan University, Shanghai, China.
⁶ Ministry of Education Key Laboratory of Contemporary Anthropology, Department of Anthropology and Human Genetics, School of Life Sciences, Fudan University, Shanghai, China.
⁷ Taizhou Institute of Health Sciences, Fudan University, Taizhou, China.
⁸ Research Unit of Dissecting the Population Genetics and Developing New Technologies for Treatment and Prevention of Skin Phenotypes and Dermatological Diseases (2019RU058), Chinese Academy of Medical Sciences, Shanghai, China.
⁹ Shenzhen Chipscreen Biosciences Co. Ltd., Shenzhen, China.
¹⁰ Department of Medical Genetics, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA.
¹¹ Center for Precision Medicine Research, Marshfield Clinic Research Institute, Marshfield, WI, USA.
¹² MOE Key Laboratory of Metabolism and Molecular Medicine, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
¹³ State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, Human Phenome Institute, School of Life Sciences and Huashan Hospital, Fudan University, Shanghai, China.
¹⁴ The Fifth People's Hospital of Shanghai and Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
¹⁵ CAS Key Laboratory of Computational Biology, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China. andrew@picb.ac.cn.
¹⁶ CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing, China. fliu@nauss.edu.sa.
¹⁷ School of Future Technology, University of Chinese Academy of Sciences, Beijing, China. fliu@nauss.edu.sa.
¹⁸ Department of Forensic Sciences, College of Criminal Justice, Naif Arab University of Security Sciences, Riyadh, Kingdom of Saudi Arabia. fliu@nauss.edu.sa.
¹⁹ CAS Key Laboratory of Computational Biology, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China. wangsijia@picb.ac.cn.
²⁰ Taizhou Institute of Health Sciences, Fudan University, Taizhou, China. wangsijia@picb.ac.cn.
²¹ Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming, China. wangsijia@picb.ac.cn.

^# Contributed equally.

PMID: 38641644
DOI: 10.1038/s41588-023-01494-9

Abstract

Methylation quantitative trait loci (mQTLs) are essential for understanding the role of DNA methylation changes in genetic predisposition, yet they have not been fully characterized in East Asians (EAs). Here we identified mQTLs in whole blood from 3,523 Chinese individuals and replicated them in additional 1,858 Chinese individuals from two cohorts. Over 9% of mQTLs displayed specificity to EAs, facilitating the fine-mapping of EA-specific genetic associations, as shown for variants associated with height. Trans-mQTL hotspots revealed biological pathways contributing to EA-specific genetic associations, including an ERG-mediated 233 trans-mCpG network, implicated in hematopoietic cell differentiation, which likely reflects binding efficiency modulation of the ERG protein complex. More than 90% of mQTLs were shared between different blood cell lineages, with a smaller fraction of lineage-specific mQTLs displaying preferential hypomethylation in the respective lineages. Our study provides new insights into the mQTL landscape across genetic ancestries and their downstream effects on cellular processes and diseases/traits.

Abstract

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