Exome-Wide Association Study Identifies East Asian-Specific Missense Variant MTHFR C136T Influencing Homocysteine Levels in Chinese Populations RH: ExWAS of tHCY in a Chinese Population

Tianzi Liu; Mohetaboer Momin; Huiyue Zhou; Qiwen Zheng; Fangfang Fan; Jia Jia; Mengyuan Liu; Minghui Bao; Jianping Li; Yong Huo; Jialin Liu; Yaning Zhang; Xuemei Mao; Xiao Han; Zhiyuan Hu; Changqing Zeng; Fan Liu; Yan Zhang

doi:10.3389/fgene.2021.717621

Exome-Wide Association Study Identifies East Asian-Specific Missense Variant MTHFR C136T Influencing Homocysteine Levels in Chinese Populations RH: ExWAS of tHCY in a Chinese Population

Front Genet. 2021 Oct 11:12:717621. doi: 10.3389/fgene.2021.717621. eCollection 2021.

Authors

Tianzi Liu^{1

2}, Mohetaboer Momin^{3

4}, Huiyue Zhou^{1

2}, Qiwen Zheng^{1

2}, Fangfang Fan^{3

4}, Jia Jia^{3

4}, Mengyuan Liu^{3

4}, Minghui Bao^{3

4}, Jianping Li^{3

4}, Yong Huo^{3

4}, Jialin Liu^{1

2

5}, Yaning Zhang^{1

2

5}, Xuemei Mao⁶, Xiao Han⁶, Zhiyuan Hu^{6

7

8}, Changqing Zeng^{1

2

5}, Fan Liu^{1

2

5}, Yan Zhang^{3

4}

Affiliations

¹ CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China.
² China National Center for Bioinformation, Beijing, China.
³ Department of Cardiology, Peking University First Hospital, Beijing, China.
⁴ Institute of Cardiovascular Disease, Peking University First Hospital, Beijing, China.
⁵ University of Chinese Academy of Sciences, Beijing, China.
⁶ Beijing P4 Healthcare Institute, Beijing, China.
⁷ CAS Key Laboratory of Standardization and Measurement for Nanotechnology, CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology of China, Beijing, China.
⁸ School of Nanoscience and Technology, Sino-Danish College, University of Chinese Academy of Sciences, Beijing, China.

Abstract

Plasma total homocysteine (tHCY) is a known risk factor of a wide range of complex diseases. No genome scans for tHCY have been conducted in East Asian populations. Here, we conducted an exome-wide association study (ExWAS) for tHCY in 5,175 individuals of Chinese Han origin, followed by a replication study in 668 Chinese individuals. The ExWAS identified two loci, 1p36.22 (lead single-nucleotide polymorphism (SNP) rs1801133, MTHFR C677T) and 16q24.3 (rs1126464, DPEP1), showing exome-wide significant association with tHCY (p < 5E-7); and both loci have been previously associated with tHCY in non-East Asian populations. Both SNPs were replicated in the replication study (p < 0.05). Conditioning on the genotype of C677T and rs1126464, we identified a novel East Asian-specific missense variant rs138189536 (C136T) of MTHFR (p = 6.53E-10), which was also significant in the replication study (p = 9.8E-3). The C136T and C677T variants affect tHCY in a compound heterozygote manner, where compound heterozygote and homozygote genotype carriers had on average 43.4% increased tHCY than had other genotypes. The frequency of the homozygote C677T genotype showed an inverse-U-shaped geospatial pattern globally with a pronounced frequency in northern China, which coincided with the high prevalence of hyperhomocysteinemia (HHCY) in northern China. A logistic regression model of HHCY status considering sex, age, and the genotypes of the three identified variants reached an area under the receiver operating characteristic curve (AUC) value of 0.74 in an independent validation cohort. These genetic observations provide new insights into the presence of multiple causal mutations at the MTHFR locus, highlight the role of genetics in HHCY epidemiology among different populations, and provide candidate loci for future functional studies.

Keywords: MTHFR C136T; MTHFR C677T; coding variants; homocysteine; hyperhomocysteinemia; population heterogeneity.