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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
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 replicati...
Autores principales: | , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8542906/ https://www.ncbi.nlm.nih.gov/pubmed/34707639 http://dx.doi.org/10.3389/fgene.2021.717621 |
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author | Liu, Tianzi Momin, Mohetaboer Zhou, Huiyue Zheng, Qiwen Fan, Fangfang Jia, Jia Liu, Mengyuan Bao, Minghui Li, Jianping Huo, Yong Liu, Jialin Zhang, Yaning Mao, Xuemei Han, Xiao Hu, Zhiyuan Zeng, Changqing Liu, Fan Zhang, Yan |
author_facet | Liu, Tianzi Momin, Mohetaboer Zhou, Huiyue Zheng, Qiwen Fan, Fangfang Jia, Jia Liu, Mengyuan Bao, Minghui Li, Jianping Huo, Yong Liu, Jialin Zhang, Yaning Mao, Xuemei Han, Xiao Hu, Zhiyuan Zeng, Changqing Liu, Fan Zhang, Yan |
author_sort | Liu, Tianzi |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-8542906 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-85429062021-10-26 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 Liu, Tianzi Momin, Mohetaboer Zhou, Huiyue Zheng, Qiwen Fan, Fangfang Jia, Jia Liu, Mengyuan Bao, Minghui Li, Jianping Huo, Yong Liu, Jialin Zhang, Yaning Mao, Xuemei Han, Xiao Hu, Zhiyuan Zeng, Changqing Liu, Fan Zhang, Yan Front Genet Genetics 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. Frontiers Media S.A. 2021-10-11 /pmc/articles/PMC8542906/ /pubmed/34707639 http://dx.doi.org/10.3389/fgene.2021.717621 Text en Copyright © 2021 Liu, Momin, Zhou, Zheng, Fan, Jia, Liu, Bao, Li, Huo, Liu, Zhang, Mao, Han, Hu, Zeng, Liu and Zhang. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Genetics Liu, Tianzi Momin, Mohetaboer Zhou, Huiyue Zheng, Qiwen Fan, Fangfang Jia, Jia Liu, Mengyuan Bao, Minghui Li, Jianping Huo, Yong Liu, Jialin Zhang, Yaning Mao, Xuemei Han, Xiao Hu, Zhiyuan Zeng, Changqing Liu, Fan Zhang, Yan 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 |
title | 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 |
title_full | 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 |
title_fullStr | 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 |
title_full_unstemmed | 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 |
title_short | 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 |
title_sort | 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 |
topic | Genetics |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8542906/ https://www.ncbi.nlm.nih.gov/pubmed/34707639 http://dx.doi.org/10.3389/fgene.2021.717621 |
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