In:
Frontiers in Genetics, Frontiers Media SA, Vol. 12 ( 2021-10-11)
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 & lt; 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 & lt; 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.
Type of Medium:
Online Resource
ISSN:
1664-8021
DOI:
10.3389/fgene.2021.717621
DOI:
10.3389/fgene.2021.717621.s001
DOI:
10.3389/fgene.2021.717621.s002
DOI:
10.3389/fgene.2021.717621.s003
DOI:
10.3389/fgene.2021.717621.s004
DOI:
10.3389/fgene.2021.717621.s005
DOI:
10.3389/fgene.2021.717621.s006
DOI:
10.3389/fgene.2021.717621.s007
DOI:
10.3389/fgene.2021.717621.s008
DOI:
10.3389/fgene.2021.717621.s009
DOI:
10.3389/fgene.2021.717621.s010
Language:
Unknown
Publisher:
Frontiers Media SA
Publication Date:
2021
detail.hit.zdb_id:
2606823-0
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