Genetic loci of beta-aminoisobutyric acid are associated with aging-related mild cognitive impairment

Abstract

We studied the genetic associations of a previously developed Metabolomic Risk Score (MRS) for Mild Cognitive Impairment (MCI) and beta-aminoisobutyric acid metabolite (BAIBA)—the metabolite highlighted by results from a genome-wide association study (GWAS) of the MCI-MRS, and assessed their association with MCI in datasets of diverse race/ethnicities. We first performed a GWAS for the MCI-MRS and BAIBA, in Hispanic/Latino adults (n = 3890) from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). We identified ten independent genome-wide significant (p value <5 × 10−8) variants associated with MCI-MRS or BAIBA. Variants associated with the MCI-MRS are located in the Alanine-Glyoxylate Aminotransferase 2 (AGXT2 gene), which is known to be associated with BAIBA metabolism. Variants associated with BAIBA are located in the AGXT2 gene and in the SLC6A13 gene. Next, we tested the variants’ association with MCI in independent datasets of n = 3178 HCHS/SOL older individuals, n = 3775 European Americans, and n = 1032 African Americans from the Atherosclerosis Risk In Communities (ARIC) study. Variants were considered associated with MCI if their p value <0.05 in the meta-analysis of the three datasets and their direction of association was consistent with expectation. Rs16899972 and rs37369 from the AGXT2 region were associated with MCI. Mediation analysis supported the mediation effect of BAIBA between the two genetic variants and MCI (p value = 0.004 for causal mediated effect). In summary, genetic variants in the AGXT2 region are associated with MCI in Hispanic/Latino, African, and European American populations in the USA, and their effect is likely mediated by changes in BAIBA levels.

Functional AGXT2 SNP rs180749 variant and depressive symptoms: Baseline data from the Aidai Cohort Study in Japan

“…Alanine-glyoxylate aminotransferase 2 (AGXT2) was first identified as an important enzyme related to the metabolism of R-3-amino isobutyrate in 1969 (Kakimoto et al 1969b ). AGXT2 single-nucleotide polymorphisms (SNPs) are related to systemic diseases [coronary artery disease (Amir et al 2018 ), carotid atherosclerosis (Yoshino et al 2014b ), chronic heart failure (Hu et al 2016 ), diabetes mellitus (DM) (Kumon et al 2022 ), and mild cognitive impairment (Granot-Hershkovitz et al 2023 )] and biological parameters [blood pressure, sugar, and creatinine (Yoshino et al 2021 )]. Missense AGXT2 SNPs rs37370 (S102N), rs37369 (V140I), rs180749 (T212I), and rs16899974 (V498L) and the haplotype of those SNPs were found to be associated with loss of AGXT2 activity (Yoshino et al 2014a , 2021 ).…”