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

Einat Granot-Hershkovitz, Brian Spitzer, Yunju Yang, Wassim Tarraf, Bing Yu, Eric Boerwinkle, Myriam Fornage, Thomas H Mosley, Charles DeCarli, Bruce S Kristal, Hector M González, Tamar Sofer

Journal: Translational psychiatry 2023;13(1):140

PMID: 37120436

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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) 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.

Address: Division of Sleep and Circadian Disorders, Brigham and Women's Hospital, Boston, MA, USA.; Department of Medicine, Harvard Medical School, Boston, MA, USA.; Brown Foundation Institute of Molecular Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA.; Institute of Gerontology, Wayne State University, Detroit, MI, USA.; Human Genetics Center, School of Public Health University of Texas Health Science Center at Houston, Houston, TX, USA.; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA.; Department of Neurology, School of Medicine, University of Mississippi Medical Center, Jackson, MS, USA.; Alzheimer's Disease Center, Department of Neurology, University of California, Davis, Sacramento, CA, USA.; Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA.; Division of Sleep and Circadian Disorders, Brigham and Women's Hospital, Boston, MA, USA. [email protected].; Department of Medicine, Harvard Medical School, Boston, MA, USA. [email protected].; Department of Biostatistics, Harvard T.H Chan School of Public Health, Boston, MA, USA. [email protected].; Division of Cardiology, Beth Israel Deaconess Medical Center, Boston, MA, USA. [email protected].

DOI: 10.1038/s41398-023-02437-y

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MeSH Terms: Aminoisobutyric Acids, Genome-Wide Association Study, Polymorphism, Single Nucleotide, Aging, Humans, Amino Acid Metabolism, Inborn Errors, Genetic Loci