Annotation of 1350 Common Genetic Variants of the 19 ALDH Multigene Family from Global Human Genome Aggregation Database (gnomAD)

Abstract

Human aldehyde dehydrogenase (ALDH) is a multigene family with 19 functional members encoding a class of diverse but important enzymes for detoxification or biotransformation of different endogenous and exogenous aldehyde substrates. Genetic mutations in the ALDH genes can cause the accumulation of toxic aldehydes and abnormal carbonyl metabolism and serious human pathologies. However, the physiological functions and substrate specificity of many ALDH genes are still unknown. Although many genetic variants of the ALDH gene family exist in human populations, their phenotype or clinical consequences have not been determined. Using the most comprehensive global human Genome Aggregation Database, gnomAD, we annotated here 1350 common variants in the 19 ALDH genes. These 1350 common variants represent all known genetic polymorphisms with a variant allele frequency of ≥0.1% (or an expected occurrence of ≥1 carrier per 500 individuals) in any of the seven major ethnic groups recorded by gnomAD. We detailed 13 types of DNA sequence variants, their genomic positions, SNP ID numbers, and allele frequencies among the seven major ethnic groups worldwide for each of the 19 ALDH genes. For the 313 missense variants identified in the gnomAD, we used two software algorithms, Polymorphism Phenotyping (PolyPhen) and Sorting Intolerant From Tolerant (SIFT), to predict the consequences of the variants on the structure and function of the enzyme. Finally, gene constraint analysis was used to predict how well genetic mutations were tolerated by selection forces for each of the ALDH genes in humans. Based on the ratio of observed and expected variant numbers in gnomAD, the three ALDH1A gene members, ALDH1A1, ALDH1A2, and ALDH1A3, appeared to have the lowest tolerance for loss-of-function mutations as compared to the other ALDH genes (# observed/# expected ratio 0.15–0.26). These analyses suggest that the ALDH1A1, ALDH1A2, and ALDH1A3 enzymes may serve a more essential function as compared with the other ALDH enzymes; functional loss mutations are much less common in healthy human populations than expected. This informatic analysis may assist the research community in determining the physiological function of ALDH isozymes and associate common variants with clinical phenotypes.

A cryo-electron microscopic approach to elucidate protein structures from human brain microsomes

“…It should be noted that a mutation on residue T555 of DPYSL2 to an alanine has been observed to cause the impairment of dendritic growth in cerebellar Purkinje cells ( Winkler et al, 2020 ), although the C-terminal residues 507–572 of DPYSL2 were not included in the structural model. (iii) For the ALDH1A1 enzyme, there is strong evidence that the A134S and I140T missense mutants are strongly linked to congenital heart disease ( Chen et al, 2021 ).…”

Identification of Genetic Variations in the NAD-Related Pathways for Patients with Major Depressive Disorder: A Case-Control Study in Taiwan

“…This implies that the variants of the ALDH8A1 or other ALDH isozymes may also play a role in maintaining the balance of NAD levels. A total of 1350 common ALDH genetic variants have been compiled recently based on the gnomAD human genome database [43]. Therefore, we investigated a selected panel of the common East Asian ALDH variants between our MDD cases and the healthy controls.…”

Aldehydes, Aldehyde Metabolism, and the ALDH2 Consortium

“…Although much attention focuses on ALDH2 and the ALDH2*2 genetic variant regarding aldehyde metabolism, this enzyme is also only one of 19 enzymes within the aldehyde dehydrogenase family. In this regard, Che-Hong Chen et al used the global human Genome Aggregation Database (gnomAD) to identify genetic variants for the ALDH family followed by the Polymorphism Phenotyping (PolyPhen) and Sorting Intolerant From Tolerant (SIFT) tools to predict how genetic variants affect structure and function for ALDH enzymes [ 29 ]. The key finding was that the ALDH1A gene members (ALDH1A1, ALDH1A2, and ALDH1A3) have the lowest tolerance for loss-of-function mutations as compared to the other ALDH genes, and are much less common in healthy human populations than expected relative to other ALDH enzyme variants.…”