Display options
Cite
Chen CH, Kraemer BR, Lee L, et al. Annotation of 1350 Common Genetic Variants of the 19 ALDH Multigene Family from Global Human Genome Aggregation Database (gnomAD). Biomolecules. 2021;11(10)doi: 10.3390/biom11101423.
Chen, C. H., Kraemer, B. R., Lee, L., & Mochly-Rosen, D. (2021). Annotation of 1350 Common Genetic Variants of the 19 ALDH Multigene Family from Global Human Genome Aggregation Database (gnomAD). Biomolecules, 11(10), . https://doi.org/10.3390/biom11101423
Chen, Che-Hong, et al. "Annotation of 1350 Common Genetic Variants of the 19 ALDH Multigene Family from Global Human Genome Aggregation Database (gnomAD)." Biomolecules vol. 11,10 (2021). doi: https://doi.org/10.3390/biom11101423
Chen CH, Kraemer BR, Lee L, Mochly-Rosen D. Annotation of 1350 Common Genetic Variants of the 19 ALDH Multigene Family from Global Human Genome Aggregation Database (gnomAD). Biomolecules. 2021 Sep 29;11(10). doi: 10.3390/biom11101423. PMID: 34680056; PMCID: PMC8533364.
Copy Download .nbib Format: NLM
Share it on

Biomolecules. 2021 Sep 29;11(10). doi: 10.3390/biom11101423.

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

Biomolecules

Che-Hong Chen, Benjamin R Kraemer, Lucia Lee, Daria Mochly-Rosen

Affiliations

  1. Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.

PMID: 34680056 PMCID: PMC8533364 DOI: 10.3390/biom11101423

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.

Keywords: ALDH; aldehyde; aldehyde dehydrogenase; genetic variants; gnomAD

References

  1. J Biol Chem. 1991 Jul 5;266(19):12257-65 - PubMed
  2. Nat Struct Biol. 1997 Apr;4(4):317-26 - PubMed
  3. J Biol Chem. 2000 Dec 29;275(52):41210-8 - PubMed
  4. J Biol Chem. 2007 Feb 16;282(7):4382-4392 - PubMed
  5. Free Radic Biol Med. 2003 May 1;34(9):1178-89 - PubMed
  6. Expert Opin Drug Metab Toxicol. 2008 Jun;4(6):697-720 - PubMed
  7. Drug Metab Dispos. 2010 Oct;38(10):1679-87 - PubMed
  8. Free Radic Biol Med. 1991;11(1):81-128 - PubMed
  9. Nat Commun. 2020 May 27;11(1):2539 - PubMed
  10. Adv Exp Med Biol. 1997;414:9-13 - PubMed
  11. Pharmacol Rev. 2007 Jun;59(2):125-50 - PubMed
  12. Drug Metab Rev. 2004 May;36(2):279-99 - PubMed
  13. Nurs J India. 1995 Jan;86(1):4-6 - PubMed
  14. Nat Protoc. 2016 Jan;11(1):1-9 - PubMed
  15. Eur J Hum Genet. 2020 Jan;28(1):88-94 - PubMed
  16. BMC Neurol. 2019 Dec 29;19(1):345 - PubMed
  17. Biochemistry. 1987 Sep 8;26(18):5679-84 - PubMed
  18. Nat Rev Drug Discov. 2004 Sep;3(9):739-48 - PubMed
  19. Pharmacol Rev. 2012 Jul;64(3):520-39 - PubMed
  20. Front Biosci (Landmark Ed). 2015 Jan 01;20:335-76 - PubMed
  21. Nature. 2020 May;581(7809):434-443 - PubMed
  22. Nucleic Acids Res. 2017 Jan 4;45(D1):D840-D845 - PubMed
  23. Nat Commun. 2020 May 27;11(1):2523 - PubMed
  24. DNA Repair (Amst). 2020 Apr;88:102806 - PubMed
  25. Hum Mutat. 2005 Jul;26(1):1-10 - PubMed
  26. Pharmacology. 2000 Sep;61(3):192-8 - PubMed
  27. Ann Hum Genet. 2009 May;73(Pt 3):335-45 - PubMed
  28. Chem Biol Interact. 2003 Feb 1;143-144:5-22 - PubMed
  29. Proc Natl Acad Sci U S A. 1984 Jan;81(1):258-61 - PubMed
  30. PLoS Med. 2009 Mar 24;6(3):e50 - PubMed
  31. Biomolecules. 2015 Nov 05;5(4):2987-3008 - PubMed
  32. Nature. 2016 Aug 17;536(7616):285-91 - PubMed
  33. Alcohol Res Health. 2006;29(4):245-54 - PubMed
  34. Nature. 2020 May;581(7809):452-458 - PubMed
  35. Nat Med. 2020 Jun;26(6):869-877 - PubMed
  36. Nature. 2020 May;581(7809):444-451 - PubMed
  37. Hum Genomics. 2011 May;5(4):283-303 - PubMed
  38. Nat Med. 2006 Mar;12(3):307-9 - PubMed
  39. J Biomed Sci. 2017 Jan 5;24(1):3 - PubMed
  40. Free Radic Biol Med. 2006 Nov 1;41(9):1459-69 - PubMed
  41. Hum Genomics. 2005 Jun;2(2):138-43 - PubMed
  42. Front Mol Biosci. 2021 May 14;8:659550 - PubMed
  43. Nat Methods. 2010 Apr;7(4):248-9 - PubMed
  44. J Biol Chem. 2005 Aug 26;280(34):30550-6 - PubMed
  45. Metab Brain Dis. 2021 Aug;36(6):1413-1417 - PubMed
  46. Biochemistry. 1996 Apr 9;35(14):4457-67 - PubMed
  47. Exp Eye Res. 1996 Jul;63(1):117-20 - PubMed
  48. DNA Repair (Amst). 2007 Aug 1;6(8):1145-54 - PubMed
  49. Enzyme. 1992;46(4-5):239-44 - PubMed
  50. Nature. 2020 May;581(7809):459-464 - PubMed
  51. EBioMedicine. 2020 May;55:102753 - PubMed
  52. Biochimie. 2021 Apr;183:49-54 - PubMed

Publication Types

Grant support