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GWAS of serum ALT and AST reveals an association of SLC30A10 Thr95Ile with hypermanganesemia symptoms

Author

Listed:
  • Lucas D. Ward

    (Alnylam Pharmaceuticals)

  • Ho-Chou Tu

    (Alnylam Pharmaceuticals)

  • Chelsea B. Quenneville

    (Alnylam Pharmaceuticals)

  • Shira Tsour

    (Alnylam Pharmaceuticals)

  • Alexander O. Flynn-Carroll

    (Alnylam Pharmaceuticals)

  • Margaret M. Parker

    (Alnylam Pharmaceuticals)

  • Aimee M. Deaton

    (Alnylam Pharmaceuticals)

  • Patrick A. J. Haslett

    (Alnylam Pharmaceuticals)

  • Luca A. Lotta

    (Regeneron Genetics Center)

  • Niek Verweij

    (Regeneron Genetics Center)

  • Manuel A. R. Ferreira

    (Regeneron Genetics Center)

  • Aris Baras

    (Regeneron Genetics Center)

  • Gregory Hinkle

    (Alnylam Pharmaceuticals)

  • Paul Nioi

    (Alnylam Pharmaceuticals)

Abstract

Understanding mechanisms of hepatocellular damage may lead to new treatments for liver disease, and genome-wide association studies (GWAS) of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) serum activities have proven useful for investigating liver biology. Here we report 100 loci associating with both enzymes, using GWAS across 411,048 subjects in the UK Biobank. The rare missense variant SLC30A10 Thr95Ile (rs188273166) associates with the largest elevation of both enzymes, and this association replicates in the DiscovEHR study. SLC30A10 excretes manganese from the liver to the bile duct, and rare homozygous loss of function causes the syndrome hypermanganesemia with dystonia-1 (HMNDYT1) which involves cirrhosis. Consistent with hematological symptoms of hypermanganesemia, SLC30A10 Thr95Ile carriers have increased hematocrit and risk of iron deficiency anemia. Carriers also have increased risk of extrahepatic bile duct cancer. These results suggest that genetic variation in SLC30A10 adversely affects more individuals than patients with diagnosed HMNDYT1.

Suggested Citation

  • Lucas D. Ward & Ho-Chou Tu & Chelsea B. Quenneville & Shira Tsour & Alexander O. Flynn-Carroll & Margaret M. Parker & Aimee M. Deaton & Patrick A. J. Haslett & Luca A. Lotta & Niek Verweij & Manuel A., 2021. "GWAS of serum ALT and AST reveals an association of SLC30A10 Thr95Ile with hypermanganesemia symptoms," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-24563-1
    DOI: 10.1038/s41467-021-24563-1
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    Cited by:

    1. Xianyong Yin & Lap Sum Chan & Debraj Bose & Anne U. Jackson & Peter VandeHaar & Adam E. Locke & Christian Fuchsberger & Heather M. Stringham & Ryan Welch & Ketian Yu & Lilian Fernandes Silva & Susan K, 2022. "Genome-wide association studies of metabolites in Finnish men identify disease-relevant loci," Nature Communications, Nature, vol. 13(1), pages 1-14, December.

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