Genome-wide association study identifies a functional myostatin variant increasing lean mass in humans

  1. Adalheidur Larusdottir
  2. Unnur Teitsdottir
  3. Vinicius Tragante
  4. Frosti Palsson
  5. Anna Kristinsdottir
  6. Grimur Hjorleifsson Eldjarn
  7. Lilja Stefansdottir
  8. Asmundur Oddsson
  9. Hildur Aegisdottir
  10. Unnur Styrkarsdottir
  11. Mariana Bustamante
  12. Thorunn Olafsdottir
  13. Audunn Snaebjarnarson
  14. Thorhildur Olafsdottir
  15. Gudmundur Einarsson
  16. Sigurjon Gudjonsson
  17. Gisli Halldorsson
  18. Egil Ferkingstad
  19. Arnar Sigurdarson Sandholt
  20. Felix Vaura
  21. Fanny-Dhelia Pajuste
  22. Samuli Ripatti
  23. Aarno Palotie
  24. Triin Laisk
  25. Reedik Magi
  26. Sisse Ostrowski
  27. Ole Pedersen
  28. Erik Sørensen
  29. Johan Bundgaard
  30. Christian Erikstrup
  31. Christina Mikkelsen
  32. Mie Topholm Bruun
  33. Bitten Aagaard
  34. Henrik Ullum
  35. Henning Bundgaard
  36. Jannicke Igland
  37. Ole Andreassen
  38. Jan Haavik
  39. R Lumbers
  40. Sonia Shah
  41. Nick Sunderland
  42. Jiayue-Clara Jiang
  43. Kirk U. Knowlton
  44. Lincoln Nadauld
  45. DBDS Genomic Consortium
  46. Estonian Biobank Research Team
  47. FinnGen FinnGen
  48. Gudmundur Thorgeirsson
  49. Patrick Sulem
  50. Unnur Thorsteinsdottir
  51. Ragnar Bjarnason
  52. Erna Ivarsdottir
  53. Gardar Sveinbjornsson
  54. Rosa Thorolfsdottir
  55. Gudmundur Norddahl
  56. Valgerdur Steinthorsdottir
  57. Gudmar Thorleifsson
  58. Hilma Holm
  59. Anna Helgadottir
  60. Daniel Gudbjartsson
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Abstract

Muscle mass is central to physical function and metabolic health 1 , but can decrease with disease, aging 2 and weight loss interventions 3-5 . As such interventions become more widely used, agents that preserve or increase muscle mass are needed. To identify such therapeutic opportunities, we performed genome-wide association meta-analyses (GWAS) of arm, leg, trunk and total lean mass measured by dual-energy X-ray absorptiometry (DXA), a widely used method to estimate muscle mass. We identified 63 loci, including the rare missense variant in MSTN (p.Ile225Thr, rs143242500), which had the largest effect on leg lean mass (β = 0.28 SD [95% CI: 0.19, 0.37], P = 1.9 × 10 -9 ). MSTN encodes myostatin, a negative regulator of skeletal muscle mass and a therapeutic target for muscle wasting disorders 6 . p.Ile225Thr is the first genome-wide significant association in MSTN in humans with functional consequences and could provide further insight into long-term systemic effects of myostatin inhibition.

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