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Disentangling the genetics of lean mass.

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This study identified a new genetic locus for lean body mass (LM) and found that its effect on metabolic health depends on its relationship with fat mass. Different fat mass adjustments impact genetic discoveries for LM.

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Area of Science:

  • Genetics
  • Metabolic Health
  • Body Composition

Background:

  • Lean body mass (LM) is crucial for mobility and metabolism.
  • Previous genetic studies on LM adjusted for fat mass may have missed key signals.
  • Understanding genetic influences on LM requires careful consideration of fat mass adjustments.

Purpose of the Study:

  • To investigate how different fat mass adjustments affect the genetic architecture of LM.
  • To identify novel genetic loci associated with LM.
  • To explore the distinct roles of LM-associated loci in relation to fat mass.

Main Methods:

  • Genome-wide association analyses were conducted on whole-body LM in over 38,000 individuals of European ancestry.
  • LM was measured using dual-energy X-ray absorptiometry or bioelectrical impedance analysis.
  • Analyses included models with no fat adjustment, percentage of body mass fat adjustment, and fat mass in kilograms adjustment.

Main Results:

  • Seven single-nucleotide polymorphisms (SNPs) in distinct loci, including a novel LM locus (TNRC6B), were replicated in nearly 47,000 individuals.
  • Loci affecting both LM and fat mass in the same direction were termed "sumo wrestler" loci (e.g., FTO, MC4R).
  • Loci specifically impacting LM were termed "body builder" loci (e.g., VCAN, ADAMTSL3), with differing metabolic associations.

Conclusions:

  • One novel LM locus, TNRC6B, was identified.
  • Genetically determined increases in LM can have either detrimental or beneficial metabolic effects, contingent on their association with fat mass.
  • The impact of genetic factors on metabolic traits is influenced by how they interact with both lean and fat mass.