Disentangling the genetics of lean mass

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.