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Lean Body Mass Meta-Analysis Leads to New Loci

NEW YORK (GenomeWeb) – A new meta-analysis has identified a handful of new and known loci with significant ties to lean body mass over some or all of the body.

Members of an international team brought together genotyping data for more than 100,000 individuals genotyped for dozens of past studies. Their initial search for variants related to overall lean body mass and lean body mass on the arms and legs led to 21 suspicious SNPs — a set they whittled down to eight main loci through replication analyses. 

In particular, the team saw five loci influencing lean body mass over the whole body, including SNPS in and around the HSD17B11, VCAN, ADAMTSL3, IRS1, and FTO genes. Three of the same variants, in VCAN, ADAMTSL3, and IRS1, remained at the end of the appendicular lean body mass analysis, which focused on muscle tone on individuals' arms and legs. The results appeared online yesterday in Nature Communications.

"Our findings shed light on pathophysiological mechanisms underlying lean mass variation and potential complex interrelations between the genetic architecture of muscle mass, fat mass, body height, and metabolic disease," senior author Douglas Kiel, a researcher affiliated with the Institute for Aging Research, Harvard Medical School, and Beth Israel Deaconess Medical Center, and his co-authors wrote.

An individual's skeletal muscle — the main component of lean body mass — profoundly impacts his or her strength, stamina, mobility, and balance, the team explained. And those factors, in turn, contribute to health and quality of life, as evidenced by some of the symptoms that take hold in aging individuals who lose skeletal muscle.

Given the apparent heritability of lean mass patterns, the researchers reasoned that it may be possible to find new genetic factors in such muscle features by amalgamating information from many body composition-focused genome-wide association studies.

The team began by analyzing genotyping data for 38,292 individuals of European ancestry between the ages of 18 and 100 whose whole-body composition had been documented with X-ray absorptiometry or bioelectrical impedance analysis profiling for 20 prior studies.

Arm and leg-specific lean body mass measurements were also available for 28,330 of the individuals, the researchers explained, and factors ranging from fat mass and height to individuals' age and sex were taken into account when estimating overall and appendicular lean body mass.

When the team took the 21 SNPs forward for replication in another 48,125 participants with whole body composition data and in 42,258 individuals with appendicular lean mass measurements, it found five main SNPs of interest near HSD17B11, VCAN, ADAMTSL3, IRS1, and FTO.

When the researchers searched data from the Genetic Investigation of Anthropometric Traits (GIANT) consortium, they found that some of the same SNPs showed ties to other body traits, such as body mass index, hip circumference, or waist circumference.

Even so, the authors argued that "[g]enetic determinants of lean body mass cannot be studied specifically by using anthropometric measures such as height, waist circumference, hip circumference, or BMI, as evidenced by our finding of associations between genetic loci and lean mass that were not observed in results from the GIANT consortium."

The team also considered potential regulatory and/or expression quantitative trait loci roles for the SNPs based on comparisons with data from other large research efforts such as ENCODE and the Epigenetic Roadmap Project.