Background. Total lean mass (LEAN-tot) is one of the three major components of body weight. Its deterioration is a risk factor for frailty. Despite this, there are few studies examining the contribution of genetic factors.

Objective. To examine the contribution of genetic factors for LEAN-tot variation, including a genome-wide search for the genes.

Research Methods. Dual-energy X-ray absoprtiometry (DXA) measurements of LEAN-tot were obtained from each of the 3180 UK females, (509 monozygotic and 1081 dizygotic twin pairs). Contribution of genetic factors was assessed using variance component analysis. A genome-wide linkage analysis was performed on the dizygotic twins using a modified version of the Haseman-Elston method.

Results. Age, body height, total fat and bone mass (FAT-tot, BMD-tot) were correlated with LEAN-tot and commonly explained 52% of the LEAN-tot variation. The crude h² was 74.0±4.0%, after adjustment for the above factors, 65.2±4.6% was attributable to independent genetic effects. Significant (p<0.001) genetic correlations were found between LEAN-tot and BMD-tot and LEAN-tot and FAT-tot. Adjusted only for age, LEAN-tot showed no significant linkage. After adjustment for all covariates, significant linkage (LOD = 4.49 and 3.62) was observed at chromosome 12q24.3 and 14q22.3 respectively. Additional peaks of interest were on 7p15.3-15.1 (LOD = 2.86) and 8p22 (LOD = 2.83).

Conclusions. LEAN-tot measured by DXA is highly heritable, independent of other body measures. This first genomic search for genes associated with the lean component of body mass suggests significant linkage to QTLs on chromosomes 12 and 14.