Pleiotropic relationships among measures of bone mineral density, bone geometry, lean muscle mass and fat mass

Osteoporosis, sarcopenia and changes in fat distribution with age increase risk of fractures, affect quality of life, and are of major public health significance. Investigations into the genetic architecture of endophenotypes of these conditions could lead to better prediction of who is at greatest risk as well as revealing targets for therapies to delay disease onset or diminish their effects on afflicted individuals. Covariation among these conditions may be due to pleiotropy, although little is known about the specific genes involved. I explored relationships among twenty-two measures of arm and leg bone mineral density and geometry, arm and leg lean mass and arm and leg fat mass using data from two populations of Afro-Caribbeans from the island of Tobago: a sample of 1,937 unrelated men aged ≥ 40 years and a set of 470 men and women aged ≥ 18 years in seven extended pedigrees (mean family size = 67). I also performed genomewide association (GWA) studies of lumber spine and femoral neck bone mineral density (BMD) and fractures in an older (aged ≥ 70 years) population of European and African Americans ( n = 1,663 and 1,139 respectively). Hierarchical and principal component (PC) analysis revealed three clusters: (1) a "geometry group" that comprises mostly bone geometry traits and leanmass (PC1); (2) a "density group" that comprises mostly BMD traits (PC2); and (3) a "fat mass group" that comprises measures of fat mass (PC3). Estimates of residual heritability ranged from 0.206 to 0.763 (p < 0.007 for all traits). Linkage analysis revealed significant evidence (LOD > 3.3) for quantitative trait loci (QTLs) on two chromosomes: 10q for PC1 and tibial periosteal circumference and 21q for PC3 and arm fat mass. GWA analyses of BMD and fractures in European and African Americans revealed several dozen potential candidate loci with suggestive levels of significance ( p ≤ 5 x 10-6), the most promising of which is SLC4A7 on 3q24.1, a sodium bicarbonate cotransporter expressed in osteoclasts. Thus, I present evidence for specific QTLs with pleiotropic effects on multiple body composition traits, as well as loci associated with arealBMDand fracture risk. Additional analyses of these regions could reveal genes that jointly influence susceptibility to osteoporosis, sarcopenia and obesity.