Published work: So far our grop have have contributed to numerous genomic discoveries in the musculoskeletal field, achieved together with researchers from > 30 countries brought together by GEFOS consortium. In the early 2008 Richards, Rivadeneira et al [ref] identified two variants associated with lumbar spine and femoral neck bone mineral density (BMD) mapping to LRP5 and TNFRSF11B (OPG) in only 8,557 individuals; genes implicated in well-established bone metabolism pathways. Nevertheless, the largest yield in discoveries has been facilitated by the rise of GEFOS collaborative network giving way to large-scale GWAS meta-analyses that identified novel bone regions and pathways. The first meta-analysis of the GEFOS consortium (Ntotal=19,195) identified 13 novel loci associated with BMD [ref] followed by a second GEFOS meta-analysis (Ndiscovery=32,961) which replicated the majority of known BMD loci and identified additional 32 novel loci (Ntotal=83,894) [ref]. Fourteen of the BMD-associated loci were also associated with osteoporotic fractures, with those mapping to FAM210A, SLC25A13, LRP5, MEPE, SPTBN1 and DKK1 showing strongest association. This study was followed by additional large meta-analysis by Zheng et al [ref] which have provided evidence that low-frequency non-coding variants also have large effects on BMD and fracture. Next, in 2018 Medina et al. [ref] in a meta-analysis of 30 GWASs (Ntotal=66,628) identified 80 loci associated with total body BMD, of which 36 had not been previously identified. Moreover, in the age-stratified analyses only two loci displayed evidence for age-specific effects, including variants in ESR1 and in close proximity to RANKL. These findings suggest that most of the genes identified throughout the life-course, exert an effect on peak BMD acquisition and this effect can still be observed decades later [ref]. In 2018, Trajanoska et al. [ref] conducted the largest GWAS on osteoporotic fractures to date comprising 37,857 cases and 227,116 non-cases with replication in up to 300,000 individuals (147,200 cases). Altogether, the effort identified 15 fracture loci with modest effects. Interestingly, all identified loci were known BMD loci.
Ongoing work: Currently there are several ongoing efforts within the GEFOS to further expand the genetic determinants influencing DXA-derived bone parameters including femoral neck and lumbar spine BMD and a novel endophenotypes such as the trabecular bone score led by XXX and XXX.
Genetic discoveries muscle-related phenotypes
Osteoporosis (i.e., low bone mass) and sarcopenia (i.e., low lean mass) are common and costly comorbid diseases of aging, and there is an urgent need to prevent and treat both to reduce their associated morbidity and mortality and their consequences fractures and falls. Therefore, the work of the GEFOS consortium have expanded to evaluate the genetic determinants of muscle-related phenotypes.
Published work In 2015, collaborators from the GEFOS consortium identified five loci (HSD17B11, VCAN, ADAMTSL3, IRS1, and FTO) associated with lean mass (total and/or appendicular) [ref], which constitutes a good proxy for skeletal muscle mass. In a follow-up study TNRV6B as identified as additional lean mass locus after more stringent adjustment for fat [ref]. A grip strength GWAS, a proxy for muscular function, have been more fruitful, yielding up to 30 loci associated with continuous measures of grip strength or binary muscle weakness [refs].
Genetics of bone and muscle interactions

Ongoing work: Bone mineral density (BMD) and lean mass (LM) are highly heritable traits with shared heritability estimate ranging between 30 and 70% in adults. This covariation can be result of developmental, homeostatic, mechanical and ageing processes, some of which may be due to pleiotropy. Currently we have ongoing efforts to Identify pleotropic regions associated with lean mass and bone mass measured by DXA using bivariate GWA analysis.