Genetics of osteoporosis and bone disease (ASBMR 2012)

Abstract

A broad swath of data, generated from a refreshing variety of study methodologies, was presented at the 2012 ASBMR meeting in Minneapolis MN that highlighted how far bone genetics has come. Several examples are presented herein. New Directions for Single Phenotype Genome-Wide Association StudyGenome-wide association study (GWAS) no longer focusses just on spine and hip bone mineral density (BMD) in large adult cohorts, but rather it is being broadened to include previously under-examined populations, such as children, and for the identification of causative genes for specific skeletal conditions. Two examples are presented below. Dr Kemp presented data showing that skull BMD is an informative phenotype when measured in children, 1 as GWAS conducted using this phenotype yielded previously known BMD loci. However, a novel locus on 6q23.2 (EYA4 gene) was also found. This was a relatively small sample for a GWAS, and it will be interesting to see what can be learned from larger cohorts. It is as yet unclear what the role of this 6q23.2 locus is in bone, and whether it is a locus whose primary function relates to growth and skeletal maturation. The Erasmus group presented an interesting latebreaking abstract that not only demonstrated that Scheuermann's disease, a form of osteochondrosis of the spine, has a prevalence of about 4% in the Dutch population, but that SNPs in the vicinity of TLL1 are associated with this condition. 2 Candidate Gene IdentificationAs illuminating as GWAS has been, association is still not causation and does not explain function. As resequencing becomes more affordable, the genetics field is moving, with mixed results, toward trying to find the causative polymorphisms for disease. The Framingham and Cardiovascular Health Study groups presented results from a targeted resequencing effort focused on four previously identified GWAS loci for BMD. They resequenced loci at 1p31.3 (WLS), 5q14.3 (MEF2C), 11p11.2 (LRP4) and 20p12.2 (JAG2) in 200 subjects who had extremely low BMD. They showed that rare variants in the vicinity of the LRP4 gene have the potential to be causal. 3 The Oxford Endocrinology group presented work in which they identified the pathologic mutations causative for sub-types of familial hypocalciuric hypercalcemia (FHH) in genes other than the calcium-sensing receptor (CASR). They showed that FHH-2 is caused by mutations of GNA11, 4 a functional candidate that transduces the CASR signal, and found a three-nucleotide deletion that results in omission of the Ile199 residue. Transfection studies in the cell line HEK293 (human embryonic kidney 293) cells confirmed its functional importance. This mutation was not found in non-FHH-2 patients, but the mutation cosegregated with the disorder in 21 members of an extended pedigree. In a second abstract, this group showed that FHH-3 arises from a mutation in AP2S1. 5 Whole-exome sequencing revealed a Arg15Cys missense mutation in three affected individuals from two unrelated FHH-3 kindreds. This residue is highly conserved evolutionarily, an...

Update on the Genetic Basis of Disorders of the Musculoskeletal System (ECTS 2013)

“…Variants in ADAMTSL3 have been reported to influence body stature, 6 and to influence both femoral neck bone width and appendicular lean mass as identified by a bivariate analyses presented at the 2012 ASBMR meeting. 7 The authors consider that the low yield in identified variants (despite the very large sample size of the study) might be a consequence of the wide age range of the participants, obscuring differential genetic effects on muscle mass accrual or lean mass loss.…”