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MEETING REPORTS Musculoskeletal Genetics and -Omics IBMS BoneKEy. 2011 February;8(2):112-122 http://www.bonekey-ibms.org/cgi/content/full/ibmske;8/2/112 doi: 10.1138/20110496 MEETING REPORTS Musculoskeletal Genetics and -Omics: Meeting Report from the 32nd Annual Meeting of the American Society for Bone and Mineral Research October 15-19, 2010 in Toronto, Ontario, Canada Yi-Hsiang Hsu, Kannabiran Nandakumar, and David Karasik Institute for Aging Research, Hebrew SeniorLife, and Harvard Medical School, Boston, Massachusetts, USA The 2010 Annual Meeting of the ASBMR genes involved in pathways relevant to was held in the gorgeous city of Toronto, known bone biology, i.e., genes in the WNT capital of Ontario, from October 15-19. The pathway (WNT16, AXIN1, WNT4, LRP5, steady number of active participants CTNNB1, GPR177, FOXC2), genes in the highlights the importance of this meeting for NF-κB pathway (AKAP11, TNSFR11B, the field of calcified tissues and beyond. RANK, OPG) and/or genes coding for some Indeed, this year’s meeting was a success in of the SOX family of transcription factors general, and included many new and (SOX4, SOX6, SOX9). Interestingly, interesting studies concerning the genetics skeletal site specificity and sex specificity of musculoskeletal diseases. Recent were observed for several loci, indicative of advances in high-throughput “-omics” the complex genetic architecture of BMD technologies have greatly increased the variation and the multiple biological scale and scope of genomics research, and pathways involved in its regulation. this was evident throughout the highly sophisticated research presented this year. As a trade-off between a large sample size Some highlights of the meeting regarding with normally distributed BMD and a sample the molecular epidemiology of osteoporosis with extreme BMD values, other and related conditions are summarized here. investigators chose approaches such as extreme truncate selection. Thus, Duncan et Genome-wide Association Studies al. (2) performed GWAS in 2,073 women (GWAS) for Osteoporosis (postmenopausal women aged 55-85 years) with either high (z = +1.5 to +4) or low (z = - This year, as in previous years, GWAS have 1.5 to -4) total hip BMD. Following the produced multiple interesting forays into the GWAS, 127 SNPs were studied in complex genetic regulation of osteoporosis replication cohorts from Australia and susceptibility. GWAS have become better Europe (including > 10,000 women with powered due to the availability of genome- normally distributed total hip BMD values). wide genotyping in ever larger samples. Three novel loci associated with BMD were Thus, Karol Estrada, a recipient of the identified in the discovery at p-values < 10-4 ASBMR Young Investigator Award, and confirmed in the replication set (p- presented on behalf of the international values < 0.05); these pointed out GEFOS consortium (1) a meta-analysis of biologically-relevant genes, GALNT3, 17 GWAS for lumbar spine and femoral LTBP3, and CLCN7, which were not neck bone mineral density (BMD), with ~ discovered by previous GWAS with large 2.7 million single nucleotide polymorphisms sample sizes of normally distributed BMD. (SNPs) in individuals of mostly Caucasian The authors thus make the case for the (n = 32,000) ancestry. The meta-analysis extreme ascertainment scheme, which detected 34 loci associated at stringent, corresponds to gains in power for gene - genome-wide significant p-values ≤ 5 x 10 discovery. However, three novel genes were 8 . Some of these 34 loci map within or near discovered, and given that statistical power 112 Copyright 2011 International Bone & Mineral Society IBMS BoneKEy. 2011 February;8(2):112-122 http://www.bonekey-ibms.org/cgi/content/full/ibmske;8/2/112 doi: 10.1138/20110496 depends on several factors, such as effect =0.52) and LS BMD (ρG =0.40), but not with size, sample size, heterogeneity among tibial or phalangeal SOS. studied samples, phenotype definition uncertainties etc., the potential power gain Bone Geometry by the extreme ascertainment scheme needs to be further evaluated in numerical FN bone geometry is an important predictor studies. of bone strength and risk of hip fractures. Two GWAS for FN bone geometry were Other Osteoporosis-Related Traits and also presented, one by a group from the Conditions University of Missouri, Kansas City Medical School (5), and another by the GEFOS Multiple quantitative traits serve as proxies Consortium (6). for the risk of osteoporosis. There is still debate regarding the extent to which the Deng et al. (5) studied a sample of 2,500 genetic architecture is similar between the unrelated Caucasians. A common genetic measured traits. variant, rs6578987, located approximately 8kb downstream of the insulin-like growth Quantitative Ultrasound (QUS) factor 2 (IGF2) gene was suggestively associated with two indices of femoral bone Alireza Moayyeri, on behalf of the GEFOS geometry: cortical thickness (p = 1 x 10-7) Consortium (3), presented a meta-analysis and buckling ratio (BR, p = 1 x 10-6). Given of seven GWAS with heel QUS (12,286 the well-known function of IGF2 in bone participants) and two additional studies with metabolism, the study provided compelling heel pDXA (1,377 participants). Strong evidence that IGF2 may affect FN bone association signals were found for heel geometry variation and thus the risk of hip broadband ultrasound attenuation (BUA) on fracture. chromosome 7q31 (near/in FAM3C, WNT16 and C7orf58) and on chromosome In a large meta-analysis (9,100 women and 6q25, as well as suggestive evidence of 4,100 men) of GWAS by the GEFOS association on chromosomes 6q22, 16p13, Consortium, Hsu et al. (6) found that the 2p21 and 20q13. The top signal on most significant association with FN length chromosome 7q31 showed a partial (FNL) in both sexes was observed on overlap with BMD GWAS in the GEFOS chromosome 10q24, a locus where study (see (1) above). This confirms the cytochrome P450 family member CYP17A1 non-independent nature of DXA BMD and is mapped. Suggestive associations were QUS at different skeletal sites; they seem found between genes for transmembrane to measure essentially the same properties proteins, TPRA1/GPR175, and neck-shaft of bones. The existing genetic correlation angle (NSA) and between TMEM38B and between BMD and QUS is not surprising, FNL. Also, several female-specific especially in light of another study, associations were identified, such as an presented by Nguyen et al. (4). These association between forkhead box Q1 investigators studied correlations between (FOXQ1) with NSA, and between OR4K14 BMD and QUS measurements in adult and FN section modulus. Larger sample individuals from 33 multigenerational sizes are needed to formally test for sex- families from the Dubbo Osteoporosis specific associations and to fine-map the Genetics Study. BMD at the femoral neck above genes. (FN), lumbar spine (LS) and total body (TB) was measured by DXA, and speed of Paget's Disease of Bone sound (SOS) at the distal radius (DR), midshaft of tibia and proximal phalanges This year’s Most Outstanding Clinical was measured by Sunlight Omnisense Abstract award went to Omar Albagha from QUS. Strong genetic correlations (ρG) were the University of Edinburgh, who presented found between all three BMD GWAS of Paget's disease of bone (PDB) measurements (ρG from 0.55 to 0.81), as (7). PDB is a late-onset metabolic bone well as between DR SOS and FN BMD (ρG disease characterized by focal areas of 113 Copyright 2011 International Bone & Mineral Society IBMS BoneKEy. 2011 February;8(2):112-122 http://www.bonekey-ibms.org/cgi/content/full/ibmske;8/2/112 doi: 10.1138/20110496 increased bone remodeling affecting ~ 8% and therefore, an antibody for IL-6 might of older men and ~5% of women; its etiology serve as a treatment option for DMD bones. is due primarily to increased activity of osteoclasts. The only mutated gene reported Bone and Cardiovascular Diseases and replicated to date is SQSTM1, which encodes the protein sequestosome-1/p62. Both osteoporosis and cardiovascular Therefore this GWAS excluded PDB cases disease are frequent in the aged population with any SQSTM1 mutations. In a sample of and seem to be associated with the aging 750 PDB cases and 2,699 controls, GWAS process; this might be due to shared discovered (and then replicated in an environmental or genetic determinants, or independent set), four top genes: CSF1, both. Kuipers and colleagues (10) which encodes macrophage colony- calculated the genetic correlations between stimulating factor (M-CSF) on chromosome these two diseases in 377 adult individuals 1p13; OPTN, which encodes optineurin on from seven large multi-generational families chromosome 10p13; TNFRSF11A of African ancestry. They observed that the (chromosome 18q21), which encodes mean arterial diameter of the common RANK, a critical agent in osteoclast carotid artery (measured by ultrasound) differentiation and function; and TM7SF4 had a significant genetic correlation with (which encodes DC-STAMP) on total hip BMD measured by DXA (ρG = - chromosome 8q22. The latter gene is a new 0.47, P = 0.002), as well as with trabecular addition to already-published PDB GWAS vBMD at the radius measured by pQCT (ρG (8) thanks to a larger sample. = -0.48, P = 0.001). Osteoporosis and Related Conditions Coronary artery calcification (CAC) is another measure of subclinical The study of bone and mineral tissue atherosclerosis. Yerges-Armstrong and biology can offer important insight into the colleagues (11) evaluated associations of pathophysiology of other processes and the genotype scores (from LS BMD GWAS conditions; this was convincingly of (12)) with CAC measured by electron demonstrated by several groups. beam CT, in a modest sample of Old Order Amish. They found that an increasing Bone and Muscle number of high BMD alleles were associated with lower CAC quantity (p = 0.046), and The genetics of sarcopenia and muscle especially that one BMD SNP on dysfunction in relation to bone health was chromosome 13q14 seemed to be also included in the lectures presented associated with CAC.
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