Imperial College London

ProfessorGrahamWilliams

Faculty of MedicineDepartment of Metabolism, Digestion and Reproduction

Clinical Professor of Endocrinology
 
 
 
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Contact

 

+44 (0)20 3313 1383graham.williams

 
 
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Location

 

10N5Commonwealth BuildingHammersmith Campus

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Summary

 

Publications

Publication Type
Year
to

186 results found

Leitch VD, Bassett JHD, Williams GR, 2020, Role of thyroid hormones in craniofacial development, NATURE REVIEWS ENDOCRINOLOGY, ISSN: 1759-5029

Journal article

Leitch VD, Brassill MJ, Rahman S, Butterfield NC, Ma P, Logan JG, Boyde A, Evans H, Croucher PI, Batterham RL, Williams GR, Bassett JHDet al., 2019, PYY is a negative regulator of bone mass and strength, Bone, Vol: 127, Pages: 427-435, ISSN: 8756-3282

ObjectiveBone loss in anorexia nervosa and following bariatric surgery is associated with an elevated circulating concentration of the gastrointestinal, anorexigenic hormone, peptide YY (PYY). Selective deletion of the PYY receptor Y1R in osteoblasts or Y2R in the hypothalamus results in high bone mass, but deletion of PYY in mice has resulted in conflicting skeletal phenotypes leading to uncertainty regarding its role in the regulation of bone mass. As PYY analogs are under development for treatment of obesity, we aimed to clarify the relationship between PYY and bone mass.MethodsThe skeletal phenotype of Pyy knockout (KO) mice was investigated during growth (postnatal day P14) and adulthood (P70 and P186) using X-ray microradiography, micro-CT, back-scattered electron scanning electron microscopy (BSE-SEM), histomorphometry and biomechanical testing.ResultsBones from juvenile and Pyy KO mice were longer (P < 0.001), with decreased bone mineral content (P < 0.001). Whereas, bones from adult Pyy KO mice had increased bone mineral content (P < 0.05) with increased mineralisation of both cortical (P < 0.001) and trabecular (P < 0.001) compartments. Long bones from adult Pyy KO mice were stronger (maximum load P < 0.001), with increased stiffness (P < 0.01) and toughness (P < 0.05) compared to wild-type (WT) control mice despite increased cortical vascularity and porosity (P < 0.001). The increased bone mass and strength in Pyy KO mice resulted from increases in trabecular (P < 0.01) and cortical bone formation (P < 0.05).ConclusionsThese findings demonstrate that PYY acts as a negative regulator of osteoblastic bone formation, implicating increased PYY levels in the pathogenesis of bone loss during anorexia or following bariatric surgery.

Journal article

Beck-Cormier S, Lelliott CJ, Logan JG, Lafont DT, Leitch VD, Butterfield NC, Protheroe HJ, Croucher PI, Baldock PA, Gaultier-Lintia A, Nicolas G, Bon N, Sourice S, Guicheux J, Beck L, Williams GR, Bassett JHDet al., 2019, Slc20a2, encoding the phosphate transporter PiT2, is a novel genetic determinant of bone quality and strength, Journal of Bone and Mineral Research, Vol: 34, Pages: 1101-1114, ISSN: 1523-4681

Osteoporosis is characterized by low bone mineral density (BMD) and fragility fracture and affects over 200 million people worldwide. Bone quality describes the material properties that contribute to strength independently of BMD, and its quantitative analysis is a major priority in osteoporosis research. Tissue mineralization is a fundamental process requiring calcium and phosphate transporters. Here we identify impaired bone quality and strength in Slc20a2–/– mice lacking the phosphate transporter SLC20A2. Juveniles had abnormal endochondral and intramembranous ossification, decreased mineral accrual, and short stature. Adults exhibited only small reductions in bone mass and mineralization but a profound impairment of bone strength. Bone quality was severely impaired in Slc20a2–/– mice: yield load (–2.3 SD), maximum load (–1.7 SD), and stiffness (–2.7 SD) were all below values predicted from their bone mineral content as determined in a cohort of 320 wild‐type controls. These studies identify Slc20a2 as a physiological regulator of tissue mineralization and highlight its critical role in the determination of bone quality and strength.

Journal article

Freudenthal B, Shetty S, Butterfield NC, Logan JG, Han CR, Zhu X-G, Astapova I, Hollenberg AN, Cheng S-Y, Bassett JHD, Williams Get al., 2019, Genetic and pharmacological targeting of transcriptional repression in resistance to thyroid hormone alpha, Thyroid, Vol: 29, ISSN: 1050-7256

Background Thyroid hormones act in bone and cartilage via thyroid hormone receptor α (TRα). In the absence of T3, TRα interacts with co-repressors, including nuclear receptor co-repressor-1 (NCoR1), which recruit histone deacetylases (HDACs) and mediate transcriptional repression. Dominant-negative mutations of TRα cause resistance to thyroid hormone α (RTHα; OMIM 614450), characterized by excessive repression of T3 target genes leading to delayed skeletal development, growth retardation and bone dysplasia. Treatment with thyroxine has been of limited benefit even in mildly affected individuals and there is a need for new therapeutic strategies. We hypothesized that (i) the skeletal manifestations of RTHα are mediated by the persistent TRα/NCoR1/HDAC repressor complex containing mutant TRα, and (ii) treatment with the HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) would ameliorate these manifestations. Methods We determined the skeletal phenotypes of (i) Thra1PV/+ mice, a well characterized model of RTHα, (ii) Ncor1ΔID/ΔID mice, which express an NCoR1 mutant that fails to interact with TRα, and (iii) Thra1PV/+Ncor1ΔID/ΔID double mutant adult mice. Wild-type, Thra1PV/+, Ncor1ΔID/ΔID, and Thra1PV/+Ncor1ΔID/ΔID double mutant mice were also treated with SAHA to determine whether HDAC inhibition results in amelioration of skeletal abnormalities. Results Thra1PV/+ mice had a severe skeletal dysplasia characterized by short stature, abnormal bone morphology and increased bone mineral content. Despite normal bone length, Ncor1ΔID/ΔID mice displayed increased cortical bone mass, mineralization and strength. Thra1PV/+Ncor1ΔID/ΔID double mutant mice displayed only a small improvement of skeletal abnormalities compared to Thra1PV/+ mice. Treatment with SAHA to inhibit histone deacetylation had no beneficial or detrimental effects on bo

Journal article

Rauner M, Baschant U, Roetto A, Pellegrino RM, Rother S, Salbach-Hirsch J, Weidner H, Hintze V, Campbell G, Petzold A, Lemaitre R, Henry I, Bellido T, Theurl I, Altamura S, Colucci S, Muckenthaler MU, Schett G, Komla-Ebri DSK, Bassett JHD, Williams GR, Platzbecker U, Hofbauer LCet al., 2019, Transferrin receptor 2 controls bone mass and pathological bone formation via BMP and Wnt signaling (vol 1, pg 111, 2019), NATURE METABOLISM, Vol: 1, Pages: 584-584

Journal article

Morris JA, Kemp JP, Youlten SE, Laurent L, Logan JG, Chai RC, Vulpescu NA, Forgetta V, Kleinman A, Mohanty ST, Sergio CM, Quinn J, Nguyen-Yamamoto L, Luco A-L, Vijay J, Simon M-M, Pramatarova A, Medina-Gomez C, Trajanoska K, Ghirardello EJ, Butterfield NC, Curry KF, Leitch VD, Sparkes PC, Adoum A-T, Mannan NS, Komla-Ebri DSK, Pollard AS, Dewhurst HF, Hassall TAD, Beltejar M-JG, Adams DJ, Vaillancourt SM, Kaptoge S, Baldock P, Cooper C, Reeve J, Ntzani EE, Evangelou E, Ohlsson C, Karasik D, Rivadeneira F, Kiel DP, Tobias JH, Gregson CL, Harvey NC, Grundberg E, Goltzman D, Adams DJ, Lelliott CJ, Hinds DA, Ackert-Bicknell CL, Hsu Y-H, Maurano MT, Croucher PI, Williams GR, Bassett JHD, Evans DM, Richards JBet al., 2019, An atlas of genetic influences on osteoporosis in humans and mice (vol 51, pg 258, 2019), NATURE GENETICS, Vol: 51, Pages: 920-920, ISSN: 1061-4036

Journal article

Butterfield NC, Logan JG, Waung J, Williams GR, Bassett JHDet al., 2019, Quantitative X-Ray Imaging of Mouse Bone by Faxitron., Methods Mol Biol, Vol: 1914, Pages: 559-569

This chapter describes the use of point projection digital microradiography for rapid imaging and quantitation of bone mineral content in mice.

Journal article

Bassett J, Williams GR, Logan J, Ghirardello E, Butterfield N, Curry K, Leitch V, Sparkes P, Adoum A, Mannan N, Pollard A, Komla-Ebri Det al., 2019, An atlas of genetic influences on osteoporosis in humans and mice, Nature Genetics, Vol: 51, Pages: 258-266, ISSN: 1061-4036

Osteoporosis is a common aging-related disease diagnosed primarily using bone mineral density (BMD). We assessed genetic determinants of BMD as estimated by heel quantitative ultrasound in 426,824 individuals, identifying 518 genome-wide significant loci (301 novel), explaining 20% of its variance. We identified 13 bone fracture loci, all associated with estimated BMD (eBMD), in ~1.2 million individuals. We then identified target genes enriched for genes known to influence bone density and strength (maximum odds ratio (OR) = 58, P = 1 × 10−75) from cell-specific features, including chromatin conformation and accessible chromatin sites. We next performed rapid-throughput skeletal phenotyping of 126 knockout mice with disruptions in predicted target genes and found an increased abnormal skeletal phenotype frequency compared to 526 unselected lines (P < 0.0001). In-depth analysis of one gene, DAAM2, showed a disproportionate decrease in bone strength relative to mineralization. This genetic atlas provides evidence linking associated SNPs to causal genes, offers new insight into osteoporosis pathophysiology, and highlights opportunities for drug development.

Journal article

Jo S, Fonseca TL, Da Costa Bocco BM, Fernandes GW, McAninch EA, Bolin AP, Da Conceição RR, De Castro JPW, Ignacio DL, Egri P, Németh D, Fekete C, Bernardi MM, Leitch VD, Mannan NS, Curry KF, Butterfield NC, Bassett JHD, Williams GR, Gereben B, Ribeiro MO, Bianco ACet al., 2019, Type 2 deiodinase polymorphism causes ER stress and hypothyroidism in the brain, Journal of Clinical Investigation, Vol: 129, Pages: 230-245, ISSN: 0021-9738

Levothyroxine (LT4) is a form of thyroid hormone used to treat hypothyroidism. In the brain, T4 is converted to the active form T3 by the type 2 deiodinase (D2). Thus, it is intriguing that carriers of the Thr92Ala polymorphism in the D2 gene (DIO2) exhibit clinical improvement when liothyronine (LT3) is added to LT4 therapy. Here we report that D2 is a cargo protein in endoplasmic reticulum Golgi intermediary compartment (ERGIC) vesicles, recycling between ER and Golgi. The Thr92 to Ala substitution (Ala92-D2) caused ER stress and activated the unfolded protein response (UPR); Ala92-D2 accumulated in the trans-Golgi and generated less T3, all of which was restored by eliminating ER stress with the chemical chaperone 4-phenyl butyric acid (4-PBA). An Ala92-Dio2 polymorphism-carrying mouse exhibited UPR and hypothyroidism in distinct brain areas. The mouse refrained from physical activity, slept more and required additional time to memorize objects. Enhancing T3 signaling in the brain with LT3 improved cognition, whereas restoring proteostasis with 4-PBA eliminated the Ala92-Dio2 phenotype. In contrast, primary hypothyroidism intensified the Ala92-Dio2 phenotype, with only partial response to LT4 therapy. Disruption of cellular proteostasis and reduced Ala92-D2 activity may explain the failure of LT4 therapy in carriers of Thr92Ala-DIO2.

Journal article

Rauner M, Baschant U, Roetto A, Pellegrino RM, Rother S, Salbach-Hirsch J, Weidner H, Hintze V, Campbell G, Petzold A, Lemaitre R, Henry I, Bellido T, Theurl I, Altamura S, Colucci S, Muckenthaler MU, Schett G, Komla Ebri D, Bassett JHD, Williams GR, Platzbecker U, Hofbauer LCet al., 2019, Transferrin receptor 2 controls bone mass and pathological bone formation via BMP and Wnt signaling, Nature Metabolism, Vol: 1, Pages: 111-124, ISSN: 2522-5812

Transferrin receptor 2 (Tfr2) is mainly expressed in the liver and controls iron homeostasis. Here, we identify Tfr2 as a regulator of bone homeostasis that inhibits bone formation. Mice lacking Tfr2 display increased bone mass and mineralization independent of iron homeostasis and hepatic Tfr2. Bone marrow transplantation experiments and studies of cell-specific Tfr2 knockout mice demonstrate that Tfr2 impairs BMP-p38MAPK signaling and decreases expression of the Wnt inhibitor sclerostin specifically in osteoblasts. Reactivation of MAPK or overexpression of sclerostin rescues skeletal abnormalities in Tfr2 knockout mice. We further show that the extracellular domain of Tfr2 binds BMPs and inhibits BMP-2-induced heterotopic ossification by acting as a decoy receptor. These data indicate that Tfr2 limits bone formation by modulating BMP signaling, possibly through direct interaction with BMP either as a receptor or as a co-receptor in a complex with other BMP receptors. Finally, the Tfr2 extracellular domain may be effective in the treatment of conditions associated with pathological bone formation.

Journal article

Gregson CL, Newell F, Leo PJ, Clark GR, Paternoster L, Marshall M, Forgetta V, Morris JA, Ge B, Bao X, Duncan Bassett JH, Williams GR, Youlten SE, Croucher PI, Davey Smith G, Evans DM, Kemp JP, Brown MA, Tobias JH, Duncan ELet al., 2018, Genome-wide association study of extreme high bone mass: contribution of common genetic variation to extreme BMD phenotypes and potential novel BMD-associated genes, Bone, Vol: 114, Pages: 62-71, ISSN: 8756-3282

BACKGROUND: Generalised high bone mass (HBM), associated with features of a mild skeletal dysplasia, has a prevalence of 0.18% in a UK DXA-scanned adult population. We hypothesized that the genetic component of extreme HBM includes contributions from common variants of small effect and rarer variants of large effect, both enriched in an extreme phenotype cohort. METHODS: We performed a genome-wide association study (GWAS) of adults with either extreme high or low BMD. Adults included individuals with unexplained extreme HBM (n = 240) from the UK with BMD Z-scores ≥+3.2, high BMD females from the Anglo-Australasian Osteoporosis Genetics Consortium (AOGC) (n = 1055) with Z-scores +1.5 to +4.0 and low BMD females also part of AOGC (n = 900), with Z-scores -1.5 to -4.0. Following imputation, we tested association between 6,379,332 SNPs and total hip and lumbar spine BMD Z-scores. For potential target genes, we assessed expression in human osteoblasts and murine osteocytes. RESULTS: We observed significant enrichment for associations with established BMD-associated loci, particularly those known to regulate endochondral ossification and Wnt signalling, suggesting that part of the genetic contribution to unexplained HBM is polygenic. Further, we identified associations exceeding genome-wide significance between BMD and four loci: two established BMD-associated loci (5q14.3 containing MEF2C and 1p36.12 containing WNT4) and two novel loci: 5p13.3 containing NPR3 (rs9292469; minor allele frequency [MAF] = 0.33%) associated with lumbar spine BMD and 11p15.2 containing SPON1 (rs2697825; MAF = 0.17%) associated with total hip BMD. Mouse models with mutations in either Npr3 or Spon1 have been reported, both have altered skeletal phenotypes, providing in vivo validation that these genes are physiologically important in bone. NRP3 regulates endochondral ossification and skeletal growth, whilst SPON1 modulates TGF-β regulated BMP-driven osteoblast differentiation. Rs9292469

Journal article

Trajanoska K, Morris JA, Oei L, Zheng H-F, Evans DM, Kiel DP, Ohlsson C, Richards JB, Rivadeneira Fet al., 2018, Assessment of the genetic and clinical determinants of fracture risk: genome wide association and mendelian randomisation study, BMJ, Vol: 362, ISSN: 0959-8138

Objectives To identify the genetic determinants of fracture risk and assess the role of 15 clinical risk factors on osteoporotic fracture risk.Design Meta-analysis of genome wide association studies (GWAS) and a two-sample mendelian randomisation approach.Setting 25 cohorts from Europe, United States, east Asia, and Australia with genome wide genotyping and fracture data.Participants A discovery set of 37 857 fracture cases and 227 116 controls; with replication in up to 147 200 fracture cases and 150 085 controls. Fracture cases were defined as individuals (>18 years old) who had fractures at any skeletal site confirmed by medical, radiological, or questionnaire reports. Instrumental variable analyses were performed to estimate effects of 15 selected clinical risk factors for fracture in a two-sample mendelian randomisation framework, using the largest previously published GWAS meta-analysis of each risk factor.Results Of 15 fracture associated loci identified, all were also associated with bone mineral density and mapped to genes clustering in pathways known to be critical to bone biology (eg, SOST, WNT16, and ESR1) or novel pathways (FAM210A, GRB10, and ETS2). Mendelian randomisation analyses showed a clear effect of bone mineral density on fracture risk. One standard deviation decrease in genetically determined bone mineral density of the femoral neck was associated with a 55% increase in fracture risk (odds ratio 1.55 (95% confidence interval 1.48 to 1.63; P=1.5×10−68). Hand grip strength was inversely associated with fracture risk, but this result was not significant after multiple testing correction. The remaining clinical risk factors (including vitamin D levels) showed no evidence for an effect on fracture.Conclusions This large scale GWAS meta-analysis for fracture identified 15 genetic determinants of fracture, all of which also influenced bone mineral density. Among the clinical risk factors for fracture assesse

Journal article

Van Vliet NA, Noordam R, Van Klinken JB, Westendorp RGJ, Bassett JHD, Williams GR, Van Heemst Det al., 2018, Thyroid stimulating hormone and bone mineral density: evidence from a two-sample Mendelian randomization study and a candidate gene association study, Journal of Bone and Mineral Research, Vol: 33, Pages: 1318-1325, ISSN: 1523-4681

With population aging, prevalence of low bone mineral density (BMD) and associated fracture risk are increased. To determine whether low circulating thyroid stimulating hormone (TSH) levels within the normal range are causally related to BMD, we conducted a two-sample Mendelian randomization (MR) study. Furthermore, we tested whether common genetic variants in the TSH receptor (TSHR) gene and genetic variants influencing expression of TSHR (eQTLs) are associated with BMD. For both analyses, we used summary-level data of genome-wide association studies (GWAS) investigating BMD of the femoral neck (N = 32,735) and the lumbar spine (N = 28,498) in cohorts of European ancestry from the Genetic Factors of Osteoporosis (GEFOS) Consortium. For the MR study, we selected 20 genetic variants that were previously identified for circulating TSH levels in a GWAS meta-analysis (N = 26,420). All independent genetic instruments for TSH were combined in analyses for both femoral neck and lumbar spine BMD. In these studies, we found no evidence that a genetically determined 1 standard deviation (SD) decrease in circulating TSH concentration was associated with femoral neck BMD (0.003 SD decrease in BMD per SD decrease of TSH, 95% C.I. -0.053; 0.048, P = 0.92) or lumbar spine BMD (0.010 SD decrease in BMD per SD decrease of TSH, 95% C.I. -0.069; 0.049, P = 0.73). A total of 706 common genetic variants have been mapped to the TSHR locus and expression loci for TSHR. However, none of these genetic variants were associated with BMD at the femoral neck or lumbar spine. In conclusion, we found no evidence for a causal effect of circulating TSH on BMD, nor did we find any association between genetic variation at the TSHR locus or expression thereof and BMD. This article is protected by copyright. All rights reserved.

Journal article

Pereira M, Petretto E, Gordon S, Bassett JHD, Williams GR, Behmoaras Jet al., 2018, Common signalling pathways in macrophage and osteoclast multinucleation., J Cell Sci, Vol: 131

Macrophage cell fusion and multinucleation are fundamental processes in the formation of multinucleated giant cells (MGCs) in chronic inflammatory disease and osteoclasts in the regulation of bone mass. However, this basic cell phenomenon is poorly understood despite its pathophysiological relevance. Granulomas containing multinucleated giant cells are seen in a wide variety of complex inflammatory disorders, as well as in infectious diseases. Dysregulation of osteoclastic bone resorption underlies the pathogenesis of osteoporosis and malignant osteolytic bone disease. Recent reports have shown that the formation of multinucleated giant cells and osteoclast fusion display a common molecular signature, suggesting shared genetic determinants. In this Review, we describe the background of cell-cell fusion and the similar origin of macrophages and osteoclasts. We specifically focus on the common pathways involved in osteoclast and MGC fusion. We also highlight potential approaches that could help to unravel the core mechanisms underlying bone and granulomatous disorders in humans.

Journal article

Williams GR, Boelen A, Refetoff S, 2018, 13th international workshop on resistance to thyroid hormone and thyroid hormone action., Thyroid, Vol: 28, Pages: 690-691, ISSN: 1050-7256

Journal article

Pop V, Broeren M, Wijnen H, Endendijk J, van Baar A, Wiersinga W, Williams GRet al., 2018, Longitudinal Trajectories of Gestational Thyroid Function: A New Approach to Better Understand Changes in Thyroid Function, The Journal of Clinical Endocrinology & Metabolism, Vol: 103, Pages: 2889-2900, ISSN: 0021-972X

ContextMost studies of thyroid function changes during pregnancy use a cross-sectional design comparing means between groups rather than similarities within groups.ObjectiveLatent class growth analysis (LCGA) is a novel approach to investigate longitudinal changes that provide dynamic understanding of the relationship between thyroid status and advancing pregnancy.DesignProspective observational study with repeated assessments.SettingGeneral community.PatientsEleven hundred healthy women were included at 12 weeks’ gestation.Main Outcome MeasuresThe existence of both free T4 (fT4) and TSH trajectories throughout pregnancy determined by LCGA.ResultsLCGA revealed three trajectory classes. Class 1 (n = 1019; 92.4%), a low increasing TSH reference group, had a gradual increase in TSH throughout gestation (from 1.1 to 1.3 IU/L). Class 2 (n = 30; 2.8%), a high increasing TSH group, displayed the largest increase in TSH (from 1.9 to 3.3 IU/L). Class 3 (n = 51; 4.6%), a decreasing TSH group, had the largest fall in TSH (from 3.2 to 2.4 IU/L). Subclinical hypothyroidism at 12 weeks occurred in up to 60% of class 3 women and was accompanied by elevated thyroid peroxidase antibodies (TPO-Ab) titers (50%) and a parental history of thyroid dysfunction (23%). In class 2, 70% of women were nulliparous compared with 46% in class 1 and 49% in class 3.ConclusionsLCGA revealed distinct trajectories of longitudinal changes in fT4 and TSH levels during pregnancy in 7.4% of women. These trajectories were correlated with parity and TPO-Ab status and followed patterns that might reflect differences in pregnancy-specific immune tolerance between nulliparous and multiparous women.

Journal article

Medina-Gomez C, Kemp JP, Trajanoska K, Luan J, Chesi A, Ahluwalia TS, Mook-Kanamori DO, Ham A, Hartwig FP, Evans DS, Joro R, Nedeljkovic I, Zheng H-F, Zhu K, Atalay M, Liu C-T, Nethander M, Broer L, Porleifsson G, Mullin BH, Handelman SK, Nalls MA, Jessen LE, Heppe DHM, Richards JB, Wang C, Chawes B, Schraut KE, Amin N, Wareham N, Karasik D, Van der Velde N, Ikram MA, Zemel BS, Zhou Y, Carlsson CJ, Liu Y, McGuigan FE, Boer CG, Bønnelykke K, Ralston SH, Robbins JA, Walsh JP, Zillikens MC, Langenberg C, Li-Gao R, Williams FMK, Harris TB, Akesson K, Jackson RD, Sigurdsson G, den Heijer M, van der Eerden BCJ, van de Peppel J, Spector TD, Pennell C, Horta BL, Felix JF, Zhao JH, Wilson SG, de Mutsert R, Bisgaard H, Styrkársdóttir U, Jaddoe VW, Orwoll E, Lakka TA, Scott R, Grant SFA, Lorentzon M, van Duijn CM, Wilson JF, Stefansson K, Psaty BM, Kiel DP, Ohlsson C, Ntzani E, van Wijnen AJ, Forgetta V, Ghanbari M, Logan JG, Williams GR, Bassett JHD, Croucher PI, Evangelou E, Uitterlinden AG, Ackert-Bicknell CL, Tobias JH, Evans DM, Rivadeneira Fet al., 2018, Life-Course Genome-wide Association Study Meta-analysis of Total Body BMD and Assessment of Age-Specific Effects., AJHG, Vol: 102, Pages: 88-102, ISSN: 0002-9297

Bone mineral density (BMD) assessed by DXA is used to evaluate bone health. In children, total body (TB) measurements are commonly used; in older individuals, BMD at the lumbar spine (LS) and femoral neck (FN) is used to diagnose osteoporosis. To date, genetic variants in more than 60 loci have been identified as associated with BMD. To investigate the genetic determinants of TB-BMD variation along the life course and test for age-specific effects, we performed a meta-analysis of 30 genome-wide association studies (GWASs) of TB-BMD including 66,628 individuals overall and divided across five age strata, each spanning 15 years. We identified variants associated with TB-BMD at 80 loci, of which 36 have not been previously identified; overall, they explain approximately 10% of the TB-BMD variance when combining all age groups and influence the risk of fracture. Pathway and enrichment analysis of the association signals showed clustering within gene sets implicated in the regulation of cell growth and SMAD proteins, overexpressed in the musculoskeletal system, and enriched in enhancer and promoter regions. These findings reveal TB-BMD as a relevant trait for genetic studies of osteoporosis, enabling the identification of variants and pathways influencing different bone compartments. Only variants in ESR1 and close proximity to RANKL showed a clear effect dependency on age. This most likely indicates that the majority of genetic variants identified influence BMD early in life and that their effect can be captured throughout the life course.

Journal article

Hönes GS, Rakov H, Logan J, Liao XH, Werbenko E, Pollard A, Praestholm SM, Siersbaek MS, Rijntjes E, Gassen J, Latteyer S, Engels K, Strucksberg KH, Zwanziger D, Rozman J, Autoren GMC, Klein-Hitpass L, Köhrle J, Armstrong DL, Grontved L, Bassett JHD, Williams GR, Refetoff S, Führer D, Moeller LCet al., 2017, Non-canonical thyroid hormone signaling mediates cardiometabolic effects in vivo, Proceedings of the National Academy of Sciences of the United States of America, Vol: 114, Pages: E11323-E11332, ISSN: 0027-8424

Thyroid hormone (TH) and TH receptors (TRs) α and β act by binding to TH response elements (TREs) in regulatory regions of target genes. This nuclear signaling is established as the canonical or type 1 pathway for TH action. Nevertheless, TRs also rapidly activate intracellular second-messenger signaling pathways independently of gene expression (noncanonical or type 3 TR signaling). To test the physiological relevance of noncanonical TR signaling, we generated knockin mice with a mutation in the TR DNA-binding domain that abrogates binding to DNA and leads to complete loss of canonical TH action. We show that several important physiological TH effects are preserved despite the disruption of DNA binding of TRα and TRβ, most notably heart rate, body temperature, blood glucose, and triglyceride concentration, all of which were regulated by noncanonical TR signaling. Additionally, we confirm that TRE-binding–defective TRβ leads to disruption of the hypothalamic–pituitary–thyroid axis with resistance to TH, while mutation of TRα causes a severe delay in skeletal development, thus demonstrating tissue- and TR isoform-specific canonical signaling. These findings provide in vivo evidence that noncanonical TR signaling exerts physiologically important cardiometabolic effects that are distinct from canonical actions. These data challenge the current paradigm that in vivo physiological TH action is mediated exclusively via regulation of gene transcription at the nuclear level.

Journal article

Segna D, Bauer DC, Feller M, Schneider C, Fink HA, Aubert CE, Collet T-H, da Costa BR, Fischer K, Peeters RP, Cappola AR, Blum MR, van Dorland HA, Robbins J, Naylor K, Eastell R, Uitterlinden AG, Rivadeneira Ramirez F, Gogakos A, Gussekloo J, Williams GR, Schwartz A, Cauley JA, Aujesky DA, Bischoff-Ferrari HA, Rodondi Net al., 2017, Association between subclinical thyroid dysfunction and change in bone mineral density in prospective cohorts, Journal of Internal Medicine, Vol: 283, Pages: 56-72, ISSN: 0954-6820

BackgroundSubclinical hyperthyroidism (SHyper) has been associated with increased risk of hip and other fractures, but the linking mechanisms remain unclear.ObjectiveTo investigate the association between subclinical thyroid dysfunction and bone loss.MethodsIndividual participant data analysis was performed after a systematic literature search in MEDLINE/EMBASE (1946–2016). Two reviewers independently screened and selected prospective cohorts providing baseline thyroid status and serial bone mineral density (BMD) measurements. We classified thyroid status as euthyroidism (thyroid-stimulating hormone [TSH] 0.45–4.49 mIU/L), SHyper (TSH < 0.45 mIU/L) and subclinical hypothyroidism (SHypo, TSH ≥ 4.50–19.99 mIU/L) both with normal free thyroxine levels. Our primary outcome was annualized percentage BMD change (%ΔBMD) from serial dual X-ray absorptiometry scans of the femoral neck, total hip and lumbar spine, obtained from multivariable regression in a random-effects two-step approach.ResultsAmongst 5458 individuals (median age 72 years, 49.1% women) from six prospective cohorts, 451 (8.3%) had SHypo and 284 (5.2%) had SHyper. During 36 569 person-years of follow-up, those with SHyper had a greater annual bone loss at the femoral neck versus euthyroidism: %ΔBMD = −0.18 (95% CI: −0.34, −0.02; I2 = 0%), with a nonstatistically significant pattern at the total hip: %ΔBMD = −0.14 (95% CI: −0.38, 0.10; I2 = 53%), but not at the lumbar spine: %ΔBMD = 0.03 (95% CI: −0.30, 0.36; I2 = 25%); especially participants with TSH < 0.10 mIU/L showed an increased bone loss in the femoral neck (%Δ BMD = −0.59; [95% CI: −0.99, −0.19]) and total hip region (%ΔBMD = −0.46 [95% CI: −1.05, −0.13]). In contrast, SHypo was not associated with bone loss at any site.ConclusionAmongst adults, SHyper was associated with increased femoral neck bone loss, potentially c

Journal article

Kemp JP, Morris JA, Medina-Gomez C, Forgetta V, Warrington NM, Youlten SE, Zheng J, Gregson CL, Grundberg E, Trajanoska K, Logan JG, Pollard AS, Sparkes PC, Ghirardello EJ, Allen R, Leitch VD, Butterfield NC, Komla-Ebri D, Adoum A-T, Curry KF, White JK, Kussy F, Greenlaw KM, Xu C, Harvey NC, Cooper C, Adams DJ, Greenwood CMT, Maurano MT, Kaptoge S, Rivadeneira F, Tobias JH, Croucher PI, Ackert-Bicknell CL, Bassett JHD, Williams GR, Richards JB, Evans DMet al., 2017, Identification of 153 new loci associated with heel bone mineral density and functional involvement of GPC6 in osteoporosis, Nature Genetics, Vol: 49, Pages: 1468-1475, ISSN: 1061-4036

Osteoporosis is a common disease diagnosed primarily by measurement of bone mineral density (BMD). We undertook a genome-wide association study (GWAS) in 142,487 individuals from the UK Biobank to identify loci associated with BMD as estimated by quantitative ultrasound of the heel. We identified 307 conditionally independent single-nucleotide polymorphisms (SNPs) that attained genome-wide significance at 203 loci, explaining approximately 12% of the phenotypic variance. These included 153 previously unreported loci, and several rare variants with large effect sizes. To investigate the underlying mechanisms, we undertook (1) bioinformatic, functional genomic annotation and human osteoblast expression studies; (2) gene-function prediction; (3) skeletal phenotyping of 120 knockout mice with deletions of genes adjacent to lead independent SNPs; and (4) analysis of gene expression in mouse osteoblasts, osteocytes and osteoclasts. The results implicate GPC6 as a novel determinant of BMD, and also identify abnormal skeletal phenotypes in knockout mice associated with a further 100 prioritized genes.

Journal article

Williams GR, Bassett JHD, 2017, Thyroid diseases and bone health., Journal of Endocrinological Investigation, Vol: 41, Pages: 99-109, ISSN: 0391-4097

Thyroid hormones are essential for skeletal development and are important regulators of bone maintenance in adults. Childhood hypothyroidism causes delayed skeletal development, retarded linear growth and impaired bone mineral accrual. Epiphyseal dysgenesis is evidenced by classic features of stippled epiphyses on X-ray. In severe cases, post-natal growth arrest results in a complex skeletal dysplasia. Thyroid hormone replacement stimulates catch-up growth and bone maturation, but recovery may be incomplete dependent on the duration and severity of hypothyroidism prior to treatment. A severe phenotype characteristic of hypothyroidism occurs in children with resistance to thyroid hormone due to mutations affecting THRA encoding thyroid hormone receptor α (TRα). Discovery of this rare condition recapitulated animal studies demonstrating that TRα mediates thyroid hormone action in the skeleton. In adults, thyrotoxicosis is well known to cause severe osteoporosis and fracture, but cases are rare because of prompt diagnosis and treatment. Recent data, however, indicate that subclinical hyperthyroidism is associated with low bone mineral density (BMD) and an increased risk of fracture. Population studies have also shown that variation in thyroid status within the reference range in post-menopausal women is associated with altered BMD and fracture risk. Thus, thyroid status at the upper end of the euthyroid reference range is associated with low BMD and increased risk of osteoporotic fragility fracture. Overall, extensive data demonstrate that euthyroid status is required for normal post-natal growth and bone mineral accrual, and is fundamental for maintenance of adult bone structure and strength.

Journal article

McDonald MM, Reagan MR, Youlten SE, Mohanty ST, Seckinger A, Terry RL, Pettitt JA, Simic MK, Cheng TL, Morse A, Le LMT, Abi-Hanna D, Kramer I, Falank C, Fairfield H, Ghobrial IM, Baldock PA, Little DG, Kneissel M, Vanderkerken K, Bassett JHD, Williams GR, Oyajobi BO, Hose D, Phan TG, Croucher PIet al., 2017, Inhibiting the osteocyte-specific protein sclerostin increases bone mass and fracture resistance in multiple myeloma, Blood, Vol: 129, Pages: 3452-3464, ISSN: 1528-0020

Multiple myeloma (MM) is a plasma cell cancer that develops in the skeleton causing profound bone destruction and fractures. The bone disease is mediated by increased osteoclastic bone resorption and suppressed bone formation. Bisphosphonates used for treatment inhibit bone resorption and prevent bone loss but fail to influence bone formation and do not replace lost bone, so patients continue to fracture. Stimulating bone formation to increase bone mass and fracture resistance is a priority; however, targeting tumor-derived modulators of bone formation has had limited success. Sclerostin is an osteocyte-specific Wnt antagonist that inhibits bone formation. We hypothesized that inhibiting sclerostin would prevent development of bone disease and increase resistance to fracture in MM. Sclerostin was expressed in osteocytes from bones from naive and myeloma-bearing mice. In contrast, sclerostin was not expressed by plasma cells from 630 patients with myeloma or 54 myeloma cell lines. Mice injected with 5TGM1-eGFP, 5T2MM, or MM1.S myeloma cells demonstrated significant bone loss, which was associated with a decrease in fracture resistance in the vertebrae. Treatment with anti-sclerostin antibody increased osteoblast numbers and bone formation rate but did not inhibit bone resorption or reduce tumor burden. Treatment with anti-sclerostin antibody prevented myeloma-induced bone loss, reduced osteolytic bone lesions, and increased fracture resistance. Treatment with anti-sclerostin antibody and zoledronic acid combined increased bone mass and fracture resistance when compared with treatment with zoledronic acid alone. This study defines a therapeutic strategy superior to the current standard of care that will reduce fractures for patients with MM.

Journal article

Leitch VD, Di Cosmo C, Liao XH, O'Boy S, Galliford TM, Evans H, Croucher PI, Boyde A, Dumitrescu A, Weiss RE, Refetoff S, Williams GR, Bassett JHDet al., 2017, An essential physiological role for MCT8 in bone in male mice., Endocrinology, ISSN: 0013-7227

T3 is an important regulator of skeletal development and adult bone maintenance. Thyroid hormone action requires efficient transport of T4 and T3 into target cells. We hypothesized that monocarboxylate transporter-8, encoded by Mct8 on the X-chromosome, is an essential thyroid hormone transporter in bone. To test this hypothesis, we determined the juvenile and adult skeletal phenotypes of male Mct8 knockout mice (Mct8KO) and Mct8D1D2KO compound mutants, which additionally lack the ability to convert the prohormone T4 to the active hormone T3. Prenatal skeletal development was normal in both Mct8KO and Mct8D1D2KO mice, whereas post-natal endochondral ossification and linear growth were delayed in both Mct8KO and Mct8D1D2KO mice. Furthermore, bone mass and mineralization were decreased in adult Mct8KO and Mct8D1D2KO mice, and compound mutants also had reduced bone strength. Delayed bone development and maturation in Mct8KO and Mct8D1D2KO mice is consistent with decreased thyroid hormone action in growth plate chondrocytes despite elevated serum T3 concentrations, whereas low bone mass and osteoporosis reflects increased thyroid hormone action in adult bone due to elevated systemic T3 levels. These studies identify an essential physiological requirement for MCT8 in chondrocytes, and demonstrate a role for additional transporters in other skeletal cells during adult bone maintenance.

Journal article

Hameed S, Patterson M, Dhillo W, Rahman S, Ma Y, Holton C, Gogakos A, Yeo G, Lam B, Polex-Wolf J, Fenske W, Bell J, Anastasovska J, Samarut J, Bloom S, Bassett J, Williams G, Gardiner JVet al., 2017, Thyroid hormone receptor beta in the ventromedial hypothalamus is essential for the physiological regulation of food intake and body weight, Cell Reports, Vol: 19, Pages: 2202-2209, ISSN: 2211-1247

The obesity epidemic is a significant global health issue. Improved understanding of the mechanisms that regulate appetite and body weight will provide the rationale for the design of anti-obesity therapies. Thyroid hormones play a key role in metabolic homeostasis through their interaction with thyroid hormone receptors (TRs), which function as ligand-inducible transcription factors. The TR-beta isoform (TRβ) is expressed in the ventromedial hypothalamus (VMH), a brain area important for control of energy homeostasis. Here, we report that selective knockdown of TRβ in the VMH of adult mice results in severe obesity due to hyperphagia and reduced energy expenditure. The observed increase in body weight is of a similar magnitude to murine models of the most extreme forms of monogenic obesity. These data identify TRβ in the VMH as a major physiological regulator of food intake and energy homeostasis.

Journal article

Aubert CE, Floriani C, Bauer DC, da Costa BR, Segna D, Blum MR, Collet TH, Fink HA, Cappola AR, Syrogiannouli L, Peeters RP, Åsvold BO, den Elzen WP, Luben RN, Bremner AP, Gogakos A, Eastell R, Kearney PM, Hoff M, Le Blanc E, Ceresini G, Rivadeneira F, Uitterlinden AG, Khaw KT, Langhammer A, Stott DJ, Westendorp RG, Ferrucci L, Williams GR, Gussekloo J, Walsh JP, Aujesky D, Rodondi N, Thyroid Studies Collaborationet al., 2017, Thyroid function tests in the reference range and fracture: individual participant analysis of prospective cohorts, Journal of Clinical Endocrinology & Metabolism, Vol: 102, Pages: 2719-2728, ISSN: 1945-7197

Context: Hyperthyroidism is associated with increased fracture risk, but it is not clear if lower TSH and higher free thyroxine (FT4) in euthyroid individuals are associated with fracture risk. Objective: To evaluate the association of TSH and FT4 with incident fractures in euthyroid individuals. Design: Individual participant data analysis. Setting: Thirteen prospective cohort studies with baseline examinations between 1981 and 2002. Participants: Adults with baseline TSH 0.45-4.49 mIU/L. Main Outcome Measures: Primary outcome was incident hip fracture. Secondary outcomes were any, non-vertebral, and vertebral fractures. Results were presented as hazard ratios (HR) with 95% confidence interval (CI) adjusted for age and sex. For clinical relevance, we studied TSH according to five categories: 0.45-0.99mIU/L; 1.00-1.49mIU/L; 1.50-2.49mIU/L; 2.50-3.49mIU/L; 3.50-4.49mIU/L (reference). FT4 was assessed as study-specific standard deviation increase, because assays varied between cohorts. Results: During 659,059 person-years, 2,565/56,835 participants had hip fracture (4.5%; 12 studies with data on hip fracture). The pooled adjusted HR (95% CI) for hip fracture was 1.25 (1.05-1.49) for TSH 0.45-0.99mIU/L, 1.19 (1.01-1.41) for TSH 1.00-1.49mIU/L, 1.09 (0.93-1.28) for TSH 1.50-2.49mIU/L, and 1.12 (0.94-1.33) for TSH 2.50-3.49mIU/L (P for trend = 0.004). Hip fracture was also associated with FT4 (HR [95%CI] 1.22 [1.11-1.35] per one standard deviation increase in FT4). FT4 only was associated with any and non-vertebral fracture. Results remained similar in sensitivity analyses. Conclusions: Among euthyroid adults, lower TSH and higher FT4 are associated with an increased risk of hip fracture. These findings may help refine the definition of optimal ranges of thyroid function tests.

Journal article

Freudenthal B, Williams GR, 2016, TSH suppression in the long-term follow-up of differentiated thyroid cancer, Clinical Oncology, Vol: 29, Pages: 325-328, ISSN: 0936-6555

Differentiated thyroid cancer is the commonest form of thyroid cancer, and its prognosis is favourable in the majority of cases. Suppression of thyroid stimulating hormone (TSH) by supra-physiological thyroid hormone replacement has been the mainstay of long-term management for over 60 years. However, evidence for a beneficial outcome of TSH suppression is conflicting and intervention must be balanced against adverse effects, particularly affecting the cardiovascular system and skeleton. Here we discuss the role of TSH suppression in the long-term management of differentiated thyroid cancer in the context of risk-stratification for disease recurrence and the latest clinical guidelines.

Journal article

Freudenthal B, Logan J, Sanger Institute Mouse Pipelines2, Croucher PI, Williams GR, Bassett JHDet al., 2016, Rapid phenotyping of knockout mice to identify genetic determinants of bone strength, Journal of Endocrinology, Vol: 231, Pages: R31-R46, ISSN: 1479-6805

The genetic determinants of osteoporosis remain poorly understood, and there is a large unmet need for new treatments in our ageing society. Thus, new approaches for gene discovery in skeletal disease are required to complement the current genome-wide association studies in human populations. The International Knockout Mouse Consortium (IKMC) and the International Mouse Phenotyping Consortium (IMPC) provide such an opportunity. The IKMC generates knockout mice representing each of the known protein-coding genes in C57BL/6 mice and, as part of the IMPC initiative, the Origins of Bone and Cartilage Disease project identifies mutants with significant outlier skeletal phenotypes. This initiative will add value to data from large human cohorts and provide a new understanding of bone and cartilage pathophysiology, ultimately leading to the identification of novel drug targets for the treatment of skeletal disease.

Journal article

Master A, Wójcicka A, Giżewska K, Popławski P, Williams GR, Nauman Aet al., 2016, A novel method for gene-specific enhancement of protein translation by targeting 5’UTRs of selected tumor suppressors, PLOS One, Vol: 11, ISSN: 1932-6203

BackgroundTranslational control is a mechanism of protein synthesis regulation emerging as an importanttarget for new therapeutics. Naturally occurring microRNAs and synthetic small inhibitoryRNAs (siRNAs) are the most recognized regulatory molecules acting via RNAinterference. Surprisingly, recent studies have shown that interfering RNAs may also activategene transcription via the newly discovered phenomenon of small RNA-induced geneactivation (RNAa). Thus far, the small activating RNAs (saRNAs) have only been demonstratedas promoter-specific transcriptional activators.FindingsWe demonstrate that oligonucleotide-based trans-acting factors can also specificallyenhance gene expression at the level of protein translation by acting at sequence-specifictargets within the messenger RNA 5’-untranslated region (5’UTR). We designed a set ofshort synthetic oligonucleotides (dGoligos), specifically targeting alternatively spliced5’UTRs in transcripts expressed from the THRB and CDKN2A suppressor genes. The invitro translation efficiency of reporter constructs containing alternative TRβ1 5’UTRs wasincreased by up to more than 55-fold following exposure to specific dGoligos. Moreover, wefound that the most folded 5’UTR has higher translational regulatory potential when comparedto the weakly folded TRβ1 variant. This suggests such a strategy may be especiallyapplied to enhance translation from relatively inactive transcripts containing long 5’UTRs ofcomplex structure.SignificanceThis report represents the first method for gene-specific translation enhancement usingselective trans-acting factors designed to target specific 5’UTR cis-acting elements. Thissimple strategy may be developed further to complement other available methods for geneexpression regulation including gene silencing. The dGoligo-mediated translation-enhancingapproach has the potential to be transferred to increase the translation efficiency of anysuitable targ

Journal article

Klein Hesselink MS, Nies M, Bocca G, Brouwers AH, Burgerhof JGM, van Dam EWCM, Havekes B, van den Heuvel-Eibrink MM, Corssmit EPM, Kremer LCM, Netea-Maier RT, van der Pal HJH, Peeters RP, Schmid KW, Smit JWA, Williams GR, Plukker JTM, Ronckers CM, van Santen HM, Tissing WJE, Links TPet al., 2016, Pediatric Differentiated Thyroid Carcinoma in The Netherlands: A Nationwide Follow-Up Study, The Journal of Clinical Endocrinology & Metabolism, Vol: 101, Pages: 2031-2039, ISSN: 0021-972X

Introduction:Treatment for differentiated thyroid carcinoma (DTC) in pediatric patients is based mainly on evidence from adult series due to lack of data from pediatric cohorts. Our objective was to evaluate presentation, treatment-related complications, and long-term outcome in patients with pediatric DTC in the Netherlands.Patients and methods:In this nationwide study, presentation, complications and outcome of patients with pediatric DTC (age at diagnosis ≤18 years) treated in the Netherlands between 1970 and 2013 were assessed using medical records.Results:We identified 170 patients. Overall survival was 99.4% after median follow-up of 13.5 (range 0.3–44.7) years. Extensive follow-up data were available for 105 patients (83.8% women), treated in 39 hospitals. Median age at diagnosis was 15.6 (range 5.8–18.9) years. At initial diagnosis, 43.8% of the patients had cervical lymph node metastases; 13.3% had distant metastases. All patients underwent total thyroidectomy. Radioiodine was administered to 97.1%, with a median cumulative activity of 5.66 (range 0.74–35.15) GBq. Lifelong postoperative complications (permanent hypoparathyroidism and/or recurrent laryngeal nerve injury) were present in 32.4% of the patients. At last known follow-up, 8.6% of the patients had persistent disease and 7.6% experienced a recurrence. TSH suppression was not associated with recurrences (OR 2.00, 95% CI 0.78 to 5.17, P = 0.152).Conclusions:Survival of pediatric DTC is excellent. Therefore, minimizing treatment-related morbidity takes major priority. Our study shows a frequent occurrence of lifelong postoperative complications. Adverse effects may be reduced by centralization of care, which is crucial for children with DTC.

Journal article

Bassett JH, Williams GR, 2016, Role of thyroid hormones in skeletal development and bone maintenance., Endocrine Reviews, Vol: 37, ISSN: 1945-7189

The skeleton is an exquisitely sensitive and archetypal T3-target tissue that demonstrates the critical role for thyroid hormones during development, linear growth, and adult bone turnover and maintenance. Thyrotoxicosis is an established cause of secondary osteoporosis, and abnormal thyroid hormone signaling has recently been identified as a novel risk factor for osteoarthritis. Skeletal phenotypes in genetically modified mice have faithfully reproduced genetic disorders in humans, revealing the complex physiological relationship between centrally regulated thyroid status and the peripheral actions of thyroid hormones. Studies in mutant mice also established the paradigm that T3 exerts anabolic actions during growth and catabolic effects on adult bone. Thus, the skeleton represents an ideal physiological system in which to characterize thyroid hormone transport, metabolism, and action during development, adulthood and in response to injury. Future analysis of T3 action in individual skeletal cell lineages will provide new insights into cell-specific molecular mechanisms and may ultimately identify novel therapeutic targets for chronic degenerative diseases such as osteoporosis and osteoarthritis. This review provides a comprehensive analysis of the current state-of-the-art.

Journal article

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