Sergey Ermakov

Meta-Analysis of Genome-Wide Scans for Human Adult Stature Identifies Novel Loci and Associations with Measures of Skeletal Frame Size

Recent genome-wide (GW) scans have identified several independent loci affecting human stature, but their contribution through the different skeletal components of height is still poorly understood. We carried out a genome-wide scan in 12,611 participants, followed by replication in an additional 7,187 individuals, and identified 17 genomic regions with GW-significant association with height. Of these, two are entirely novel (rs11809207 in CATSPER4, combined P-value = 6.1×10−8 and rs910316 in TMED10, P-value = 1.4×10−7) and two had previously been described with weak statistical support (rs10472828 in NPR3, P-value = 3×10−7 and rs849141 in JAZF1, P-value = 3.2×10−11). One locus (rs1182188 at GNA12) identifies the first height eQTL. We also assessed the contribution of height loci to the upper- (trunk) and lower-body (hip axis and femur) skeletal components of height. We find evidence for several loci associated with trunk length (including rs6570507 in GPR126, P-value = 4×10−5 and rs6817306 in LCORL, P-value = 4×10−4), hip axis length (including rs6830062 at LCORL, P-value = 4.8×10−4 and rs4911494 at UQCC, P-value = 1.9×10−4), and femur length (including rs710841 at PRKG2, P-value = 2.4×10−5 and rs10946808 at HIST1H1D, P-value = 6.4×10−6). Finally, we used conditional analyses to explore a possible differential contribution of the height loci to these different skeletal size measurements. In addition to validating four novel loci controlling adult stature, our study represents the first effort to assess the contribution of genetic loci to three skeletal components of height. Further statistical tests in larger numbers of individuals will be required to verify if the height loci affect height preferentially through these subcomponents of height.

Evidence that bone mineral density plays a role in degenerative disc disease: the UK Twin Spine Study

Objective Osteoarthritis (OA) and osteoporosis are often considered to lie at opposite ends of a spectrum of bone phenotypes. Lumbar degenerative disc disease (LDD) may be associated with low back pain (LBP) and is similar in many ways to OA. LDD is reported in small studies to be associated with increased spine bone mineral density (BMD). The present work aimed to confirm this association in a large population sample using MRI and explore the relationship further, in particular to determine whether it is mediated genetically. Methods A population based sample (N=908, age range 32–74 years) of UK female twins having MRI of the lumbar spine was used in this study. LDD traits and summary measures and their relationship with BMD at the lumbar spine and hip were examined using multivariate multiple regression and maximum likelihood based variance decomposition. Results There was a significant positive correlation between LDD and BMD at the lumbar spine and hip, which remained significant after adjustment for confounders. Both traits were highly heritable and the associations between them were mediated genetically. Conclusions A clear, significant and independent association of BMD at hip and lumbar spine with LDD was found which is, in part, genetically mediated. The association with the non-axial site, the hip, is of particular interest and suggests a systemic bone effect. This should encourage the search for pleiotropic genes to help in the understanding of the bone–cartilage relationship. Moreover, genetic variants identified could provide novel therapeutic targets in the management of LBP.

Family‐Based Association Study of Polymorphisms in the RUNX2 Locus with Hand Bone Length and Hand BMD

Osteoporosis is characterized by reduced bone strength. Bone size and bone mineral density (BMD) are major bone strength determinants. Identification of genes affecting the variability of these traits should improve prognosis and management of osteoporosis. This research was aimed to test the hypothesis of association of radiographic hand bone length (BL) and BMD with polymorphisms in the RUNX2 locus.

Quantitative genetic study of head size related phenotypes in ethnically homogeneous Chuvasha pedigrees

Background: It is well established that genetic factors contribute significantly to the determination of head size and shape traits variability. However, the controversies in views and findings with respect to the more specific aspects of this issue have not yet been resolved. Aim: The primary objective of the study was to examine the patterns of the intergenerational familial transmission of 12 head size related traits in a large ethnically homogeneous sample of Chuvasha pedigrees. Subjects and methods: The research was carried out on 1406 individuals belonging to 357 nuclear and more complex families. Univariate and bivariate family-based analyses were performed to establish the pattern of head traits inheritance. Results: Maximum heritability estimates ranged from 0.52 to 0.72 for traits adjusted for significant covariates. No significant sex differences were observed with respect to the genetic determination of the studied traits. Bivariate analysis of horizontal and vertical head size components suggested the existence of common genetic and environmental factors that explained 33.0% and 23.2% of the total variance of the adjusted traits, respectively. Conclusions: A significant genetic component is involved in inter-individual variation and covariation of various studied craniofacial traits. Résumé. Arrière plan: S’il est bien connu que des facteurs génétiques peuvent contribuer significativement à la variabilité des caractères de taille et de forme de la tête, il demeure cependant à propos de cette question, que les points de vue et les controverses qui entourent les résultats sont toujours d’actualité. But: L’objectif fondamental de cette étude est d’étudier les modalités de transmission familiale et intergénérationnelle de 12 caractéristiques du format de la tête dans un vaste échantillon homogène de généalogies de Chuvasha. Sujets et méthodes: L’étude a été conduite sur 1406 individus appartenant à 357 familles nucléaires et complexes. Des analyses familiales univariées et bivariées ont été exécutées afin d’établir le modèle de l’hérédité des traits de la tête. Résultats: Les estimations d’héritabilité maximum varient de 0,52 à 0,72 après ajustement pour des covariables significatives. On n’observe pas de différence sexuelle quant à la détermination génétique des caractères étudiés. L’analyse bivariée des composants du format vertical et horizontal de la tête suggère l’existence de facteurs génétiques et environnementaux communs, qui expliqueraient respectivement 33,0% et 23,2% de la variance totale des caractères ajustés. Conclusion: Un composant génétique significatif est impliqué dans la variation et la covariation interindividuelle de divers des traits craniofaciaux étudiés. Zusammenfassung. Hintergrund: Es ist allgemein bekannt, dass genetische Faktoren einen signifikanten Beitrag zur Vererbung von Kopfgröße und Kopfform leisten. Allerdings sind die strittigen Fragen hinsichtlich unterschiedlicher Meinungen und Ergebnisse bezüglich spezifischer Aspekte dieses Problemkreises noch nicht geklärt. Ziel: Das vornehmliche Studienziel war die Untersuchung des Vererbungsmodus von 12 Kopfmaßen in einer großen, ethnisch einheitlichen Stichprobe von Tschuwaschischen Familien. Probanden und Methoden: Die Untersuchung fand an 1406 Personen statt, die zu 357 Kernfamilien und größeren familiären Gruppen gehörten. Es wurden univariate und bivariate familiengestützte Analysen durchgeführt, um den Vererbungsmodus von Kopfmaßen zu klären. Ergebnisse: Schätzungen der maximalen Heritabilität schwankten von 0,52 bis 0,72 für auf signifikante Kovariate angepasste Merkmale. Es wurden keine signifikanten Geschlechtsunterschiede hinsichtlich der genetischen Ursache der untersuchten Merkmale beobachtet. Bivariate Analysen von horizontalen und vertikalen Komponenten der Kopfgröße legten nahe, dass gemeinsame genetische und Umweltfaktoren bestehen, die je 33,0%, bzw. 23,2% der Gesamtvarianz der angepassten Merkmale erklären. Zusammenfassung: Es besteht eine signifikante genetische Komponente bei der inter-individuellen Variation und Kovariation der verschiedenen untersuchten craniofacialen Merkmale. Resumen. Antecedentes: Está bien establecido que los factores genéticos contribuyen significativamente a la determinación de la variabilidad del tamaño y forma de la cabeza. Sin embargo, las controversias que atañen a los puntos de vista y resultados relacionados con aspectos más específicos de este tema, aun no han sido resueltas. Objetivo: El objetivo principal del estudio fue examinar los patrones de transmisión familiar intergeneracional de 12 rasgos relativos al tamaño cefálico, en una muestra amplia y étnicamente homogénea de pedigríes Chuvasha. Sujetos y Métodos: La investigación se realizó en 1406 individuos pertenecientes a 357 familias nucleares y complejas. Se realizaron análisis univariados y bivariados basados en familias para establecer el patrón de herencia de los rasgos de la cabeza. Resultados: Las estimaciones máximas de heredabilidad oscilaban entre 0,52 y 0,72 en los rasgos ajustados para covariantes significativas. No se observaron diferencias sexuales significativas con respecto a la determinación genética de los rasgos estudiados. El análisis bivariado de los componentes horizontales y verticales del tamaño cefálico sugería la existencia de factores genéticos y ambientales comunes que explicaban, respectivamente, el 33,0% y el 23,2% de la varianza total de los rasgos ajustados. Conclusión: Un importante componente genético está implicado en la variación interindividual y en la covariación de los diversos rasgos craneofaciales estudiados.

Family-based study of association between ENPP1 genetic variants and craniofacial morphology

Background: Human craniofacial morphology is characterized by considerable diversity among individuals. The ENPP1 gene is essential for bone physiology. However, the potential effects of its genetic variants on head size phenotypes have not yet been studied. Aim: The aim of this research was to investigate the association of polymorphisms in the ENPP1 locus with normal variability of craniofacial phenotypes. Subjects and methods: Fourteen SNPs and 13 haplotypes in the ENPP1 locus were tested for association with six head size traits in 1042 Western Eurasian individuals. Results: The most significant and consistent association was observed between upper facial height and the polymorphisms located near the promoter region and upstream from ENPP1 gene (p = 0.00009), which remained significant after adjustment for multiple testing. Additionally, association signals were detected between head breadths and lower face height, and markers residing in or close to the promoter and 3′ untranslated regions of the ENPP1 gene (p < 0.05). Conclusions: The findings obtained in this study suggest that the upstream, promoter and 3′ untranslated regions in the ENPP1 locus harbor genetic variants affecting different aspects of craniofacial morphology. Further research is required to validate the relevancy of the potentially functional ENPP1 regions to normal and pathologic craniofacial growth.

Family-based association study of ROR2 polymorphisms with an array of radiographic hand bone strength phenotypes

SummaryFor the first time the study provides evidence of association of radiographic hand bone length (BL) and bone mineral density (BMD) with polymorphisms in ROR2 gene that plays important role in skeletal development. This contributes to better understanding of bone physiology and may have application in clinical practice.Introduction and hypothesisBone size and bone mineral density (BMD) are major determinants of bone strength. Identification of genes affecting these traits’ variability is important for better understanding of normal and pathological bone physiology and identification of the individuals at risk for bone fracture. This study tested the hypothesis of association of radiographic hand bone length (BL) and BMD with polymorphisms in ROR2 gene that is important in skeletal development.MethodsNineteen ROR2 SNPs were genotyped in 705 individuals, belonging to 212 nuclear families. The four tagging SNPs (tSNPs) and the pairwise haplotypes between adjacent tSNPs were tested for association with series of hand BL and BMD measurements, adjusted for covariates, using family-based association tests.ResultsWe observed significant associations with BL and BMD mean values for all 18 studied hand bones (p = 0.0080, 0.0030), mean BL and BMD for proximal phalanges (p = 0.0218, 0.0060) and metacarpal bones (p = 0.0014, 0.0004). In the latter, the association remained significant after correction for multiple testing.ConclusionsThe region of the first through the second ROR2 introns is most likely to contain the functional polymorphism/s responsible for the observed associations. Further studies are required to identify the ROR2 functional polymorphism/s affecting bone size and BMD variation.

Outlines of the Biochemistry of Osteoarthritis

Osteoarthritis (OA) is a complex, age dependent disease in which various factors, including metabolic changes, are all major contributors to its onset and progression. Anatomically, OA embraces the whole joint, i.e. articular cartilage, subchondral bone alterations and joint-lining synovial membrane. Correspondingly, OA development involves elaborate interactions of cartilaginous tissue metabolism and maintenance, osteogenesis, mineralization and inflammation of the synovial membrane. Identification of the molecular pathways and individual factors involved in OA etiology, understanding of mechanisms of their action and interaction are necessary conditions for developing the accurate diagnostic and prognostic tools and for providing OA patients effective treatment. There is a major progress in understanding of the molecular mechanisms of OA appearance and progression, which are pointing out to the network of biochemical factors important for normal functioning of the joints and changes leading to OA. The present review summarizes the data on the efficacy of the relevant biochemical factors affecting all the components of the joint and that could be therefore useful targets in treatment of OA. However, despite the dramatic growth of the knowledge concerning the biochemistry of OA and discovery of a number of useful biomarkers the real breakthrough in this area is still not achieved.

A significant association exists between receptor tyrosine kinase-like orphan receptor 2 gene variants and the OPG/RANKL ratio in human plasma

SummaryThere is a paucity of studies investigating association between ROR2 gene variants and osteoporosis and osteoarthritis-related phenotypes. The published literature suggests that osteoprotegerin (OPG) and receptor activator of nuclear factor-kB ligand (RANKL) are essential for bone metabolism and correlate with osteoarthritis manifestation and progression. The present study provides evidence of the significant association between ROR2 variants and the OPG/RANKL ratio in human plasma. The present results also suggest significant association between ROR2 polymorphisms and severity of radiographic hand osteoarthritis.IntroductionDespite the importance of the ROR-2 in skeletal physiology, there is a paucity of studies investigating the potential association of ROR2 gene variants with phenotypes relevant to osteoporosis and osteoarthritis. On the other hand, there is a considerable body of literature suggesting that OPG and RANKL and their ratio (OPG/RANKL) are essential for regulating bone resorption. This is also correlated with osteoarthritis manifestation and progression. The present study therefore examines whether ROR2 polymorphisms may be associated with the OPG/RANKL ratio and hand osteoarthritis (HOA).MethodsThe study was conducted in a family-based sample of 1,515 Caucasian individuals, assessed for radiographic hand osteoarthritis, using the Kellgren/Lawrence score. Of these, 865 individuals were genotyped for 19 SNPs, relatively equally covering the ROR2 locus, and their plasma levels of OPG and RANKL were assayed. The association between the selected SNPs and OPG, along with the OPG/RANKL ratio and HOA, was explored using the pedigree disequilibrium test.ResultsOf the total of 57 tests, 16 nominally significant results (p < 0.05) were obtained, which is considerably more than the three normally expected for type I error. The significant association signals for all three phenotypes were mapped to the intron 1 region. The most significant results were detected between OPG/RANKL and rs7048756 (p < 0.0005) and between adjacent rs4744107 and Kellgren/Lawrence score (p = 0.006).ConclusionsThe present study provides evidence of the significant association between ROR2 variants and the OPG/RANKL ratio in human plasma and also suggests ROR2 association with HOA.

Genetic determinants of circulating levels of tumor necrosis factor receptor II and their association with TNF-RII gene polymorphisms.

BACKGROUND Tumor necrosis factor alpha (TNFalpha) is a cytokine involved in inflammatory, immune, and metabolic events. TNFalpha signals are mediated through activation of two receptors, one of which is tumor necrosis factor receptor TNF-RII. OBJECTIVE To examine the effects of genetic and environmental factors on TNF-RII plasma concentration and its association with polymorphisms in the TNF-RII gene locus. METHODS The levels of sTNF-RII were determined in 897 individuals. The association between sTNF-RII and polymorphisms in its structural gene locus was examined by pedigree-based association analyses (PDT) and transmission disequilibrium tests (TDTs). RESULTS 49.57% of the adjusted sTNF-RII variability was attributable to genetic factors. sTNF-RII plasma levels were nominally associated with the genomic region spanning TNF-RII promoter and the first intron, represented by rs976881 (p=0.029). Although after correction for multiple testing this PDT signal formally did not reach statistical significance, it was reflected also in series of TDTs and further confirmed by association observed for haplotype of rs976881 with rs590368 (nominal p=0.006) and by ANOVA. CONCLUSIONS sTNF-RII plasma concentration is determined by both genetic and environmental factors. Our results suggest association between sTNF-RII levels and polymorphisms in vicinity to TNF-RII promoter region. This finding requires further thorough validation in other populations.

Complex segregation analysis of two principal components derived from horizontal and vertical head size traits.

Background: There is a wealth of publications establishing the involvement of genetic factors in the determination of inter-individual variability of head size traits. However, little is known about the mode of inheritance of craniofacial traits in the healthy population. Aim: The aims of this study were to investigate the mode of inheritance of horizontal (HOC) and vertical (VEC) components of head dimensions, and to test the hypothesis of a common major gene for these traits. Subjects and methods: The study was conducted on 1406 individuals belonging to 357 pedigrees. Univariate and bivariate complex segregation analyses were conducted on two principal components, HOC and VEC, extracted from 10 original head traits. Results: The hypothesis of Mendelian transmission was accepted in both studied traits. The inferred major genes explained 54.0% and 45.6% of HOC and VEC variance, adjusted for covariates. For both traits an additive mode of major gene alleles interaction was suggested. No positive evidence for a common major gene for both HOC and VEC was obtained. Conclusion: We conclude that head size in horizontal and vertical dimensions is determined by two different major genes together with modest and minor effect genes, the latter being partly shared by HOC and VEC.