Common variants in the GDF5-UQCC region are associated with variation in human height

Sanna, Serena; Jackson, Anne; Nagaraja, Ramaiah; Willer, Cristen J.; Chen, Wei Min; Bonnycastle, Lori L.; Shen, Haiqing; Timpson, Nicholas J.; Lettre, Guillaume; Usala, Gianluca; Chines, Peter S.; Stringham, Heather M.; Scott, Laura J.; Dei, Mariano; Lai, Sandra; Albai, Giuseppe; Crisponi, Laura; Naitza, Silvia; Doheny, Kimberly F.; Pugh, Elizabeth; Ben-Shlomo, Yoav; Ebrahim, Shah; Lawlor, Debbie A.; Bergman, Richard N.; Watanabe, Richard M.; Uda, Manuela; Tuomilehto, Jaakko; Coresh, Josef; Hirschhorn, Joel N.; Shuldiner, Alan R.; Schlessinger, David; Collins, Francis S.; Smith, George Davey; Boerwinkle, Eric; Cao, Antonio; Boehnke, Michael; Abecasis, Gonçalo R.; Mohlke, Karen L.

doi:10.1038/ng.74

Cited by 364 publications

(278 citation statements)

References 28 publications

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“…Genetic variations in the GDF5 locus have been reported to be involved in the pathogenesis of rheumatoid arthritis and to influence human height, hip axis length and fracture risk in the elderly (Rouault et al, 2010;Vaes et al, 2009). Furthermore, association of variant T allele with other musculoskeletal phenotypes, including variation in Achilles tendon pathology, fracture risk and congenital dysplasia of the hip, has also been reported (Posthumus et al, 2010;Sanna et al, 2008).…”

Section: Discussionmentioning

confidence: 98%

Association of Polymorphism in Growth and Differentiation Factor 5 Gene With Osteoarthritis Knee

Mishra¹,

Sanghi²,

Sharma³

et al. 2013

American Journal of Biochemistry and Biotechnology

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The present study investigated to identify the association of polymorphism in GDF-5 gene with osteoarthritis in North Indian population. In a case-control study, 300 cases with knee osteoarthritis and an equal number of age and gender matched healthy controls were included. Cases were diagnosed using the ACR Guidelines of Knee Osteoarthritis (KOA). Clinical symptoms were assessed with the knee specific WOMAC index and VAS for knee pain. The severity of disease was determined by radiological KL grades (Kellgren Lawren). The variant genotype of GDF-5 was found to be present at significantly higher frequency in cases than in controls, resulting in about 1.79 fold increase in risk to OA. Genotype distributions of the GDF-5 also showed significant association of variant allele with clinical score of OA patients. An association between the+104T/C GDF5 polymorphism with knee OA and clinical symptom of OA in Indian population further demonstrate a strong genetic influence of this SNP in KOA.

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Section: Discussionmentioning

confidence: 98%

Association of Polymorphism in Growth and Differentiation Factor 5 Gene With Osteoarthritis Knee

Mishra¹,

Sanghi²,

Sharma³

et al. 2013

American Journal of Biochemistry and Biotechnology

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“…Height loss is largely explained by the change in spine length (ChinappenHorsley et al 2008). Therefore, unsurprisingly, recent genome-wide association studies (GWAS) for adult height identified, among other bone-related genes, GDF5, a cartilage-derived morphogenetic protein (Soranzo et al 2009;Sanna et al 2008;Weedon et al 2008). Earlier, it was suggested that ESR1 polymorphisms influence the age-related decrease in stature (Ioannidis et al 2004).…”

Section: Biomarkers Of Agingmentioning

confidence: 99%

How pleiotropic genetics of the musculoskeletal system can inform genomics and phenomics of aging

Karasik

2010

AGE

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Genetic study can provide insight into the biologic mechanisms underlying inter-individual differences in susceptibility to (or resistance to) organisms' aging. Recent advances in molecular genetics and genetic epidemiology provide the necessary tools to perform a study of the genetic sources of biological aging. However, to be successful, the genetic study of a complex condition requires a heritable phenotype to be developed and validated. Genome-wide association studies offer an unbiased approach to identify new candidate genes for human diseases. It is hypothesized that convergent results from multiple aging-related traits will point out the genes responsible for the general aging of the organism. This perspective focuses on the musculoskeletal aging as an example of an approach to identify a downstream common pathway that summarizes aging processes. Since the musculoskeletal traits are linked to the state of many vital functions, disability, and ultimately survival rates, we postulate that there is significance in studying musculoskeletal aging. Construction of an integrated phenotype of aging can be achieved based on shared genetics among multiple musculoskeletal biomarkers. Valid biomarkers from other systems of the organism should be similarly explored. The new composite aging score needs to be validated by determining whether it predicts all-cause mortality, incidences of major chronic diseases, and disability late in life. Comprehensive databases on biomarkers of musculoskeletal aging in multiple large cohort studies, along with information on various health outcomes, are needed to validate the proposed measure of biological aging.

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“…For some traits such as height in humans, this is indeed the case, with the largest reported QTLs explaining only a small fraction of the genetic variance (e.g. Sanna et al, 2008;Visscher, 2008).…”

Section: Introductionmentioning

confidence: 99%

Increased accuracy of artificial selection by using the realized relationship matrix

Hayes¹,

2009

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SummaryDense marker genotypes allow the construction of the realized relationship matrix between individuals, with elements the realized proportion of the genome that is identical by descent (IBD) between pairs of individuals. In this paper, we demonstrate that by replacing the average relationship matrix derived from pedigree with the realized relationship matrix in best linear unbiased prediction (BLUP) of breeding values, the accuracy of the breeding values can be substantially increased, especially for individuals with no phenotype of their own. We further demonstrate that this method of predicting breeding values is exactly equivalent to the genomic selection methodology where the effects of quantitative trait loci (QTLs) contributing to variation in the trait are assumed to be normally distributed. The accuracy of breeding values predicted using the realized relationship matrix in the BLUP equations can be deterministically predicted for known family relationships, for example half sibs. The deterministic method uses the effective number of independently segregating loci controlling the phenotype that depends on the type of family relationship and the length of the genome. The accuracy of predicted breeding values depends on this number of effective loci, the family relationship and the number of phenotypic records. The deterministic prediction demonstrates that the accuracy of breeding values can approach unity if enough relatives are genotyped and phenotyped. For example, when 1000 full sibs per family were genotyped and phenotyped, and the heritability of the trait was 0 . 5, the reliability of predicted genomic breeding values (GEBVs) for individuals in the same full sib family without phenotypes was 0 . 82. These results were verified by simulation. A deterministic prediction was also derived for random mating populations, where the effective population size is the key parameter determining the effective number of independently segregating loci. If the effective population size is large, a very large number of individuals must be genotyped and phenotyped in order to accurately predict breeding values for unphenotyped individuals from the same population. If the heritability of the trait is 0 . 3, and N e =1000, approximately 5750 individuals with genotypes and phenotypes are required in order to predict GEBVs of un-phenotyped individuals in the same population with an accuracy of 0 . 7.

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Common variants in the GDF5-UQCC region are associated with variation in human height

Cited by 364 publications

References 28 publications

Association of Polymorphism in Growth and Differentiation Factor 5 Gene With Osteoarthritis Knee

Association of Polymorphism in Growth and Differentiation Factor 5 Gene With Osteoarthritis Knee

How pleiotropic genetics of the musculoskeletal system can inform genomics and phenomics of aging

Increased accuracy of artificial selection by using the realized relationship matrix

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