The Impact of Large-Scale Genomic Methods in Orthopaedic Disorders: Insights from Genome-Wide Association Studies

Paria, Nandina; Copley, Lawson A.; Herring, John A.; Kim, Harry K.W.; Richards, B. Stephens; Sucato, Daniel J.; Rios, Jonathan J.; Wise, Carol A.

doi:10.2106/jbjs.m.00398

Cited by 3 publications

(1 citation statement)

References 78 publications

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“…One method, high-density microarray-based genotyping, enables testing of greater than one million single nucleotide polymorphisms (SNPs) spaced across the genome. Measuring SNP content and signal intensity reveals gains and losses of genetic material known as copy number variations, or CNVs, typically at higher resolution than a traditional karyotype [12,13]. Microarray-based genotyping also yields information about SNP heterozygosity.…”

Section: Introductionmentioning

confidence: 99%

Genomic Analyses of Patients With Unexplained Early-Onset Scoliosis

et al. 2014

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Study Design To test for rare genetic mutations, a cohort of patients with unexplained early onset scoliosis (EOS) was screened using high-density microarray genotyping. A cohort of patients with adolescent idiopathic scoliosis (AIS) was similarly screened, and the results were compared. Summary of background data Patients with scoliosis in infancy or early childhood (EOS) are at high risk for progressive deformity and associated problems including respiratory compromise. EOS is frequently associated with genetic disorders, but many patients present with non-specific clinical features and without an associated diagnosis. We hypothesized that EOS in these patients may be caused by rare genetic mutations detectable by next-generation genomic methods. Methods We ascertained 24 patients with unexplained EOS from pediatric orthopedic clinics. We genotyped them, along with 39 connecting family members, using the Illumina OmniExpress-12 v1.0 beadchip. Resulting genotypes were analyzed for chromosomal changes, specifically copy number variation (CNV) and absence of heterozygosity (AOH). We screened 482 AIS patients and 744 healthy controls, which were similarly genotyped with the same beadchip, for chromosomal changes identified in the EOS cohort. Results Copy number variation (CNV) and absence of heterozygosity (AOH) analyses revealed a genetic diagnosis of chromosome 15q24 microdeletion syndrome in one patient, and maternal uniparental disomy of chromosome 14 in a second patient. Prior genetic testing and clinical evaluations had been negative in both cases. A large novel chromosome 10 deletion was likely causal in a third EOS patient. These mutations identified in the EOS patients were absent in AIS patients and controls, and thus not associated with AIS or found in asymptomatic individuals. Conclusions Our data underscore the utility of updated genetic evaluations including high-density microarray-based genotyping and other “next-generation” methods in patients with unexplained EOS, even where prior genetic studies were negative. These data also suggest the intriguing possibility that other mutations detectable by whole genome sequencing, as well as epigenetic effects, await discovery in the EOS population.

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Section: Introductionmentioning

confidence: 99%

Genomic Analyses of Patients With Unexplained Early-Onset Scoliosis

et al. 2014

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Overview of Next Generation, High-Throughput Molecular Genetic Methods

Rios

2015

Molecular Genetics of Pediatric Orthopaedic Disorders

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CORR® ORS Richard A. Brand Award: Disruption in Peroxisome Proliferator-Activated Receptor-γ (PPARG) Increases Osteonecrosis Risk Through Genetic Variance and Pharmacologic Modulation

Wyles

Paradise

Houdek

et al. 2019

Clin Orthop Relat Res

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Background The pathophysiology of osteonecrosis of the femoral head (ONFH) is poorly understood, and the diagnosis is idiopathic in as many as 40% of patients. Genetic and epigenetic etiologies have been postulated, yet no single nucleotide polymorphisms (SNPs) with intuitive biologic implications have been elucidated. Questions/purposes (1) Do individuals with ONFH share common biologically relevant genetic variants associated with disease development? (2) What is the mechanism by which these SNPs may impact the expression or function of the affected gene or protein? Methods This retrospective genome-wide association study (GWAS) evaluated participants from the Mayo Clinic Biobank and Mayo Clinic Genome Consortium between August 2009 and March 2017. We included every patient with atraumatic ONFH in each of these respective registries and every control patient in a previous GWAS with an acceptable platform to perform statistical imputation. The study was performed in two phases, with an initial discovery cohort and a subsequent validation cohort. The initial discovery cohort consisted of 102 patients with ONFH and 4125 controls. A logistic regression analysis was used to evaluate associations between SNPs and the risk of ONFH, adjusted for age and sex. Seven SNPs were identified in a gene of biological interest, peroxisome proliferator-activated receptor gamma (PPARG), which were then evaluated in a subsequent validation cohort of 38 patients with ONFH and 464 controls. Age, sex, race, and previous steroid exposure were similar between patients with ONFH and controls in both the discovery and validation cohorts. Separate from the two-phase genetic investigation, we performed targeted pharmacosurveillance to evaluate the risk association between the use of antidiabetic thiazolidinediones, a class of PPARG agonists, and development of ONFH by referencing 9,638,296 patient records for individuals treated at Mayo Clinic. Results A combined analysis of the discovery and validation cohorts revealed that seven SNPs were tightly clustered adjacent to the 3’ end of PPARG, suggesting an association with the risk of ONFH (p = 1.58 x 10-2-5.50 x10-6). PPARG gene-level significance was achieved (p = 3.33 x 10-6) when all seven SNPs were considered. SNP rs980990 had the strongest association with the risk of ONFH (odds ratio [OR], 1.95; 95% CI, 1.46-2.59; p = 5.50 x 10-6). The seven identified SNPs were mapped to a region near the PPARG gene and fell in a highly conserved region consisting of several critical transcription factor binding sites. Nucleotide polymorphisms at these sites may compromise three-dimensional chromatin organization and alter PPARG 3’ end interactions with its 5’ promoter and transcription start site. Pharmacosurveillance identified that patients who were exposed to thiazolidinediones had an increased relative risk of developing ONFH of 5.6 (95% CI, 4.5-7.1). Conclusions We found that disruption of PPARG regulatory domains is linked to an increased risk of ONFH. Mechanistically, aberrant regulation of PPARG compromises musculoskeletal differentiation because this master regulator creates a proadipogenic and antiosteogenic state. Furthermore, PPARG alters steroid metabolism and vasculogenesis, processes that are inextricably linked with ONFH. Pharmacologically, predisposition to ONFH was further exposed with thiazolidinedione use, which upregulates the expression of PPARG and is known to alter bone metabolism. Collectively, these findings provide a foundation to perform confirmatory studies of our proposed mechanism in preclinical models to develop screening diagnostics and potential therapies in patients with limited options. Level of Evidence Level III, prognostic study.

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The Impact of Large-Scale Genomic Methods in Orthopaedic Disorders: Insights from Genome-Wide Association Studies

Cited by 3 publications

References 78 publications

Genomic Analyses of Patients With Unexplained Early-Onset Scoliosis

Genomic Analyses of Patients With Unexplained Early-Onset Scoliosis

Overview of Next Generation, High-Throughput Molecular Genetic Methods

CORR® ORS Richard A. Brand Award: Disruption in Peroxisome Proliferator-Activated Receptor-γ (PPARG) Increases Osteonecrosis Risk Through Genetic Variance and Pharmacologic Modulation

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