16 research outputs found
Deciphering osteoarthritis genetics across 826,690 individuals from 9 populations
Osteoarthritis affects over 300 million people worldwide. Here, we conduct a genome-wide association study meta-analysis across 826,690 individuals (177,517 with osteoarthritis) and identify 100 independently associated risk variants across 11 osteoarthritis phenotypes, 52 of which have not been associated with the disease before. We report thumb and spine osteoarthritis risk variants and identify differences in genetic effects between weight-bearing and non-weight-bearing joints. We identify sex-specific and early age-at-onset osteoarthritis risk loci. We integrate functional genomics data from primary patient tissues (including articular cartilage, subchondral bone, and osteophytic cartilage) and identify high-confidence effector genes. We provide evidence for genetic correlation with phenotypes related to pain, the main disease symptom, and identify likely causal genes linked to neuronal processes. Our results provide insights into key molecular players in disease processes and highlight attractive drug targets to accelerate translation
Rare SLC13A1 variants associate with intervertebral disc disorder highlighting role of sulfate in disc pathology
Publisher Copyright: © 2022, The Author(s).Back pain is a common and debilitating disorder with largely unknown underlying biology. Here we report a genome-wide association study of back pain using diagnoses assigned in clinical practice; dorsalgia (119,100 cases, 909,847 controls) and intervertebral disc disorder (IDD) (58,854 cases, 922,958 controls). We identify 41 variants at 33 loci. The most significant association (ORIDD = 0.92, P = 1.6 × 10−39; ORdorsalgia = 0.92, P = 7.2 × 10−15) is with a 3’UTR variant (rs1871452-T) in CHST3, encoding a sulfotransferase enzyme expressed in intervertebral discs. The largest effects on IDD are conferred by rare (MAF = 0.07 − 0.32%) loss-of-function (LoF) variants in SLC13A1, encoding a sodium-sulfate co-transporter (LoF burden OR = 1.44, P = 3.1 × 10−11); variants that also associate with reduced serum sulfate. Genes implicated by this study are involved in cartilage and bone biology, as well as neurological and inflammatory processes.Peer reviewe
Deciphering osteoarthritis genetics across 826,690 individuals from 9 populations
Osteoarthritis affects over 300 million people worldwide. Here, we conduct a genome-wide association study meta-analysis across 826,690 individuals (177,517 with osteoarthritis) and identify 100 independently associated risk variants across 11 osteoarthritis phenotypes, 52 of which have not been associated with the disease before. We report thumb and spine osteoarthritis risk variants and identify differences in genetic effects between weight-bearing and non-weight-bearing joints. We identify sex-specific and early age-at-onset osteoarthritis risk loci. We integrate functional genomics data from primary patient tissues (including articular cartilage, subchondral bone, and osteophytic cartilage) and identify high-confidence effector genes. We provide evidence for genetic correlation with phenotypes related to pain, the main disease symptom, and identify likely causal genes linked to neuronal processes. Our results provide insights into key molecular players in disease processes and highlight attractive drug targets to accelerate translation
International economic relations and sustainable development
Монографія присвячена дослідженню теоретичних та практичних аспектів сталого розвитку на сучасному етапі міжнародних економічних відносин. Розглядаються інноваційні методичні підходи та економічні механізми забезпечення сталого розвитку на регіональному, національному та міжнародному рівнях. Наведено науково обгрунтовані рекомендації щодо досягнення економічних, соціальних та екологічних цілей сталого розвитку шляхом зміцнення інтеграційних процесів та міжнародного співробітництва між країнами світу.Монография посвящена исследованию теоретических и практических аспектов устойчивого развития на современном этапе международных экономических отношений. Рассмотрены инновационные методические подходы и экономические механизмы для обеспечения устойчивого развития на региональном, национальном и международном уровнях. Даны научно обоснованные рекомендации по достижению экономических, социальных и экологических целей устойчивого развития посредством укрепления интеграционных процессов и международного сотрудничества между странами мира.Monograph is devoted to the research of theoretical and practical aspects of the sustainable development at the present stage of international economic relations. Innovative methodic approaches and economic mechanisms to provide sustainable development at the regional, national and international levels are considered. Scientifically grounded recommendations to achieve economic, social and ecological aims of the sustainable development through the strengthening of integration processes and international cooperation between countries of the world are given
Using multivariable Mendelian randomization to estimate the causal effect of bone mineral density on osteoarthritis risk, independently of body mass index
Objectives: Observational analyses suggest that high bone mineral density (BMD) is a risk factor for osteoarthritis (OA); it is unclear whether this represents a causal effect or shared aetiology and whether these relationships are body mass index (BMI)-independent. We performed bidirectional Mendelian randomization (MR) to uncover the causal pathways between BMD, BMI and OA. Methods: One-sample (1S)MR estimates were generated by two-stage least-squares regression. Unweighted allele scores instrumented each exposure. Two-sample (2S)MR estimates were generated using inverse-variance weighted random-effects meta-analysis. Multivariable MR (MVMR), including BMD and BMI instruments in the same model, determined the BMI-independent causal pathway from BMD to OA. Latent causal variable (LCV) analysis, using weight-adjusted femoral neck (FN)-BMD and hip/knee OA summary statistics, determined whether genetic correlation explained the causal effect of BMD on OA. Results: 1SMR provided strong evidence for a causal effect of BMD estimated from heel ultrasound (eBMD) on hip and knee OA {odds ratio [OR]hip = 1.28 [95% confidence interval (CI) = 1.05, 1.57], p = 0.02, ORknee = 1.40 [95% CI = 1.20, 1.63], p = 3 × 10-5, OR per standard deviation [SD] increase}. 2SMR effect sizes were consistent in direction. Results suggested that the causal pathways between eBMD and OA were bidirectional (βhip = 1.10 [95% CI = 0.36, 1.84], p = 0.003, βknee = 4.16 [95% CI = 2.74, 5.57], p = 8 × 10-9, β = SD increase per doubling in risk). MVMR identified a BMI-independent causal pathway between eBMD and hip/knee OA. LCV suggested that genetic correlation (i.e. shared genetic aetiology) did not fully explain the causal effects of BMD on hip/knee OA. Conclusions: These results provide evidence for a BMI-independent causal effect of eBMD on OA. Despite evidence of bidirectional effects, the effect of BMD on OA did not appear to be fully explained by shared genetic aetiology, suggesting a direct action of bone on joint deterioration
Targeted resequencing of a locus for heparin-induced thrombocytopenia on chromosome 5 identified in a genome-wide association study
Deciphering osteoarthritis genetics across 826,690 individuals from 9 populations
Osteoarthritis affects over 300 million people worldwide. Here, we
conduct a genome-wide association study meta-analysis across 826,690
individuals (177,517 with osteoarthritis) and identify 100 independently
associated risk variants across 11 osteoarthritis phenotypes, 52 of
which have not been associated with the disease before. We report thumb
and spine osteoarthritis risk variants and identify differences in
genetic effects between weight-bearing and non-weight-bearing joints. We
identify sex-specific and early age-at-onset osteoarthritis risk loci.
We integrate functional genomics data from primary patient tissues
(including articular cartilage, subchondral bone, and osteophytic
cartilage) and identify high-confidence effector genes. We provide
evidence for genetic correlation with phenotypes related to pain, the
main disease symptom, and identify likely causal genes linked to
neuronal processes. Our results provide insights into key molecular
players in disease processes and highlight attractive drug targets to
accelerate translation