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

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

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. © 2021 The Author(s). Published by Oxford University Press on behalf of the International Epidemiological Association

Rare SLC13A1 variants associate with intervertebral disc disorder highlighting role of sulfate in disc pathology

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. © 2022, The Author(s)

Author Correction: Rare SLC13A1 variants associate with intervertebral disc disorder highlighting role of sulfate in disc pathology (Nature Communications, (2022), 13, 1, (634), 10.1038/s41467-022-28167-1)

The original version of this Article contained an error in Fig. 3, in which the blue and red trend lines on the left plot were incorrect. In addition, the text “Dorsalgia variants” in the table should have been italicized and underlined. The correct version of Fig. 3 is: (Figure presented.) which replaces the previous incorrect version: (Figure presented.). This has been corrected in both the PDF and HTML versions of the Article. © The Author(s) 2022

Rare SLC13A1 variants associate with intervertebral disc disorder highlighting role of sulfate in disc pathology

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. © 2022, The Author(s)

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. © 2021 The Author

Variations in management of A3 and A4 cervical spine fractures as designated by the AO Spine Subaxial Injury Classification System

OBJECTIVE Optimal management of A3 and A4 cervical spine fractures, as defined by the AO Spine Subaxial Injury Classification System, remains controversial. The objectives of this study were to determine whether significant management variations exist with respect to 1) fracture location across the upper, middle, and lower subaxial cervical spine and 2) geographic region, experience, or specialty. METHODS A survey was internationally distributed to 272 AO Spine members across six geographic regions (North America, South America, Europe, Africa, Asia, and the Middle East). Participants’ management of A3 and A4 subaxial cervical fractures across cervical regions was assessed in four clinical scenarios. Key characteristics considered in the vignettes included degree of neurological deficit, pain severity, cervical spine stability, presence of comorbidities, and fitness for surgery. Respondents were also directly asked about their preferences for operative management and misalignment acceptance across the subaxial cervical spine. RESULTS In total, 155 (57.0%) participants completed the survey. Pooled analysis demonstrated that surgeons were more likely to offer operative intervention for both A3 (p < 0.001) and A4 (p < 0.001) fractures located at the cervicothoracic junction compared with fractures at the upper or middle subaxial cervical regions. There were no significant variations in management for junctional incomplete (p = 0.116) or complete (p = 0.342) burst fractures between geographic regions. Surgeons with more than 10 years of experience were more likely to operatively manage A3 (p < 0.001) and A4 (p < 0.001) fractures than their younger counterparts. Neurosurgeons were more likely to offer surgical stabilization of A3 (p < 0.001) and A4 (p < 0.001) fractures than their orthopedic colleagues. Clinicians from both specialties agreed regarding their preference for fixation of lower junctional A3 (p = 0.866) and A4 (p = 0.368) fractures. Overall, surgical fixation was recommended more often for A4 than A3 fractures in all four scenarios (p < 0.001). CONCLUSIONS The subaxial cervical spine should not be considered a single unified entity. Both A3 and A4 fracture subtypes were more likely to be surgically managed at the cervicothoracic junction than the upper or middle subaxial cervical regions. The authors also determined that treatment strategies for A3 and A4 subaxial cervical spine fractures varied significantly, with the latter demonstrating a greater likelihood of operative management. These findings should be reflected in future subaxial cervical spine trauma algorithms. © 2022 The authors