Mendelian randomization (MR) studies carried out among patients with a particular health condition should establish the genetic instrument influences the exposure in that subgroup, however this is normally investigated in the general population. Here, we investigated whether the genetic associations of four cis-acting C-reactive protein (CRP) variants differed between participants with and without three cardiometabolic conditions: obesity, type 2 diabetes, and cardiovascular disease. Associations of cis-genetic variants with CRP differed between obese and non-obese individuals. A multivariable analysis suggested strong independent associations of the gene-by-body mass index (BMI) interaction on CRP (P<1.18×10−8 for the CRP variants). Applying MR, we observed strong causal effect of BMI on CRP (P=2.14×10−65). In summary, our study indicates that genetic associations with CRP differ across disease sub-groups, with evidence to suggest that BMI is an effect modifier. MR studies of disease progression should report on the genetic instrument-exposure association in the disease subgroup under investigation.

Anabolic treatment options for osteoporosis remain limited. One approach to discovering novel anabolic drug targets is to identify genetic causes of extreme high bone mass (HBM). We investigated a pedigree with unexplained HBM within the UK HBM study, a national cohort of probands with HBM and their relatives. Whole exome sequencing (WES) in a family with HBM identified a rare heterozygous missense variant (NM_004482.4:c.1657C > T, p.Arg553Trp) in GALNT3, segregating appropriately. Interrogation of data from the UK HBM study and the Anglo-Australasian Osteoporosis Genetics Consortium (AOGC) revealed an unrelated individual with HBM with another rare heterozygous variant (NM_004482.4:c.831 T > A, p.Asp277Glu) within the same gene. In silico protein modeling predicted that p.Arg553Trp would disrupt salt-bridge interactions, causing instability of GALNT3, and that p.Asp277Glu would disrupt manganese binding and consequently GALNT3 catalytic function. Bi-allelic loss-of-function GALNT3 mutations alter FGF23 metabolism, resulting in hyperphosphatemia and causing familial tumoral calcinosis (FTC). However, bone mineral density (BMD) in FTC cases, when reported, has been either normal or low. Common variants in the GALNT3 locus show genome-wide significant associations with lumbar, femoral neck, and total body BMD. However, no significant associations with BMD are observed at lociThis is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Background: Spinal stenosis is a common condition among older individuals, with significant morbidity attached. Little is known about its risk factors but degenerative conditions, such as osteoarthritis (OA) have been identified for their mechanistic role. This study aims to explore causal relationships between anthropometric risk factors, osteoarthritis, and spinal stenosis using Mendelian randomization (MR) techniques. Methods: We applied two-sample univariable and multivariable MR to investigate the causal relationships between genetic liability for select risk factors (including adiposity and skeletal traits) and spinal stenosis. Next, we examined the genetic relationship between osteoarthritis and spinal stenosis with LD score regression and CAUSE MR method. Using multivariable MR, osteoarthritis and BMI were then tested as potential mediators of the causal pathways identified. Results: Our analysis revealed strong evidence for the effect of higher BMI (OR=1.54, 95% CI: 1.41-1.69, p-value=2.7 x 10-21), waist (OR=1.43, 95% CI: 1.15-1.79, p-value=1.5 x 10-3) and hip (OR=1.50, 95% CI: 1.27-1.78, p-value=3.3 x 10-6) circumference on spinal stenosis. Strong associations were observed for higher bone mineral density (BMD): total body (OR=1.21, 95% CI: 1.12-1.29, p-value=1.6 x 10-7), femoral neck (OR=1.35, 95% CI: 1.09-1.37, p-value=7.5 x 10-7), and lumbar spine (OR=1.38, 95% CI: 1.25-1.52, p-value=4.4 x 10-11). We detected high genetic correlations between spinal stenosis and osteoarthritis (rg range: 0.47-0.66), with Bayesian CAUSE results supporting a causal effect of osteoarthritis on spinal stenosis (ORall OA=1.6, 95% CI:1.41-1.79). Direct effects of BMI, total body/femoral neck/lumbar spine BMD on spinal stenosis remained after adjusting for osteoarthritis and/or BMI in the multivariable MR. Conclusions: Genetic susceptibility to anthropometric risk factors, particularly higher BMI and bone mineral density can increase the risk of spinal stenosis, independent of osteoarthritis status. These results improve our understanding of spinal stenosis aetiology and may inform preventative strategies and treatments.