Background: Kidney stone disease (KSD) is linked to obesity, metabolic syndrome and biochemical alterations including higher serum calcium concentration. The mechanisms by which these phenotypes associate with KSD are uncertain. We aimed to establish the effects of adiposity on KSD using conventional and genetic epidemiological techniques. Methods: We assessed observational associations between measures of adiposity and incident KSD in 479,405 people from the UK Biobank. To facilitate Mendelian randomization (MR) analyses, we undertook genome-wide association studies (GWAS) of KSD in the UK Biobank in combined and sex-specific subsets. Univariable, multivariable and mediation MR analyses were used to calculate odds ratio (OR) or beta coefficient (β) for risk of KSD per genetically instrumented higher marker of adiposity, metabolic syndrome parameter, biochemical phenotype, and inflammation and identify violations of MR assumptions. Findings: Observational analyses demonstrated that measures of central adiposity (waist-hip ratio, WHR, and waist circumference, WC) are more strongly associated with incident KSD than measures of general adiposity (body mass index, BMI). Three novel KSD-GWAS loci were identified (SLC2A12, TRPV5, and SLC28A1); no sex-specific loci were detected. MR analyses established that higher central adiposity is causally linked to both KSD and higher adjusted serum calcium concentrations independent of BMI (one standard deviation higher WHR: OR for KSD=1.43, p=4.1x10-6; β for serum calcium concentration=0.12mol/L, p=2.7x10-7). Mediation analyses indicated that 12% of the effect of WHR on KSD is due its role in elevating serum calcium concentration. Our MR studies indicated that other components of the metabolic syndrome, serum uric acid levels, and biomarkers of inflammation are unlikely to be implicated in the causation of KSD. Interpretation: Our study indicates that visceral adipose depots elevate serum calcium concentration and cause an increased risk of KSD. Therapies targeting central adipose deposition may affect calcium homeostasis and have utility for the prevention of KSD.

This research was conducted using the UK Biobank Resource under application number 885. Work was supported by grants from Kidney Research UK (RP_030_20180306) to S.A.H., A.W., M.G., B.W.T., and D.F., National Institute for Health Research (N.I.H.R) Oxford Biomedical Research Centre to R.V.T and D.F., and the Wellcome Trust to S.A.H, and M.G. (204826/z/16/z), and R.V.T. (106995/z/15/z). C.E.L. is a N.I.H.R Academic Clinical Fellow. A.W. is an N.I.H.R Academic Clinical Lecturer. S.A.H. is a Wellcome Trust Clinical Career Development Fellow. J.B., B.L. and N.E.A. acknowledge support from UK Biobank (which is a charitable company largely funded by the Medical Research Council and Wellcome Trust). M.M. and A.M. are employees of Genetech and hold stock in Roche. M.V.H. was supported by a British Heart Foundation Intermediate Clinical Research Fellowship (FS/18/23/33512) when involved in this work. M.V.H. is an employee of 23andMe and holds stock in 23andMe. G.C. acknowledges support from the National Institutes of Health (R01 DK115727 and K24 DK091417) and is an employee of OM1, Inc.

Work was supported by grants from Kidney Research UK (RP_030_20180306) to S.A.H., A.W., M.G., B.W.T., and D.F., National Institute for Health Research (N.I.H.R) Oxford Biomedical Research Centre to R.V.T and D.F., and the Wellcome Trust to S.A.H, and M.G. (204826/z/16/z), and R.V.T. (106995/z/15/z). C.E.L. is a N.I.H.R Academic Clinical Fellow. A.W. is an N.I.H.R Academic Clinical Lecturer. S.A.H. is a Wellcome Trust Clinical Career Development Fellow. J.B., B.L. and N.E.A. acknowledge support from UK Biobank (which is a charitable company largely funded by the Medical Research Council and Wellcome Trust). M.M. and A.M. are employees of Genetech and hold stock in Roche. M.V.H. was supported by a British Heart Foundation Intermediate Clinical Research Fellowship (FS/18/23/33512) when involved in this work. M.V.H. is an employee of 23andMe and holds stock in 23andMe. G.C. acknowledges support from the National Institutes of Health (R01 DK115727 and K24 DK091417) and is an employee of OM1, Inc.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

This research was conducted using the UK Biobank Resource under application number 885.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.

Yes

Individual participant data utilised in the preparation of this manuscript is available via the UK Biobank. Summary statistics for novel GWAS will be available via figshare at the time of publication.