Abstract Urinary stone disease (USD) is a major health burden affecting >10% of the UK population at some time. While stone disease is strongly associated with lifestyle, genetic factors also predispose to USD: common genetic variants at multiple loci from genome-wide association studies account for 5% of the estimated 45% heritability of the disorder. We investigated the extent to which rare genetic variation contributes to the unexplained heritability of USD. Among participants of the UK 100,000 genome project, we identified 374 unrelated individuals assigned diagnostic codes indicative of USD. We performed whole genome gene-based variant burden testing and polygenic risk scoring against a control population of 24,930 genetic ancestry matched controls. We observed (and replicated in an independent dataset) exome-wide significant enrichment (P=2.61x10-07) of monoallelic rare, predicted damaging variants in SLC34A3 (previously associated with autosomal recessive hereditary hypophosphataemic rickets with hypercalciuria) present in 19 (5%) cases compared with 1.6% of controls. The risk of USD with a monoallelic SLC34A3 variant (OR=3.75, 95% CI 2.27-5.91) was greater than the top decile of polygenic risk (OR=2.31, 95% CI 1.12-3.51). Addition of the SLC34A3 variant binary to a linear model including polygenic score increased the estimated variance explained, increasing the liability adjusted pseudo-R2 from 5.1% to 14.2%. We also observed significant association at OR9K2, an olfactory receptor, but this signal was not replicated. In this cohort rare variants in SLC34A3 were the most important genetic risk factor for USD, with levels of pathogenicity intermediate between the fully penetrant rare variants linked with Mendelian disorders and the weaker effects of common variants associated with USD. These findings explain some of the heritability unexplained by prior common variant GWAS.

The authors have declared no competing interest.

OSA is funded by an MRC Clinical Research Training Fellowship (MR/S021329/1). MYC is funded by a Kidney Research UK Clinical Research Fellowship (TF_004_20161125). DPG is supported by the St Peters Trust for Kidney, Bladder and Prostate Research.

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:

Ethical approval for the 100KGP was granted by the Research Ethics Committee for East of England Cambridge South (REC Ref14/EE/1112).

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

Genomic and phenotype data from participants recruited to the 100KGP can be accessed by application to Genomics England Ltd (https://www.genomicsengland.co.uk/about-gecip/joining-research-community/). Code for the case-control ancestry-matching algorithm can be found at https://github.com/APLevine/PCA_Matching.

https://github.com/APLevine/PCA_Matching