{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T05:02:01Z","timestamp":1784523721822,"version":"3.55.0"},"reference-count":37,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T00:00:00Z","timestamp":1784505600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Mitochondrial dysfunction is linked to urolithiasis, but causal genetic drivers remain unclear. We integrated multi-omics data using Mendelian randomization to identify mitochondrial-related genes causally associated with urolithiasis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We obtained mitochondrial methylation (mQTL), gene expression (eQTL), and protein abundance (pQTL) from respective quantitative trait locus (QTL) studies along with GWAS summary data for nephrolithiasis, ureterolithiasis and bladder calculus from the Million Veteran Program (discovery), with replication in FinnGen and UK Biobank. Summary-data-based Mendelian randomization (SMR) and colocalization were applied to infer causality.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Integrated analysis identified\n                      <jats:italic>FXN<\/jats:italic>\n                      as the leading candidate for nephrolithiasis. Genetically elevated circulating FXN protein was inversely associated with nephrolithiasis risk (OR 0.69, 95% CI 0.56\u20130.84). This protective effect was supported at the epigenetic level:\n                      <jats:italic>FXN<\/jats:italic>\n                      methylation at cg14656297 and cg13974534 correlated with lower nephrolithiasis risk. For ureterolithiasis, higher GRHPR protein levels were protective (OR 0.81, 95% CI 0.71\u20130.91). In a mouse kidney stone model,\n                      <jats:italic>Fxn<\/jats:italic>\n                      expression and frataxin protein levels were decreased, providing correlative\n                      <jats:italic>in vivo<\/jats:italic>\n                      support consistent with human genetic findings.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This multi-omics MR study links mitochondrial genes, particularly FXN, to urolithiasis risk. Although colocalization evidence was weak (PP.H4\u00a0=\u00a00.0239) and replication in independent cohorts was not statistically significant, the multi\u2212omics consistency across methylation, expression, and protein levels prioritizes FXN as a hypothesis\u2212generating candidate for further investigation. Because all QTL data are blood\u2212 or plasma\u2212derived, this study provides blood\/plasma QTL\u2212based genetic prioritization rather than kidney\u2212specific causal inference.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1876576","type":"journal-article","created":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T04:20:39Z","timestamp":1784521239000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Multi-omics Mendelian randomization integrating GWAS, eQTL, mQTL and pQTL data prioritizes mitochondrial gene FXN as a hypothesis\u2212generating candidate for nephrolithiasis"],"prefix":"10.3389","volume":"17","author":[{"given":"Yanting","family":"Wu","sequence":"first","affiliation":[{"name":"Department of Urology, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University","place":["Guangzhou, China"]},{"name":"Greater Bay Area Institute of Precision Medicine (Guangzhou), School of Life Sciences, Fudan University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shikai","family":"Ye","sequence":"additional","affiliation":[{"name":"Greater Bay Area Institute of Precision Medicine (Guangzhou), School of Life Sciences, Fudan University","place":["Guangzhou, China"]},{"name":"School of Biological Sciences and Engineering, South China University of Technology","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ping","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Urology, The Sixth Affiliated Hospital of Jinan University","place":["Dongguan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zichi","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Urology, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiyuan","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Urology, The Ninth People\u2019s Hospital of Nanhai District","place":["Foshan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Bian","sequence":"additional","affiliation":[{"name":"Department of Urology, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming","family":"Sheng","sequence":"additional","affiliation":[{"name":"Department of Urology, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dehui","family":"Lai","sequence":"additional","affiliation":[{"name":"Department of Urology, The Fifth Affiliated Hospital of 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