Background Chronic kidney disease (CKD) represents a leading non-communicable disease, significantly contributing to global morbidity and mortality. Mendelian randomization studies (MR) have been integral in providing robust evidence that increased body mass index (BMI) has a causal impact on CKD. However, dissecting which specific mechanisms are primarily responsible for disease development remains challenging.

Objective To explore whether the effects of BMI to kidney function are driven primarily by brain-or adipose-tissue derived gene expression using tissue-partitioned Mendelian randomization (MR).

Methods We employ two-sample univariable and multivariable MR methodology that segregates genetic variants associated with BMI based on colocalization with gene expression in either brain or subcutaneous adipose tissue. We utilize sets of adipose and brain expression quantitative trait loci (eQTLs) that demonstrated colocalization with BMI (86 and 140 loci respectively). We also use GWAS summary statistics of creatinine and cystatin C based eGFR (eGFRcrea and eGFRcys; N=460,826), blood urea nitrogen (BUN; N = 852,678), eGFR decline (N= 34,874 cases) and CKD (defined as eGFRcrea <60=ml=min−1 per 1.73=m2; N= 41,395) of European ancestry.

Results Univariable MR showed consistent positive associations between BMI and CKD (OR = 1.24, 95% CI: 1.2–1.3) and inverse associations with eGFRcys (beta = –0.05, 95% CI: –0.06 to –0.046). Both brain-and adipose-instrumented BMI showed similar effect sizes. However, in multivariable MR, neither brain-nor adipose-specific BMI variants showed clear independent effects on CKD (ORadipose= 1.24, 95% CIadipose= 0.87 to 1.65, ORbrain= 1.18, 95%CIbrain = 0.9 to 1.54) or other kidney function traits.

Conclusions While genetically predicted BMI was associated with kidney function, our tissue-partitioned MR analysis found no strong evidence that brain or subcutaneous adipose tissue derived gene expression independently drive this relationship. This suggests overlapping or additive mechanisms through which BMI influences kidney function.

TGR is a full-time employee of GSK. All other authors declared no conflict of interest associated with this study.

AB received support from HUNT Center for Molecular and Clinical Epidemiology (MCE), Institute of Public Health and Nursing, Faculty of Medicine and Health Sciences, NTNU for the PhD study.

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:

N/A

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, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

All summary-level data analysed in this study is publicly available.