Inference of causal and pleiotropic effects with multiple weak genetic instruments: application to effect of adiponectin on type 2 diabetes

Current methods for Mendelian randomization studies have several limitations: to construct unlinked genetic instruments they can use only one SNP from each clump of exposure-associated SNPs, they require that weak instruments are excluded, and they rely on makeshift procedures for downweighting outliers to allow inference of causality in the presence of pleiotropic effects. This paper describes methods that overcome these limitations. A scalar instrument is constructed from all exposure-associated SNPs in each clump, and inference of causality is based on marginalizing over the distribution of pleiotropic effects. To demonstrate the approach, we tested the effect of circulating levels of adiponectin, encoded by ADIPOQ , on the risk of type 2 diabetes. Genotypic instruments were constructed from 24 unlinked trans -pQTLs detected in Icelanders using the Somalogic platform and 43 detected in the UK Biobank study using the Olink platform. These instruments were tested for association with type 2 diabetes in a non-overlapping subset of the UK Biobank cohort. In contrast to the results of earlier Mendelian randomization studies of adiponectin that used only a cis -pQTL, with multiple trans -pQTLs there was clear evidence for a causal effect: standardized log odds ratio -0.38 (95% CI -0.5 to -0.25) using DeCODE instruments and -0.33 (95% CI -0.43 to -0.23) using UK Biobank instruments. Guidelines for the design of Mendelian randomization studies that recommend exclusion of weak instruments, or restricting the instruments to cis -acting variants where the exposure under study is a gene transcript or gene product, should be reassessed. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement No specific funding was received for this work. This research has been conducted using the UK Biobank Resource under application number [23652]. The development of the GENOSCORES platform was supported by a Springboard Award (SBF006/1109) to AS from the Academy of Medical Sciences, supported in turn by the Wellcome Trust, the UK Government Department of Business, Energy and Industrial Strategy, the British Heart Foundation, and Diabetes UK. AI was supported by the Medical Research Council Cross Disciplinary Fellowship (XDF) Programme (MC\_FE\_00035). ### Author Declarations 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 UK Biobank study was granted in 2011 by the North West Multi-centre Research Ethics Committee (11/NW/0382), and renewed every five years since then. Informed consent was obtained for all participants in UK Biobank. The work described herein was approved by the UK Biobank under application number 23652 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 UK Biobank data are available to approved researchers via managed access. A guide to accessing data is available at [https://biobank.ctsu.ox.ac.uk/crystal/exinfo.cgi?src=accessing\_data\_guide][1] . [1]: https://biobank.ctsu.ox.ac.uk/crystal/exinfo.cgi?src=accessing_data_guide