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A Guide for Selection of Genetic Instruments in Mendelian Randomization Studies of Type 2 Diabetes and HbA1c: Toward an Integrated Approach

Garfield, Victoria; Salzmann, Antoine; Burgess, Stephen; Chaturvedi, Nish; (2023) A Guide for Selection of Genetic Instruments in Mendelian Randomization Studies of Type 2 Diabetes and HbA1c: Toward an Integrated Approach. Diabetes , 72 (2) pp. 175-183. 10.2337/db22-0110. Green open access

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Abstract

In this study we examine the instrument selection strategies currently used throughout the type 2 diabetes and HbA1c Mendelian randomization (MR) literature. We then argue for a more integrated and thorough approach, providing a framework to do this in the context of HbA1c and diabetes. We conducted a literature search for MR studies that have instrumented diabetes and/or HbA1c. We also used data from the UK Biobank (UKB) (N = 349,326) to calculate instrument strength metrics that are key in MR studies (the F statistic for average strength and R2 for total strength) with two different methods ("individual-level data regression" and Cragg-Donald formula). We used a 157-single nucleotide polymorphism (SNP) instrument for diabetes and a 51-SNP instrument (with partition into glycemic and erythrocytic as well) for HbA1c. Our literature search yielded 48 studies for diabetes and 22 for HbA1c. Our UKB empirical examples showed that irrespective of the method used to calculate metrics of strength and whether the instrument was the main one or included partition by function, the HbA1c genetic instrument is strong in terms of both average and total strength. For diabetes, a 157-SNP instrument was shown to have good average strength and total strength, but these were both substantially lesser than those of the HbA1c instrument. We provide a careful set of five recommendations to researchers who wish to genetically instrument type 2 diabetes and/or HbA1c. In MR studies of glycemia, investigators should take a more integrated approach when selecting genetic instruments, and we give specific guidance on how to do this.

Type: Article
Title: A Guide for Selection of Genetic Instruments in Mendelian Randomization Studies of Type 2 Diabetes and HbA1c: Toward an Integrated Approach
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.2337/db22-0110
Publisher version: https://doi.org/10.2337/db22-0110
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: Humans, Diabetes Mellitus, Type 2, Glycated Hemoglobin, Mendelian Randomization Analysis, Polymorphism, Single Nucleotide, Genome-Wide Association Study
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science > Population Science and Experimental Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science > Population Science and Experimental Medicine > MRC Unit for Lifelong Hlth and Ageing
URI: https://discovery.ucl.ac.uk/id/eprint/10165575
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