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

In this study we examine the instrument selection strategies currently used throughout the type 2 diabetes and HbA(1c) Mendelian randomization (MR) literature. We then argue for a more integrated and thorough approach, providing a framework to do this in the context of HbA(1c) and diabetes. We conducted a literature search for MR studies that have instrumented diabetes and/or HbA(1c). 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 R-2 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 HbA(1c). Our literature search yielded 48 studies for diabetes and 22 for HbA(1c). 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 HbA(1c) 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 HbA(1c) instrument. We provide a careful set of five recommendations to researchers who wish to genetically instrument type 2 diabetes and/or HbA(1c). 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.