A Guide for Selection of Genetic Instruments in Mendelian randomisation (MR) studies of Type-2 diabetes and HbA1c: towards an integrated approach

This study examines the instrument selection strategies currently employed throughout the type-2 diabetes and HbA1c 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 Mendelian randomisation studies that have instrumented diabetes and/or HbA1c. We also used data from the UK Biobank (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-SNP instrument for diabetes and a 51-SNP instrument (as well as partitioned into glycaemic and erythrocytic) 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 was partitioned 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 and total strength, but these were both substantially smaller 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. MR studies of glycaemia should take a more integrated approach when selecting genetic instruments and we give specific guidance on how to do this.