Causal effects of body mass index on glycaemic traits in African and European populations: a Mendelian randomization...

Higher body mass index (BMI) is associated with higher levels of HbA1c and glucose in conventional observational studies from sub-Saharan Africa, but its causal relationship in this population has not been explored. Mendelian randomization (MR) which leverages genetic variants can strengthen causal inference. However, its application in African ancestry populations is limited. The aim of this study was to determine whether causal effects of BMI on glycated haemoglobin (HbA1c) and random glucose differ between African and European populations.

We used two-sample MR to estimate the effects of BMI on HbA1c and random glucose in adults of African and European ancestries. We conducted a cross-ancestry BMI genome-wide association study (GWAS) from the Africa-Wits International Network for the Demographic Evaluation of Populations and Their Health (INDEPTH) Partnership for Genomic Studies (AWI-Gen) dataset of African adults (N=10,476) and the largest BMI GWAS in Europeans (N∼700,000). From the cross-ancestry GWAS we identified 428 independent genome-wide significant variants and of those, 363 single nucleotide polymorphisms (SNPs) had consistent direction of effect in both Africans and Europeans. These variants were then used as genetic instruments to proxy BMI for both Africans and Europeans. Primary outcome data for African and European populations were obtained from UK Biobank summary statistics for HbA1c (5,790 Africans and 400,825 Europeans) and random glucose (5,750 Africans and 314,916 Europeans), with additional results for HbA1c from the MAGIC multi-ancestry GWAS comprised of Ugandan individuals (N=4,441), African Americans (N= 6,647), and Europeans (N=146,806). Main analyses used the inverse variance weighted (IVW) method, with sensitivity analyses conducted using MR-Egger, weighed median and weighted mode approaches.

The main IVW analyses in UK Biobank provided support for higher BMI causally increasing HbA1c levels in both Africans (0.26 SD higher HbA1c per 1 SD BMI, 95% CI 0.07, 0.45) and Europeans (0.27 SD higher HbA1c per 1 SD BMI, 95% CI 0.22, 0.32). UK Biobank main analyses also supported higher BMI increasing random glucose in Africans (0.21 SD higher mean glucose per 1 SD BMI, 95%CI 0.03, 0.37) and Europeans (0.15 SD higher mean glucose per 1 SD BMI, 95%CI 0.12, 0.18). Sensitivity analyses suggested these results were not biased by unbalanced horizontal pleiotropy. Results from MAGIC also showed that higher BMI causally increased HbA1c in Europeans (0.04% higher HbA1c per 1 SD BMI, 95% CI 0.02, 0.05), though results for African Americans (0.01% higher HbA1c per 1 SD BMI, 95% CI -0.05, 0.07) and Ugandans (0.02% lower HbA1c per 1 SD BMI, 95% CI -0.10, 0.05) spanned the null.

We have found broadly similar effects of BMI on HbA1c and random blood glucose in African and European populations. However, much larger GWAS of glycaemic traits in African and other non-European populations are needed to strengthen causal inference and support equitable translation of these findings. The method that we have used to obtain identical strong genetic instrumental variables (IVs) for both European and African populations may have value for other MR studies interested in exploring differences in effects between different population groups.

What is already known about this subject?: Conventional observational studies in sub-Saharan Africa show a positive association between higher body mass index (BMI) and higher glycated haemoglobin (HbA1c) and glucose levels.These associations may be influenced by confounding and reverse causation.Mendelian randomization (MR) evidence in European populations show that higher BMI is causally associated with increased HbA1c and glucose, but the application of MR in African ancestry populations is limited.What is the key question?: Does higher BMI causally influence the levels of HbA1c and random glucose similarly in African and European populations?What are the new findings?: Higher BMI increased HbA1c and random glucose in both African and European adults, with similar estimates in both populations.We demonstrated how MR can be used to investigate population-specific differences in the health effects of the same exposures between African and European populations.How might this impact on clinical practice in the foreseeable future?: Improved causal understanding may strengthen prevention strategies targeting adiposity to reduce the risk of type 2 diabetes in sub-Saharan African populations.