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This study used Mendelian randomization to investigate whether higher body mass index (BMI) causally increases blood sugar levels in African and European populations. The researchers found that higher BMI increased both HbA1c and random glucose levels in both populations, with broadly similar effect sizes. In UK Biobank data, each 1 standard deviation increase in BMI raised HbA1c by approximately 0.26-0.27 standard deviations in both Africans and Europeans, though confidence intervals for African populations were wider due to smaller sample sizes.
Why it matters
This provides genetic evidence that the relationship between obesity and elevated blood sugar is causal and similar across populations, which has important implications for diabetes prevention strategies globally. However, the findings highlight the urgent need for larger genomic studies in African populations to enable more precise causal inference and ensure that genetic research benefits all populations equitably.
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⚠️ Preprint – Noch nicht peer-reviewed
Dieser Artikel wurde noch nicht von unabhängigen Experten begutachtet. Die Ergebnisse sind vorläufig und sollten mit Vorsicht interpretiert werden.
Aims/hypothesis 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. Methods 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. Results 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. Conclusion/interpretation 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.