Methylenetetrahydrofolate Reductase (mthfr) Polymorphisms And Neural Tube Defects In African Populations: A Global Meta-Analysis And Population Genetic Characterization In Uganda

Author

• Nana Ekua Entsiwa Adenu-MensahFollow

Date of Award

January 2026

Document Type

Open Access Thesis

Degree Name

Medical Doctor (MD)

Department

Medicine

First Advisor

Steven Schiff

Abstract

Background: Neural tube defects (NTDs) affect 1.9 per 1,000 births globally, with the highest burden occurring in African populations that remain underrepresented in genetic epidemiology. The methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms reduce enzyme activity and have been associated with increased NTD risk in several populations, though their relevance across African regions remains unclear.

Methods: We conducted: (1) an updated systematic review and meta-analysis of MTHFR C677T and A1298C polymorphisms and NTD risk (66 studies, ~22,000 participants); (2) population-level genotype characterization of 978 Ugandan children using whole-genome sequencing; and (3), a comparative analysis of MTHFR C677T allele frequencies across African regions using data from 12 studies (2,794 individuals).

Results: Globally, the MTHFR C677T was associated with increased NTD risk across multiple genetic models (allelic, OR=1.24, 95% CI: 1.15-1.34, p<0.0001), with strongest effects observed in Asian populations associations (allelic, OR=1.39, 95% CI: 1.19-1.63, p<0.0001) and moderate effect in Caucasian populations (allelic, OR=1.18, 95% CI: 1.08-1.29, p<0.0001). The A1298C variant showed no independent association. The Ugandan cohort exhibited low T allele frequency (4.91%), among lowest worldwide. Across Africa, marked regional heterogeneity was observed, with a five-fold difference between East Africa: 5.23% and North Africa: 31.84%, reflecting population history and Eurasian admixture.

Conclusions: Although MTHFR C677T is a well-documented genetic risk factor for NTDs globally, profound population-specific frequency variation alters its public health relevance. In East African populations, like our Ugandan cohort, where the variant is rare, this inter-population variation may reflect evolutionary pressures such as malaria-driven selection, warranting further investigation into how infectious disease exposure shapes genetic architecture of folate metabolism. These findings necessitate region-specific prevention strategies and caution against monolithic interventions.

Comments

This is an Open Access Thesis.

Recommended Citation

Adenu-Mensah, Nana Ekua Entsiwa, "Methylenetetrahydrofolate Reductase (mthfr) Polymorphisms And Neural Tube Defects In African Populations: A Global Meta-Analysis And Population Genetic Characterization In Uganda" (2026). Yale Medicine Thesis Digital Library. 4368.
https://elischolar.library.yale.edu/ymtdl/4368