Whole Genome Sequencing of 1,030 Ugandan Infants Characterizes the Distribution of the MTHFR Gene C677T Mutation and Associations with Ancestral Admixture Genetics and Neural Tube Defects

Introduction: Neural tube defects (NTDs) are associated with nutritional, environmental, and genetic factors. Studies performed in North America, Europe, and Asia, have described single nucleotide polymorphisms (SNPs) in the Methylenetetrahydrofolate reductase (MTHFR) gene, commonly C677T, which reduce the normal MTHFR enzyme activity, and are associated with NTDs. There is a dearth of research characterizing the MTHFR gene mutation in Africa, a genetically diverse continent, with a high incidence of NTDs.

Methods: Blood samples were collected from a cohort of 400 infants with hydrocephalus and
800 with neonatal sepsis in Uganda. Low depth (4X) whole genome sequencing was conducted. Genomic data was processed, and ancestry of the patients was characterized using principal component and admixture analysis. SNPs on the MTHFR gene were extracted using computational methods. Statistical analysis for measuring association of SNPs with the ancestral population and NTDs was done using in-house scripts.

Results: Admixture analysis identified four admixture populations within this cohort. These patterns were associated with different regions of the country, consistent with known ancient migrations across Uganda, especially between Admixture group 3 (predominantly north) and group 4 (predominantly southwest). When the proportions of these admixture groups are spatially correlated with the risk per population maps of NTDs, using a General Additive Model framework, a positive association between Admixture group 3 and NTDs is revealed (p = 6.89e-5, ES=0.22). The frequency of the homozygous recessive genotype of the MTHFR C677T variant was 0.68%, and heterozygous genotype was 7.96%. There was no significant association with admixture data (p=0.117).

Conclusion : Our model predicts a positive association between Admixture group 3 and NTDs. Genotype frequencies of MTHFR C677T in our dataset are consistent with sparse data collected in other Central African populations, higher than Southern African groups and lower than Northern African samples, and also lower than in many East Asian and South American populations.