Aberrant One-Carbon Metabolism and Ancestral Genetics Underlie Edematous Severe Acute Malnutrition

Severe acute malnutrition (SAM) contributes to the death of millions of children under age five annually. SAM is clinically classified as non-edematous SAM (NESAM) or the more severe edematous SAM (ESAM), which is more common in east-central Africa and the Caribbean. The reason some children develop ESAM while others develop NESAM remains unclear; however, recent studies have identified aberrant one-carbon metabolism (OCM) in ESAM relative to NESAM. Here, we assess genetic variants at 103 loci known to influence OCM, and determine their association with ESAM in 711 samples from Jamaica and Malawi. Seven OCM loci showed evidence of association across both populations, including five associated with homocysteine and folate metabolism (MTHFR, AHCYL1, PRICKLE2, GABBR2, and PLD2). Three SNPs in PLD2, PRICKLE2, and GABBR2, genotyped using cell-free DNA from serum metabolomic samples, supported causal effects on ESAM risk through homocysteine-related metabolites. Cumulatively, OCM-related variants showed more association with ESAM than expected by chance (z = 3.06), with differing effect magnitudes in the two populations. By leveraging chromosomelevel patterns of intracontinental African admixture, we demonstrate that OCM variant associations with ESAM occur on a shared east-African ancestral genetic background. Finally, using whole genome sequence data from eight African populations, we demonstrate that several OCM loci have outlier signatures of selection in multiple populations, including the ESAM-associated PLD2 locus. These findings strengthen support for aberrant OCM in ESAM pathogenesis, with implications for current interventions, and highlight the potential of cell-free DNA, intra-continental admixture, and population genetics in mapping disease risk.