Aberrant one-carbon metabolism and ancestral genetics underlie edematous severe acute malnutrition

Edematous severe childhood malnutrition is distinct from the non-edematous form of malnutrition and remains a major cause of under-five mortality. Its etiology remains unclear, although aberrant one-carbon metabolism has emerged as a potential contributor. Here, we assess genetic variants at loci known to influence one-carbon metabolism, and determine their association with edematous malnutrition in Jamaica and Malawi. Six loci show evidence of association, including four related to homocysteine and folate metabolism - AHCYL1, PRICKLE2, GABBR2, and PLD2, with SNPs at the latter three also having direct effects on homocysteine-related metabolites in Mendelian Randomization. Collectively, one-carbon metabolism-related variants were significantly associated with edematous malnutrition (z = 3.2), with population differences linked to a shared East African genetic ancestry and distinct signatures of selection. These findings strengthen evidence implicating aberrant one-carbon metabolism in edematous malnutrition and highlight the utility of cell-free DNA, intra-continental admixture, and population genetics for mapping disease risk.