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.
Authors
- Jared Redmond
- Dhriti Sengupta (ORCID: https://orcid.org/0000-0001-6315-7804)
- Aarti Jajoo (ORCID: https://orcid.org/0000-0002-0089-1697)
- Wisdom Alemya Akurugu (ORCID: https://orcid.org/0000-0001-9994-1422)
- Ananyo Choudhury (ORCID: https://orcid.org/0000-0001-8225-9531)
- Nancy J. Hall (ORCID: https://orcid.org/0000-0003-4828-8106)
- Roa Sadat (ORCID: https://orcid.org/0000-0002-3889-1414)
- Elizabeth G. Atkinson (ORCID: https://orcid.org/0000-0002-6308-776X)
- Shanker Swaminathan (ORCID: https://orcid.org/0000-0003-4625-6370)
- Carolyn Taylor‐Bryan (ORCID: https://orcid.org/0000-0002-5199-9235)
- Sharon Howell
- Marvin Ellsworth Reid (ORCID: https://orcid.org/0000-0003-4005-9384)
- Katharina Schulze (ORCID: https://orcid.org/0000-0001-8268-5565)
- Neil A. Hanchard (ORCID: https://orcid.org/0000-0003-1925-2665)
- Indi Trehan (ORCID: https://orcid.org/0000-0002-3364-6858)
- Mamana Mbiyavanga (ORCID: https://orcid.org/0000-0003-3431-895X)
- Aparna Haldipur
- Yixing Han (ORCID: https://orcid.org/0000-0001-9424-6244)
- Natasha C. Lie (ORCID: https://orcid.org/0000-0002-6207-8140)
- Colin A. McKenzie
- Solome Zewdu
- Manary Mark J.
- Kwesi Marshall
- Emilyn Banfield
- Orgen Brown
- Qing Li
- Thaddaeus May
Institutions
- National Institutes of Health (US)
- Western Cape Department of Health (ZA)
- University of Cape Town (ZA)
- Baylor College of Medicine (US)
- University of the Witwatersrand (ZA)
- University of Washington (US)
- Washington University in St. Louis (US)
- International Centre for Diarrhoeal Disease Research (BD)
- National Human Genome Research Institute (US)
- University of the West Indies (JM)
- Children's Nutrition Research Center at Baylor College of Medicine (US)
- Texas Children's Hospital (US)
- Baylor Genetics (US)
- Kamuzu University of Health Sciences (MW)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-10-15
- DOI
- https://doi.org/10.1038/s41467-026-74239-x
- Primary Topic
- Child Nutrition and Water Access
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- U.S. Department of Agriculture
- Doris Duke Charitable Foundation
- University of Cape Town
- National Institutes of Health
- Agricultural Research Service
- National Human Genome Research Institute
- National Institute of General Medical Sciences