Aberrant one-carbon metabolism and ancestral genetics underlie edematous severe acute malnutrition
Abstract
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.
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Authors: Natasha C. Lie, Yixing Han, Qing Li, Aarti Jajoo, Jared Redmond, Aparna Haldipur, Solome Zewdu, Emilyn Banfield, Shanker Swaminathan, Sharon Howell, Orgen Brown, Roa Sadat, Nancy J. Hall, Kwesi Marshall, Katharina Schulze, Thaddaeus May, Marvin Ellsworth Reid, Carolyn Taylor‐Bryan, Manary Mark J., Indi Trehan, Mamana Mbiyavanga, Wisdom Alemya Akurugu, Colin A. McKenzie, Dhriti Sengupta, Elizabeth G. Atkinson, Ananyo Choudhury, Neil A. Hanchard
Institutions: University of Washington, University of the Witwatersrand, Washington University in St. Louis, University of Cape Town, Baylor College of Medicine, National Institutes of Health, Children's Nutrition Research Center at Baylor College of Medicine, Western Cape Department of Health, Texas Children's Hospital, International Centre for Diarrhoeal Disease Research, National Human Genome Research Institute, Kamuzu University of Health Sciences, Baylor Genetics, University of the West Indies