Konzo, a disease characterized by sudden, irreversible spastic paraparesis, affecting up to 10% of the population in some regions of Sub-Saharan Africa during outbreaks, is strongly associated with dietary exposure to cyanogenic bitter cassava. The molecular mechanisms underlying the development of konzo remain largely unknown. Here, through an analysis of 16 individuals with konzo and matched healthy controls from the same outbreak zones, we identified 117 differentially methylated loci involved in numerous biological processes that may identify cyanogenic-sensitive regions of the genome, providing the first study of epigenomic alterations associated with a clinical phenotype of konzo.

Individuals with African ancestry have extensive genomic diversity but have been underrepresented in genomic research. There is also extensive global diversity in the exposome (the totality of human environmental exposures from conception onwards) which should be considered for integrative genomic and environmental health research in Africa. To address current research gaps, we organized a workshop on environmental health research in Africa in conjunction with the H3Africa Consortium and the African Society of Human Genetics meetings in Kigali, Rwanda. The workshop was open to all researchers with an interest in environmental health in Africa and involved presentations from experts within and outside of the Consortium. This workshop highlighted innovative research occurring on the African continent related to environmental health and the interplay between the environment and the human genome. Stories of success, challenges, and collaborative opportunities were discussed through presentations, breakout sessions, poster presentations, and a panel discussion. The workshop informed participants about environmental risk factors that can be incorporated into current or future epidemiology studies and addressed research design considerations, biospecimen collection and storage, biomarkers for measuring chemical exposures, laboratory strategies, and statistical methodologies. Inclusion of environmental exposure measurements with genomic data, including but not limited to H3Africa projects, can offer a strong platform for building gene-environment (G x E) research in Africa. Opportunities to leverage existing resources and add environmental exposure data for ongoing and planned studies were discussed. Future directions include expanding the measurement of both genomic and exposomic risk factors and incorporating sophisticated statistical approaches for analyzing high dimensional G x E data. A better understanding of how environmental and genomic factors interact with nutrition and infection is also needed. Considering that the environment represents many modifiable risk factors, these research findings can inform intervention and prevention efforts towards improving global health.

Konzo, a distinct upper motor neuron disease associated with a cyanogenic diet and chronic malnutrition, predominately affects children and women of childbearing age in sub-Saharan Africa. While the exact biological mechanisms that cause this disease have largely remained elusive, host-genetics and environmental components such as the gut microbiome have been implicated. Using a large study population of 180 individuals from the Democratic Republic of the Congo, where konzo is most frequent, we investigate how the structure of the gut microbiome varied across geographical contexts, as well as provide the first insight into the gut flora of children affected with this debilitating disease using shotgun metagenomic sequencing. Our findings indicate that the gut microbiome structure is highly variable depending on region of sampling, but most interestingly, we identify unique enrichments of bacterial species and functional pathways that potentially modulate the susceptibility of konzo in prone regions of the Congo.

Konzo is a neglected paralytic neurological disease associated with food (cassava) poisoning that affects the worlds poorest children and women of childbearing ages across regions of sub-Saharan Africa. Despite understanding the dietary factors that lead to konzo, the molecular markers and mechanisms that trigger this disease remain unknown. To identify potential protein biomarkers associated with a disease status, plasma was collected from two independent Congolese cohorts, a discovery cohort (n = 60) and validation cohort (n = 204), sampled 10 years apart and subjected to multiple high-throughput assays. We identified that Glutathione Peroxidase 3 (GPx3), a critical plasma-based antioxidant enzyme, was the sole protein examined that was both significantly and differentially abundant between affected and non-affected participants in both cohorts, with large reductions observed in those affected with konzo. Our findings raise the notion that reductions in key antioxidant mechanisms may be the biological risk factor for the development of konzo, particularly those mediated through pathways involving the glutathione peroxidase family.