Biology subjects

Harding, S. J.

Publications and source records attributed to Harding, S. J..

2 recordsLinked to original sources

bioRxiv2026

Population-scale immunoglobulin genetics resolves the human B-cell system

Immunoglobulins (Ig) mediate adaptive humoral immunity, yet the regulation of B-cell responses in vivo in humans remains inaccessible to direct experimentation. Here we use population-scale Ig genetics to resolve molecular regulation of the human B-cell system. Analysis of circulating IgA, IgG, IgM, and six composite Ig traits in 114,697 individuals identifies 504 genetic associations. Integration with regulatory genomics, plasma proteomics, and immunophenotyping maps these effects across the B-cell hierarchy, recovering known regulators and revealing previously unrecognized genes in humoral immunity. At key control nodes - including Fc{gamma} receptors, the immunoglobulin heavy-chain locus and the TACI-APRIL signaling axis - variants form allelic series generating graded perturbations of antibody output. Ig-associated loci show extensive overlap with autoimmunity, immunodeficiency and B-cell malignancy. These findings demonstrate that Ig traits, analyzed at population scale, encode fine-grained information about the regulation of the human B-cell system and link natural variation in humoral immunity to immune-mediated disease.

genomics↗

bioRxiv2025

Gut bacterial metabolite imidazole propionate potentiates Alzheimer's disease pathology

The gut microbiome modulates metabolic and neurovascular processes implicated in Alzheimers disease and related dementias (ADRD), but the underlying mechanisms remain unclear. Here, we identify the bacterial metabolite imidazole propionate (ImP) as a modifier of ADRD pathology. In a cohort of 1,196 cognitively unimpaired adults, higher plasma ImP levels were associated with lower preclinical cognitive scores and biomarkers of ADRD, both cross-sectionally and longitudinally. Fecal metagenomic analysis linked putative ImP producers to ADRD phenotypes. Genome-wide integrative analysis revealed a locus on chromosome 12 associated with both plasma ImP levels and AD risk in humans, supporting a host genetic contribution to ImP regulation and a causal role of this metabolite in AD. In mice, chronic ImP administration exacerbated AD-like pathology. Mechanistically, ImP impaired brain endothelial barrier and promoted tau hyperphosphorylation in primary neurons, an effect blocked by glycogen synthase kinase-3{beta} inhibition. Together, our study links ImP to hallmarks of neurodegeneration and suggest that targeting ImP may represent a potential strategy to modify ADRD risk.

pathology↗