A Neanderthal haplotype introgressed into the human genome confers protection against membranous nephropathy

ABSTRACT: Class 2 HLA and PLA2R1 alleles are exceptionally strong genetic risk factors for membranous nephropathy (MN), leading, through an unknown mechanism, to a targeted autoimmune response. Introgressed archaic haplotypes (introduced from an archaic human genome into the modern human genome) might influence phenotypes through gene dysregulation. Here, we investigated the genomic region surrounding the PLA2R1 gene. We reconstructed the phylogeny of Neanderthal and modern haplotypes in this region and calculated the probability of the observed clustering being the result of introgression or common descent. We imputed variants for the participants in our previous genome-wide association study and we compared the distribution of Neanderthal variants between MN cases and controls. The region associated with the lead MN risk locus in the PLA2R1 gene was confirmed and showed that, within a 507 kb region enriched in introgressed sequence, a stringently defined 105 kb haplotype, intersecting the coding regions for PLA2R1 and ITGB6, is inherited from Neanderthals. Thus, introgressed Neanderthal haplotypes overlapping PLA2R1 are differentially represented in MN cases and controls, with enrichment In controls suggesting a protective effect.

• Autores: Arcos Burgos, Oscar Mauricio; Voinescu, Cătălin D.; Mozere, Monika; Genovese, Giulio; Downie, Mallory L; Gupta, Sanjana; Gale, Daniel P; Bockenhauer, Detlef; Kleta, Robert; Stanescu, Horia C
• Tipo de recurso: Article of investigation
• Fecha de publicación: 2024
• Institución: Universidad de Antioquia
• Repositorio: Repositorio UdeA
• Idioma: eng
• OAI Identifier: oai:bibliotecadigital.udea.edu.co:10495/42271
• Acceso en línea: https://hdl.handle.net/10495/42271
• Palabra clave: Genoma Humano; Genome, Human; Estudio de Asociación del Genoma Completo; Genome-Wide Association Study; Insuficiencia Renal Crónica; Renal Insufficiency, Chronic; Glomerulonefritis Membranosa; Glomerulonephritis, Membranous; Síndrome Nefrótico; Nephrotic Syndrome; Haplotipos; Haplotypes; Hombre de Neandertal - genética; Neanderthals - genetics; Receptores de Fosfolipasa A2; Receptors, Phospholipase A2; https://id.nlm.nih.gov/mesh/D015894; https://id.nlm.nih.gov/mesh/D055106; https://id.nlm.nih.gov/mesh/D051436; https://id.nlm.nih.gov/mesh/D015433; https://id.nlm.nih.gov/mesh/D009404; https://id.nlm.nih.gov/mesh/D006239; https://id.nlm.nih.gov/mesh/D059125; https://id.nlm.nih.gov/mesh/D054507
• Rights: openAccess
• License: https://creativecommons.org/licenses/by/4.0/