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

Feb 19, 2024

Experts: Catalin D Voinescu, Monika Mozere, Giulio Genovese, Mallory L Downie, Sanjana Gupta, Daniel P Gale, Detlef Bockenhauer, Robert Kleta, Mauricio Arcos-Burgos, Horia C Stanescu

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.
Copyright © 2024 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

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ABOUT THE EXPERTS

Catalin D Voinescu, Monika Mozere, Giulio Genovese, Mallory L Downie, Sanjana Gupta, Daniel P Gale, Detlef Bockenhauer, Robert Kleta, Mauricio Arcos-Burgos, Horia C Stanescu

Catalin D Voinescu

Centre for Genetics and Genomics, Department of Renal Medicine, UCL Division of Medicine, University College London, London, UK.

Monika Mozere

Department of Human and Medical Genetics, Faculty of Medicine, Vilnius University, Vilnius, Lithuania.

Giulio Genovese

Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA; Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.

Mallory L Downie

Centre for Genetics and Genomics, Department of Renal Medicine, UCL Division of Medicine, University College London, London, UK.

Sanjana Gupta

Centre for Genetics and Genomics, Department of Renal Medicine, UCL Division of Medicine, University College London, London, UK.

Daniel P Gale

Centre for Genetics and Genomics, Department of Renal Medicine, UCL Division of Medicine, University College London, London, UK.

Detlef Bockenhauer

Centre for Genetics and Genomics, Department of Renal Medicine, UCL Division of Medicine, University College London, London, UK.

Robert Kleta

Centre for Genetics and Genomics, Department of Renal Medicine, UCL Division of Medicine, University College London, London, UK.

Mauricio Arcos-Burgos

Grupo de Investigación en Psiquiatría, Departamento de Psiquiatría, Instituto de Investigaciones Médicas, Facultad de Medicina, Universidad de Antioquia, Medellín, Colombia.

Horia C Stanescu

Centre for Genetics and Genomics, Department of Renal Medicine, UCL Division of Medicine, University College London, London, UK. Electronic address: h.stanescu@ucl.ac.uk.