title: Multiple rare genetic variants co-segregating with familial IgA nephropathy all act within a single immune-related network.
abstract: IgA nephropathy (IgAN) is a common complex disease with a strong genetic involvement. We aimed to identify novel, rare, highly penetrant risk variants combining family-based linkage analysis with whole-exome sequencing (WES).
  
  
  
  Linkage analysis of 16 kindreds of South Italian ancestry was performed using an 'affected-only' strategy. Eight most informative trios composed of two familial cases and an intrafamilial control were selected for WES. High-priority variants in linked regions were identified and validated using Sanger sequencing. Custom TaqMan assays were designed and carried out in the 16 kindreds and an independent cohort of 240 IgAN patients and 113 control subjects.
  
  
  
  We found suggestive linkage signals in 12 loci. After sequential filtering and validation of WES data, we identified 24 private or extremely rare (MAF <0.0003) linked variants segregating with IgAN status. These were present within coding or regulatory regions of 23 genes that merged into a common functional network. The genes were interconnected by AKT, CTNNB1, NFKB, MYC and UBC, key modulators of WNT/β-catenin and PI3K/Akt pathways, which are implicated in IgAN pathogenesis. Overlaying publicly available expression data, genes/proteins with expression notably altered in IgAN were included in this immune-related network. In particular, the network included the glucocorticoid receptor gene, NR3C1, which is the target of corticosteroid therapy routinely used in the treatment of IgAN.
  
  
  
  Our findings suggest that disease susceptibility could be influenced by multiple rare variants acting in a common network that could provide the starting point for the identification of potential drug targets for personalized therapy.
authors.affiliation: Department of Emergency and Organ Transplantation, University of Bari Aldo Moro, Bari, Italy.|C.A.R.S.O. Consortium, University of Bari, Bari, Italy.
authors.forename: S N
authors.initials: SN
authors.lastname: Cox
authors.affiliation: Department of Emergency and Organ Transplantation, University of Bari Aldo Moro, Bari, Italy.|Department of Genomics of Common Disease, Imperial College London, London, UK.
authors.forename: F
authors.initials: F
authors.lastname: Pesce
authors.affiliation: Department of Genomics of Common Disease, Imperial College London, London, UK.|Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.
authors.forename: J S
authors.initials: JS
authors.lastname: El-Sayed Moustafa
authors.affiliation: Department of Emergency and Organ Transplantation, University of Bari Aldo Moro, Bari, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Sallustio
authors.affiliation: Department of Emergency and Organ Transplantation, University of Bari Aldo Moro, Bari, Italy.|IRCCS 'de Bellis', Laboratory of Experimental Immunopathology, Bari, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Serino
authors.affiliation: Department of Genomics of Common Disease, Imperial College London, London, UK.
authors.forename: C
authors.initials: C
authors.lastname: Kkoufou
authors.affiliation: Department of Soil, Plant and Food Sciences, University of Bari Aldo Moro, Bari, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Giampetruzzi
authors.affiliation: ISSIA, CNR, Bari, Italy.
authors.forename: N
authors.initials: N
authors.lastname: Ancona
authors.affiliation: Department of Genomics of Common Disease, Imperial College London, London, UK.|Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.
authors.forename: M
authors.initials: M
authors.lastname: Falchi
authors.affiliation: Department of Emergency and Organ Transplantation, University of Bari Aldo Moro, Bari, Italy.|C.A.R.S.O. Consortium, University of Bari, Bari, Italy.
authors.forename: F P
authors.initials: FP
authors.lastname: Schena
mesh_terms: D059472:Exome; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D056914:Genomic Structural Variation; D005922:Glomerulonephritis, IGA / Q000235:genetics* / Q000276:immunology; D006801:Humans; D010375:Pedigree; D017422:Sequence Analysis, DNA
keywords: family medicine; gene polymorphism; genetics; glomerulonephritis; kidney disease