title: Genome-wide association identifies diverse causes of common variable immunodeficiency.
abstract: BACKGROUND
  Common variable immunodeficiency (CVID) is a heterogeneous immune defect characterized by hypogammaglobulinemia, failure of specific antibody production, susceptibility to infections, and an array of comorbidities.
  
  
  OBJECTIVE
  To address the underlying immunopathogenesis of CVID and comorbidities, we conducted the first genome-wide association and gene copy number variation (CNV) study in patients with CVID.
  
  
  METHODS
  Three hundred sixty-three patients with CVID from 4 study sites were genotyped with 610,000 single nucleotide polymorphisms (SNPs). Patients were divided into a discovery cohort of 179 cases in comparison with 1,917 control subjects and a replication cohort of 109 cases and 1,114 control subjects.
  
  
  RESULTS
  Our analyses detected strong association with the MHC region and association with a disintegrin and metalloproteinase (ADAM) genes (P combined = 1.96 × 10(-7)) replicated in the independent cohort. CNV analysis defined 16 disease-associated deletions and duplications, including duplication of origin recognition complex 4L (ORC4L) that was unique to 15 cases (P = 8.66 × 10(-16)), as well as numerous unique rare intraexonic deletions and duplications suggesting multiple novel genetic causes of CVID. Furthermore, the 1,000 most significant SNPs were strongly predictive of the CVID phenotype by using a Support Vector Machine algorithm with positive and negative predictive values of 1.0 and 0.957, respectively.
  
  
  CONCLUSIONS
  Our integrative genome-wide analysis of SNP genotypes and CNVs has uncovered multiple novel susceptibility loci for CVID, both common and rare, which is consistent with the highly heterogeneous nature of CVID. These results provide new mechanistic insights into immunopathogenesis based on these unique genetic variations and might allow for improved diagnosis of CVID based on accurate prediction of the CVID clinical phenotypes by using our Support Vector Machine model.
authors.affiliation: Division of Allergy and Immunology, Children's Hospital of Philadelphia Research Institute, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
authors.forename: Jordan S
authors.initials: JS
authors.lastname: Orange
authors.forename: Joseph T
authors.initials: JT
authors.lastname: Glessner
authors.forename: Elena
authors.initials: E
authors.lastname: Resnick
authors.forename: Kathleen E
authors.initials: KE
authors.lastname: Sullivan
authors.forename: Mary
authors.initials: M
authors.lastname: Lucas
authors.forename: Berne
authors.initials: B
authors.lastname: Ferry
authors.forename: Cecilia E
authors.initials: CE
authors.lastname: Kim
authors.forename: Cuiping
authors.initials: C
authors.lastname: Hou
authors.forename: Fengxiang
authors.initials: F
authors.lastname: Wang
authors.forename: Rosetta
authors.initials: R
authors.lastname: Chiavacci
authors.forename: Subra
authors.initials: S
authors.lastname: Kugathasan
authors.forename: John W
authors.initials: JW
authors.lastname: Sleasman
authors.forename: Robert
authors.initials: R
authors.lastname: Baldassano
authors.forename: Elena E
authors.initials: EE
authors.lastname: Perez
authors.forename: Helen
authors.initials: H
authors.lastname: Chapel
authors.forename: Charlotte
authors.initials: C
authors.lastname: Cunningham-Rundles
authors.forename: Hakon
authors.initials: H
authors.lastname: Hakonarson
mesh_terms: D000465:Algorithms; D001185:Artificial Intelligence; D016022:Case-Control Studies; D015331:Cohort Studies; D017074:Common Variable Immunodeficiency / Q000235:genetics*; D056915:DNA Copy Number Variations; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D020641:Polymorphism, Single Nucleotide