title: Integrated genome-wide association, coexpression network, and expression single nucleotide polymorphism analysis identifies novel pathway in allergic rhinitis.
abstract: BACKGROUND
  Allergic rhinitis is a common disease whose genetic basis is incompletely explained. We report an integrated genomic analysis of allergic rhinitis.
  
  
  METHODS
  We performed genome wide association studies (GWAS) of allergic rhinitis in 5633 ethnically diverse North American subjects. Next, we profiled gene expression in disease-relevant tissue (peripheral blood CD4+ lymphocytes) collected from subjects who had been genotyped. We then integrated the GWAS and gene expression data using expression single nucleotide (eSNP), coexpression network, and pathway approaches to identify the biologic relevance of our GWAS.
  
  
  RESULTS
  GWAS revealed ethnicity-specific findings, with 4 genome-wide significant loci among Latinos and 1 genome-wide significant locus in the GWAS meta-analysis across ethnic groups. To identify biologic context for these results, we constructed a coexpression network to define modules of genes with similar patterns of CD4+ gene expression (coexpression modules) that could serve as constructs of broader gene expression. 6 of the 22 GWAS loci with P-value ≤ 1x10-6 tagged one particular coexpression module (4.0-fold enrichment, P-value 0.0029), and this module also had the greatest enrichment (3.4-fold enrichment, P-value 2.6 × 10-24) for allergic rhinitis-associated eSNPs (genetic variants associated with both gene expression and allergic rhinitis). The integrated GWAS, coexpression network, and eSNP results therefore supported this coexpression module as an allergic rhinitis module. Pathway analysis revealed that the module was enriched for mitochondrial pathways (8.6-fold enrichment, P-value 4.5 × 10-72).
  
  
  CONCLUSIONS
  Our results highlight mitochondrial pathways as a target for further investigation of allergic rhinitis mechanism and treatment. Our integrated approach can be applied to provide biologic context for GWAS of other diseases.
authors.forename: Supinda
authors.initials: S
authors.lastname: Bunyavanich
authors.forename: Eric E
authors.initials: EE
authors.lastname: Schadt
authors.forename: Blanca E
authors.initials: BE
authors.lastname: Himes
authors.forename: Jessica
authors.initials: J
authors.lastname: Lasky-Su
authors.forename: Weiliang
authors.initials: W
authors.lastname: Qiu
authors.forename: Ross
authors.initials: R
authors.lastname: Lazarus
authors.forename: John P
authors.initials: JP
authors.lastname: Ziniti
authors.forename: Ariella
authors.initials: A
authors.lastname: Cohain
authors.forename: Michael
authors.initials: M
authors.lastname: Linderman
authors.forename: Dara G
authors.initials: DG
authors.lastname: Torgerson
authors.forename: Celeste S
authors.initials: CS
authors.lastname: Eng
authors.forename: Maria
authors.initials: M
authors.lastname: Pino-Yanes
authors.forename: Badri
authors.initials: B
authors.lastname: Padhukasahasram
authors.forename: James J
authors.initials: JJ
authors.lastname: Yang
authors.forename: Rasika A
authors.initials: RA
authors.lastname: Mathias
authors.forename: Terri H
authors.initials: TH
authors.lastname: Beaty
authors.forename: Xingnan
authors.initials: X
authors.lastname: Li
authors.forename: Penelope
authors.initials: P
authors.lastname: Graves
authors.forename: Isabelle
authors.initials: I
authors.lastname: Romieu
authors.forename: Blanca del Rio
authors.initials: Bdel R
authors.lastname: Navarro
authors.forename: M Towhid
authors.initials: MT
authors.lastname: Salam
authors.forename: Hita
authors.initials: H
authors.lastname: Vora
authors.forename: Dan L
authors.initials: DL
authors.lastname: Nicolae
authors.forename: Carole
authors.initials: C
authors.lastname: Ober
authors.forename: Fernando D
authors.initials: FD
authors.lastname: Martinez
authors.forename: Eugene R
authors.initials: ER
authors.lastname: Bleecker
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Meyers
authors.forename: W James
authors.initials: WJ
authors.lastname: Gauderman
authors.forename: Frank
authors.initials: F
authors.lastname: Gilliland
authors.forename: Esteban G
authors.initials: EG
authors.lastname: Burchard
authors.forename: Kathleen C
authors.initials: KC
authors.lastname: Barnes
authors.forename: L Keoki
authors.initials: LK
authors.lastname: Williams
authors.forename: Stephanie J
authors.initials: SJ
authors.lastname: London
authors.forename: Bin
authors.initials: B
authors.lastname: Zhang
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Raby
authors.forename: Scott T
authors.initials: ST
authors.lastname: Weiss
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D005260:Female; D053263:Gene Regulatory Networks; D056426:Genetic Loci / Q000235:genetics; D055106:Genome-Wide Association Study; D023281:Genomics / Q000379:methods*; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D065631:Rhinitis, Allergic / Q000235:genetics* / Q000276:immunology; D055815:Young Adult
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