title: Identification of a New Susceptibility Locus for Systemic Lupus Erythematosus on Chromosome 12 in Individuals of European Ancestry.
abstract: OBJECTIVE
  Genome-wide association studies (GWAS) in individuals of European ancestry identified a number of systemic lupus erythematosus (SLE) susceptibility loci using earlier versions of high-density genotyping platforms. Followup studies on suggestive GWAS regions using larger samples and more markers identified additional SLE loci in subjects of European descent. This multistage study was undertaken to identify novel SLE loci.
  
  
  METHODS
  In stage 1, we conducted a new GWAS of SLE in a North American case-control sample of subjects of European ancestry (n = 1,166) genotyped on Affymetrix Genome-Wide Human SNP Array 6.0. In stage 2, we further investigated top new suggestive GWAS hits by in silico evaluation and meta-analysis using an additional data set of subjects of European descent (>2,500 individuals), followed by replication of top meta-analysis findings in another data set of subjects of European descent (>10,000 individuals) in stage 3.
  
  
  RESULTS
  As expected, our GWAS revealed the most significant associations at the major histocompatibility complex locus (6p21), which easily surpassed the genome-wide significance threshold (P < 5 × 10(-8)). Several other SLE signals/loci previously implicated in Caucasians and/or Asians were also confirmed in the stage 1 discovery sample, and the strongest signals were observed at 2q32/STAT4 (P = 3.6 × 10(-7)) and at 8p23/BLK (P = 8.1 × 10(-6)). Stage 2 meta-analyses identified a new genome-wide significant SLE locus at 12q12 (meta P = 3.1 × 10(-8)), which was replicated in stage 3.
  
  
  CONCLUSIONS
  Our multistage study identified and replicated a new SLE locus that warrants further followup in additional studies. Publicly available databases suggest that this newly identified SLE signal falls within a functionally relevant genomic region and near biologically important genes.
authors: University of Pittsburgh, Pittsburgh, Pennsylvania.
authors: F Yesim
authors: FY
authors: Demirci
authors: University of Pittsburgh, Pittsburgh, Pennsylvania.
authors: Xingbin
authors: X
authors: Wang
authors: Oklahoma Medical Research Foundation, Oklahoma City.
authors: Jennifer A
authors: JA
authors: Kelly
authors: King's College London and Guy's Hospital, London, UK.
authors: David L
authors: DL
authors: Morris
authors: University of Pittsburgh, Pittsburgh, Pennsylvania.
authors: M Michael
authors: MM
authors: Barmada
authors: University of Pittsburgh, Pittsburgh, Pennsylvania.
authors: Eleanor
authors: E
authors: Feingold
authors: Allegheny Health Network, Pittsburgh, Pennsylvania.
authors: Amy H
authors: AH
authors: Kao
authors: Oklahoma Medical Research Foundation, Oklahoma City.
authors: Kathy L
authors: KL
authors: Sivils
authors: McGill University Health Centre, Montreal, Quebec, Canada.
authors: Sasha
authors: S
authors: Bernatsky
authors: McGill University Health Centre, Montreal, Quebec, Canada.
authors: Christian
authors: C
authors: Pineau
authors: University of Calgary, Calgary, Alberta, Canada.
authors: Ann E
authors: AE
authors: Clarke
authors: Northwestern University, Chicago, Illinois.
authors: Rosalind
authors: R
authors: Ramsey-Goldman
authors: King's College London and Guy's Hospital, London, UK.
authors: Timothy J
authors: TJ
authors: Vyse
authors: Oklahoma Medical Research Foundation, Oklahoma City.
authors: Patrick M
authors: PM
authors: Gaffney
authors: Allegheny Health Network, Pittsburgh, Pennsylvania.
authors: Susan
authors: S
authors: Manzi
authors: University of Pittsburgh, Pittsburgh, Pennsylvania.
authors: M Ilyas
authors: MI
authors: Kamboh
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D047390:Casein Kinase II / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics; D002881:Chromosomes, Human, Pair 12 / Q000235:genetics*; D002889:Chromosomes, Human, Pair 2; D002896:Chromosomes, Human, Pair 6; D002898:Chromosomes, Human, Pair 8; D003198:Computer Simulation; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D059848:HLA-DQ alpha-Chains / Q000235:genetics; D059866:HLA-DQ beta-Chains / Q000235:genetics; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000235:genetics*; D008285:Major Histocompatibility Complex / Q000235:genetics; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D050797:STAT4 Transcription Factor / Q000235:genetics; D019063:Tenascin / Q000235:genetics; D059467:Transcriptome; D044465:White People / Q000235:genetics*; D019061:src-Family Kinases / Q000235:genetics
chemical_list: D018797:Cell Cycle Proteins; D059848:HLA-DQ alpha-Chains; D059866:HLA-DQ beta-Chains; C069050:HLA-DQA1 antigen; C069051:HLA-DQB1 antigen; C118481:MSH5 protein, human; D050797:STAT4 Transcription Factor; C494090:STAT4 protein, human; D019063:Tenascin; C081865:tenascin X; C584409:BLK protein, human; D019061:src-Family Kinases; D047390:Casein Kinase II