title: Genetics of gene expression in primary immune cells identifies cell type-specific master regulators and roles of HLA alleles.
abstract: Trans-acting genetic variants have a substantial, albeit poorly characterized, role in the heritable determination of gene expression. Using paired purified primary monocytes and B cells, we identify new predominantly cell type-specific cis and trans expression quantitative trait loci (eQTLs), including multi-locus trans associations to LYZ and KLF4 in monocytes and B cells, respectively. Additionally, we observe a B cell-specific trans association of rs11171739 at 12q13.2, a known autoimmune disease locus, with IP6K2 (P = 5.8 × 10(-15)), PRIC285 (P = 3.0 × 10(-10)) and an upstream region of CDKN1A (P = 2 × 10(-52)), suggesting roles for cell cycle regulation and peroxisome proliferator-activated receptor γ (PPARγ) signaling in autoimmune pathogenesis. We also find that specific human leukocyte antigen (HLA) alleles form trans associations with the expression of AOAH and ARHGAP24 in monocytes but not in B cells. In summary, we show that mapping gene expression in defined primary cell populations identifies new cell type-specific trans-regulated networks and provides insights into the genetic basis of disease susceptibility.
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK. bfairfax@well.ox.ac.uk
authors.forename: Benjamin P
authors.initials: BP
authors.lastname: Fairfax
authors.forename: Seiko
authors.initials: S
authors.lastname: Makino
authors.forename: Jayachandran
authors.initials: J
authors.lastname: Radhakrishnan
authors.forename: Katharine
authors.initials: K
authors.lastname: Plant
authors.forename: Stephen
authors.initials: S
authors.lastname: Leslie
authors.forename: Alexander
authors.initials: A
authors.lastname: Dilthey
authors.forename: Peter
authors.initials: P
authors.lastname: Ellis
authors.forename: Cordelia
authors.initials: C
authors.lastname: Langford
authors.forename: Fredrik O
authors.initials: FO
authors.lastname: Vannberg
authors.forename: Julian C
authors.initials: JC
authors.lastname: Knight
mesh_terms: D000483:Alleles; D001327:Autoimmune Diseases / Q000209:etiology; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D005819:Genetic Markers / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006680:HLA Antigens / Q000235:genetics*; D006801:Humans; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000235:genetics; D009000:Monocytes / Q000276:immunology / Q000378:metabolism*; D047495:PPAR gamma / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D040641:Quantitative Trait Loci / Q000235:genetics*
chemical_list: D005819:Genetic Markers; D006680:HLA Antigens; C000715467:KLF4 protein, human; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D047495:PPAR gamma