title: Trans-ancestral studies fine map the SLE-susceptibility locus TNFSF4.
abstract: We previously established an 80 kb haplotype upstream of TNFSF4 as a susceptibility locus in the autoimmune disease SLE. SLE-associated alleles at this locus are associated with inflammatory disorders, including atherosclerosis and ischaemic stroke. In Europeans, the TNFSF4 causal variants have remained elusive due to strong linkage disequilibrium exhibited by alleles spanning the region. Using a trans-ancestral approach to fine-map the locus, utilising 17,900 SLE and control subjects including Amerindian/Hispanics (1348 cases, 717 controls), African-Americans (AA) (1529, 2048) and better powered cohorts of Europeans and East Asians, we find strong association of risk alleles in all ethnicities; the AA association replicates in African-American Gullah (152,122). The best evidence of association comes from two adjacent markers: rs2205960-T (P=1.71 × 10(-34) , OR=1.43[1.26-1.60]) and rs1234317-T (P=1.16 × 10(-28) , OR=1.38[1.24-1.54]). Inference of fine-scale recombination rates for all populations tested finds the 80 kb risk and non-risk haplotypes in all except African-Americans. In this population the decay of recombination equates to an 11 kb risk haplotype, anchored in the 5' region proximal to TNFSF4 and tagged by rs2205960-T after 1000 Genomes phase 1 (v3) imputation. Conditional regression analyses delineate the 5' risk signal to rs2205960-T and the independent non-risk signal to rs1234314-C. Our case-only and SLE-control cohorts demonstrate robust association of rs2205960-T with autoantibody production. The rs2205960-T is predicted to form part of a decameric motif which binds NF-κBp65 with increased affinity compared to rs2205960-G. ChIP-seq data also indicate NF-κB interaction with the DNA sequence at this position in LCL cells. Our research suggests association of rs2205960-T with SLE across multiple groups and an independent non-risk signal at rs1234314-C. rs2205960-T is associated with autoantibody production and lymphopenia. Our data confirm a global signal at TNFSF4 and a role for the expressed product at multiple stages of lymphocyte dysregulation during SLE pathogenesis. We confirm the validity of trans-ancestral mapping in a complex trait.
authors.affiliation: Department of Medical & Molecular Genetics, King's College London School of Medicine, Guy's Hospital, London, United Kingdom.
authors.forename: Harinder
authors.initials: H
authors.lastname: Manku
authors.forename: Carl D
authors.initials: CD
authors.lastname: Langefeld
authors.forename: Sandra G
authors.initials: SG
authors.lastname: Guerra
authors.forename: Talat H
authors.initials: TH
authors.lastname: Malik
authors.forename: Marta
authors.initials: M
authors.lastname: Alarcon-Riquelme
authors.forename: Juan-Manuel
authors.initials: JM
authors.lastname: Anaya
authors.forename: Sang-Cheol
authors.initials: SC
authors.lastname: Bae
authors.forename: Susan A
authors.initials: SA
authors.lastname: Boackle
authors.forename: Elizabeth E
authors.initials: EE
authors.lastname: Brown
authors.forename: Lindsey A
authors.initials: LA
authors.lastname: Criswell
authors.forename: Barry I
authors.initials: BI
authors.lastname: Freedman
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Gaffney
authors.forename: Peter A
authors.initials: PA
authors.lastname: Gregersen
authors.forename: Joel M
authors.initials: JM
authors.lastname: Guthridge
authors.forename: Sang-Hoon
authors.initials: SH
authors.lastname: Han
authors.forename: John B
authors.initials: JB
authors.lastname: Harley
authors.forename: Chaim O
authors.initials: CO
authors.lastname: Jacob
authors.forename: Judith A
authors.initials: JA
authors.lastname: James
authors.forename: Diane L
authors.initials: DL
authors.lastname: Kamen
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Kaufman
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Kelly
authors.forename: Javier
authors.initials: J
authors.lastname: Martin
authors.forename: Joan T
authors.initials: JT
authors.lastname: Merrill
authors.forename: Kathy L
authors.initials: KL
authors.lastname: Moser
authors.forename: Timothy B
authors.initials: TB
authors.lastname: Niewold
authors.forename: So-Yeon
authors.initials: SY
authors.lastname: Park
authors.forename: Bernardo A
authors.initials: BA
authors.lastname: Pons-Estel
authors.forename: Amr H
authors.initials: AH
authors.lastname: Sawalha
authors.forename: R Hal
authors.initials: RH
authors.lastname: Scofield
authors.forename: Nan
authors.initials: N
authors.lastname: Shen
authors.forename: Anne M
authors.initials: AM
authors.lastname: Stevens
authors.forename: Celi
authors.initials: C
authors.lastname: Sun
authors.forename: Gary S
authors.initials: GS
authors.lastname: Gilkeson
authors.forename: Jeff C
authors.initials: JC
authors.lastname: Edberg
authors.forename: Robert P
authors.initials: RP
authors.lastname: Kimberly
authors.forename: Swapan K
authors.initials: SK
authors.lastname: Nath
authors.forename: Betty P
authors.initials: BP
authors.lastname: Tsao
authors.forename: Tim J
authors.initials: TJ
authors.lastname: Vyse
mesh_terms: D001741:Black or African American / Q000235:genetics; D000483:Alleles; D044466:Asian People / Q000235:genetics; D002874:Chromosome Mapping; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006239:Haplotypes; D006630:Hispanic or Latino / Q000235:genetics; D006801:Humans; D015810:Linkage Disequilibrium; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000473:pathology; D008214:Lymphocytes / Q000473:pathology; D008297:Male; D016328:NF-kappa B / Q000235:genetics; D053278:OX40 Ligand / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D044465:White People / Q000235:genetics
chemical_list: D016328:NF-kappa B; D053278:OX40 Ligand; C089251:TNFSF4 protein, human