Transancestral mapping and genetic load in systemic lupus erythematosus.
Carl D LangefeldHannah C AinsworthDeborah S Cunninghame GrahamJennifer A KellyMary E ComeauMiranda C MarionTimothy D HowardPaula S RamosJennifer A CrokerDavid L MorrisJohanna K SandlingJonas Carlsson AlmlöfEduardo M Acevedo-VásquezGraciela S AlarcónAlejandra M BabiniVicente BacaAnders A BengtssonGuillermo A BerbottoMarc BijlElizabeth E BrownHermine I BrunnerMario H CardielLuis José CatoggioRicard CerveraJorge M Cucho-VenegasSolbritt Rantapää DahlqvistSandra D'AlfonsoBerta Martins Da SilvaIñigo de la Rúa FigueroaAndrea DoriaJeffrey C EdbergEmőke EndreffyJorge A Esquivel-ValerioPaul R FortinBarry I FreedmanJohan FrostegårdMercedes A GarcíaIgnacio García de la TorreGary S GilkesonDafna D GladmanIva GunnarssonJoel M GuthridgeJennifer L HugginsJudith A JamesCees G M KallenbergDiane L KamenDavid R KarpKenneth M KaufmanLeah C KottyanLászló KovácsHelle LaustrupBernard R LauwerysQuan-Zhen LiMarco A Maradiaga-CeceñaJavier MartínJoseph M McCuneDavid R McWilliamsJoan T MerrillPedro MirandaJosé F MoctezumaSwapan K NathTimothy B NiewoldLorena OrozcoNorberto Ortego-CentenoMichelle PetriChristian A PineauBernardo A Pons-EstelJanet PopePrithvi RajRosalind Ramsey-GoldmanJohn D ReveilleLaurie P RussellJosé M SabioCarlos A Aguilar-SalinasHugo R ScherbarthRaffaella ScorzaMichael F SeldinChristopher SjöwallElisabet SvenungssonSusan D ThompsonSergio M A TolozaLennart TruedssonTeresa Tusié-LunaCarlos VasconcelosLuis M ViláDaniel J WallaceMichael H WeismanJoan E WitherTushar BhangaleJorge R OksenbergJohn D RiouxPeter K GregersenAnn-Christine SyvänenLars RönnblomLindsey A CriswellChaim O JacobKathy L SivilsBetty P TsaoLaura E SchanbergTimothy W BehrensEarl D SilvermanMarta E Alarcón-RiquelmeRobert P KimberlyJohn B HarleyEdward K WakelandRobert R GrahamPatrick M GaffneyTimothy J VysePublished in: Nature communications (2017)
Systemic lupus erythematosus (SLE) is an autoimmune disease with marked gender and ethnic disparities. We report a large transancestral association study of SLE using Immunochip genotype data from 27,574 individuals of European (EA), African (AA) and Hispanic Amerindian (HA) ancestry. We identify 58 distinct non-HLA regions in EA, 9 in AA and 16 in HA (∼50% of these regions have multiple independent associations); these include 24 novel SLE regions (P<5 × 10-8), refined association signals in established regions, extended associations to additional ancestries, and a disentangled complex HLA multigenic effect. The risk allele count (genetic load) exhibits an accelerating pattern of SLE risk, leading us to posit a cumulative hit hypothesis for autoimmune disease. Comparing results across the three ancestries identifies both ancestry-dependent and ancestry-independent contributions to SLE risk. Our results are consistent with the unique and complex histories of the populations sampled, and collectively help clarify the genetic architecture and ethnic disparities in SLE.