Dataset Information

Transancestral mapping and genetic load in systemic lupus erythematosus.

ABSTRACT: 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.

SUBMITTER: Langefeld CD

PROVIDER: S-EPMC5520018 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Transancestral mapping and genetic load in systemic lupus erythematosus.

Langefeld Carl D CD Ainsworth Hannah C HC Cunninghame Graham Deborah S DS Kelly Jennifer A JA Comeau Mary E ME Marion Miranda C MC Howard Timothy D TD Ramos Paula S PS Croker Jennifer A JA Morris David L DL Sandling Johanna K JK Almlöf Jonas Carlsson JC Acevedo-Vásquez Eduardo M EM Alarcón Graciela S GS Babini Alejandra M AM Baca Vicente V Bengtsson Anders A AA Berbotto Guillermo A GA Bijl Marc M Brown Elizabeth E EE Brunner Hermine I HI Cardiel Mario H MH Catoggio Luis L Cervera Ricard R Cucho-Venegas Jorge M JM Dahlqvist Solbritt Rantapää SR D'Alfonso Sandra S Da Silva Berta Martins BM de la Rúa Figueroa Iñigo I Doria Andrea A Edberg Jeffrey C JC Endreffy Emőke E Esquivel-Valerio Jorge A JA Fortin Paul R PR Freedman Barry I BI Frostegård Johan J García Mercedes A MA de la Torre Ignacio García IG Gilkeson Gary S GS Gladman Dafna D DD Gunnarsson Iva I Guthridge Joel M JM Huggins Jennifer L JL James Judith A JA Kallenberg Cees G M CGM Kamen Diane L DL Karp David R DR Kaufman Kenneth M KM Kottyan Leah C LC Kovács László L Laustrup Helle H Lauwerys Bernard R BR Li Quan-Zhen QZ Maradiaga-Ceceña Marco A MA Martín Javier J McCune Joseph M JM McWilliams David R DR Merrill Joan T JT Miranda Pedro P Moctezuma José F JF Nath Swapan K SK Niewold Timothy B TB Orozco Lorena L Ortego-Centeno Norberto N Petri Michelle M Pineau Christian A CA Pons-Estel Bernardo A BA Pope Janet J Raj Prithvi P Ramsey-Goldman Rosalind R Reveille John D JD Russell Laurie P LP Sabio José M JM Aguilar-Salinas Carlos A CA Scherbarth Hugo R HR Scorza Raffaella R Seldin Michael F MF Sjöwall Christopher C Svenungsson Elisabet E Thompson Susan D SD Toloza Sergio M A SMA Truedsson Lennart L Tusié-Luna Teresa T Vasconcelos Carlos C Vilá Luis M LM Wallace Daniel J DJ Weisman Michael H MH Wither Joan E JE Bhangale Tushar T Oksenberg Jorge R JR Rioux John D JD Gregersen Peter K PK Syvänen Ann-Christine AC Rönnblom Lars L Criswell Lindsey A LA Jacob Chaim O CO Sivils Kathy L KL Tsao Betty P BP Schanberg Laura E LE Behrens Timothy W TW Silverman Earl D ED Alarcón-Riquelme Marta E ME Kimberly Robert P RP Harley John B JB Wakeland Edward K EK Graham Robert R RR Gaffney Patrick M PM Vyse Timothy J TJ

Nature communications 20170717

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<sup>-8</sup>), refined association si ...[more]

PMID: 28714469

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Project description:OBJECTIVES:Systemic lupus erythematosus (SLE) is a chronic multisystem genetically complex autoimmune disease characterised by the production of autoantibodies to nuclear and cellular antigens, tissue inflammation and organ damage. Genome-wide association studies have shown that variants within the major histocompatibility complex (MHC) region on chromosome 6 confer the greatest genetic risk for SLE in European and Chinese populations. However, the causal variants remain elusive due to tight linkage disequilibrium across disease-associated MHC haplotypes, the highly polymorphic nature of many MHC genes and the heterogeneity of the SLE phenotype. METHODS:A high-density case-control single nucleotide polymorphism (SNP) study of the MHC region was undertaken in SLE cohorts of Spanish and Filipino ancestry using a custom Illumina chip in order to fine-map association signals in these haplotypically diverse populations. In addition, comparative analyses were performed between these two datasets and a northern European UK SLE cohort. A total of 1433 cases and 1458 matched controls were examined. RESULTS:Using this transancestral SNP mapping approach, novel independent loci were identified within the MHC region in UK, Spanish and Filipino patients with SLE with some evidence of interaction. These loci include HLA-DPB1, HLA-G and MSH5 which are independent of each other and HLA-DRB1 alleles. Furthermore, the established SLE-associated HLA-DRB1*15 signal was refined to an interval encompassing HLA-DRB1 and HLA-DQA1. Increased frequencies of MHC region risk alleles and haplotypes were found in the Filipino population compared with Europeans, suggesting that the greater disease burden in non-European SLE may be due in part to this phenomenon. CONCLUSION:These data highlight the usefulness of mapping disease susceptibility loci using a transancestral approach, particularly in a region as complex as the MHC, and offer a springboard for further fine-mapping, resequencing and transcriptomic analysis.

Dataset Information

Transancestral mapping and genetic load in systemic lupus erythematosus.

Publications

Transancestral mapping and genetic load in systemic lupus erythematosus.

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