Application of the experimental design of genome-wide association studies (GWASs) is now 10 years old (young), and here we review the remarkable range of discoveries it has facilitated in population and complex-trait genetics, the biology of diseases, and translation toward new therapeutics. We predict the likely discoveries in the next 10 years, when GWASs will be based on millions of samples with array data imputed to a large fully sequenced reference panel and on hundreds of thousands of samples with whole-genome sequencing data.

10 Years of GWAS Discovery: Biology, Function, and Translation

We undertook a meta-analysis of six Crohn's disease genome-wide association studies (GWAS) comprising 6,333 affected individuals (cases) and 15,056 controls and followed up the top association signals in 15,694 cases, 14,026 controls and 414 parent-offspring trios. We identified 30 new susceptibility loci meeting genome-wide significance (P < 5 × 10⁻⁸). A series of in silico analyses highlighted particular genes within these loci and, together with manual curation, implicated functionally interesting candidate genes including SMAD3, ERAP2, IL10, IL2RA, TYK2, FUT2, DNMT3A, DENND1B, BACH2 and TAGAP. Combined with previously confirmed loci, these results identify 71 distinct loci with genome-wide significant evidence for association with Crohn's disease.

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Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci

An Expanded View of Complex Traits: From Polygenic to Omnigenic

Recent work has demonstrated that some functional categories of the genome contribute disproportionately to the heritability of complex diseases. Here we analyze a broad set of functional elements, including cell type-specific elements, to estimate their polygenic contributions to heritability in genome-wide association studies (GWAS) of 17 complex diseases and traits with an average sample size of 73,599. To enable this analysis, we introduce a new method, stratified LD score regression, for partitioning heritability from GWAS summary statistics while accounting for linked markers. This new method is computationally tractable at very large sample sizes and leverages genome-wide information. Our findings include a large enrichment of heritability in conserved regions across many traits, a very large immunological disease-specific enrichment of heritability in FANTOM5 enhancers and many cell type-specific enrichments, including significant enrichment of central nervous system cell types in the heritability of body mass index, age at menarche, educational attainment and smoking behavior.

/pdf/partitioning-heritability-by-functional-annotation-using-13dk84e4b8.pdf

Partitioning heritability by functional annotation using genome-wide association summary statistics.

Ulcerative colitis and Crohn's disease are the two main forms of inflammatory bowel disease (IBD). Here we report the first trans-ancestry association study of IBD, with genome-wide or Immunochip genotype data from an extended cohort of 86,640 European individuals and Immunochip data from 9,846 individuals of East Asian, Indian or Iranian descent. We implicate 38 loci in IBD risk for the first time. For the majority of the IBD risk loci, the direction and magnitude of effect are consistent in European and non-European cohorts. Nevertheless, we observe genetic heterogeneity between divergent populations at several established risk loci driven by differences in allele frequency (NOD2) or effect size (TNFSF15 and ATG16L1) or a combination of these factors (IL23R and IRGM). Our results provide biological insights into the pathogenesis of IBD and demonstrate the usefulness of trans-ancestry association studies for mapping loci associated with complex diseases and understanding genetic architecture across diverse populations.

/pdf/association-analyses-identify-38-susceptibility-loci-for-3qpzjdvcbc.pdf

Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations

Réponse spécifique T anti-Epstein-Barr virus et traitements par méthotrexate et anti-TNFα chez les patients atteints de rhumatismes inflammatoires chroniques

Resume Le syndrome de Blau est une affection granulomateuse rare a transmission autosomale dominante. Les signes cardinaux de cette affection sont une triade regroupant arthrites, eruptions cutanees et uveites. Cependant, la decouverte de mutations de CARD15 comme etant a l’origine de ce syndrome a permis d’elargir le spectre des manifestations cliniques associees a ces mutations, faisant de ce syndrome une affection tres proche au plan clinique de la sarcoidose. CARD15 code pour une proteine de l’immunite innee reconnaissant des structures peptidiques issues d’agents bacteriens a Gram positif ou negatif. Neanmoins, les mutations en cause dans le syndrome de Blau ne sont pas localisees dans le site de reconnaissance par CARD15 de ces agents bacteriens mais sont localisees dans une region du gene conduisant a une oligomerisation spontanee de CARD15 et ainsi une activation de la voie NFkB, observation ayant fait integrer le syndrome de Blau dans le spectre des maladies auto-inflammatoires.

Le syndrome de Blau

OBJECTIVES
To compare the features of difficult-to-treat rheumatoid arthritis (D2TRA) patients using 2 different definitions according to the previous failure of targeted therapies.


PATIENTS & METHODS
We stratified consecutive RA patients treated at Cochin Hospital into two groups, a D2TRA group and a non-D2TRA group, according to two definitions of D2TRA. Both definitions defined D2TRA as RAs failing at least two targeted therapies, with a different mechanism of action for the EULAR-D2TRA or without prejudging the mechanism of action and for the Alternative D2TRA definition.


RESULTS
We included 320 consecutive RA patients. We identified 76 EULAR-D2TRA and 244 non-DTRA patients, and 120 Alternative D2TRA and 200 non-DTRA patients.Compared to non-D2TRA, D2TRA patients from both definitions were more likely to have lower socio-economic level, positive rheumatoid factor, interstitial lung disease, higher DAS28-CRP and were more likely to respond to rituximab and JAK inhibitors. Although EULAR and Alternative D2TRA displayed similar clinical and biological features, they were characterized by different therapeutic profiles. We observed fewer patients receiving methotrexate in the Alternative D2TRA group (53% vs 64%, p = 0.046).Patients with Alternative D2TRA not fulfilling the EULAR definition (n = 44) had all received two successive first-line TNF inhibitors, a monoclonal antibody and a soluble receptor, and were comparable to EULAR-D2TRAs with regards to all other characteristics.


CONCLUSION
Low socioeconomic status, diabetes, ILD, and absence of combination with methotrexate allow identification of D2TRA. In addition, the inclusion of patients failing two TNF inhibitors in the EULAR definition of D2TRA, as "early-D2TRA", would facilitate the rapid identification of D2TRA patients.

Characteristics of patients with difficult-to-treat rheumatoid arthritis in a French single-centre hospital.

Background Tumor Necrosis Factor alpha (TNFα) is a key cytokine in inflammatory rheumatic diseases. TNF inhibitors (TNFi) has revolutionized treatment of rheumatic diseases, but may cause flares of multiple sclerosis (MS). Two Single Nucleotide Polymorphisms, (SNPs) rs1800693 and rs4149584, located within TNF receptor superfamilly 1 (TNFRSF1A) locus have been shown to increase the risk of developing MS [1]. The rs1800693*G allele leads to a dysfunctional TNFα soluble receptor that inhibits TNFα signaling while rs4149584 is involved in TNF receptor associated periodic syndrome. Objectives The aim of this study was to look for a possible the association between TNFRSF1A polymorphisms and demyelinating complications occurring during TNFi therapy. Methods Patients who presented with a demyelinating disorder (central or peripheral involvement) while treated with TNFi (cases), were recruited between March 2013 and December 2015, through the physicians involved in the CRI (“Club Rhumatismes et Inflammation”) a nationwide network of the French Society of Rheumatology. Rheumatoid arthritis patients treated with TNFi, from the French ReAct cohort, and who did not develop demyelinating complication constituted the control population (n=294). The frequency of rs1800693 and rs4149584 TNFRSF1A SNPs were compared between cases and controls. Results Twenty-four cases with demyelinating disorders, recruited from 11 centers with a median age of 39.7 years (range 30.4–75.8); of which 16 (67%) were females were included in the study. Neurological symptoms occurred after a median of 18.3 (1–66) months of anti TNFi; 15 (62.5%) had central neurologic involvement and 9 (37.5%) had peripheral involvement. The median follow-up was 26 (4–54) Months. No significant difference in the frequency of the rs1800693 MS risk-alleles (39,5% for cases vs 38,6% for controls) was observed. Similarly no difference was observed between cases (2%) and controls (4%) for rs4149584. Conclusions This study was unable to show an association between MS-associated SNPs within TNFRSF1A locus and the occurrence of demyelination while taking TNFi, suggesting that demyelination might be linked to other genetic factors or other pathways. References De Jager PL, Jia X, Wang J, et al. Meta-analysis of genome scans and replication identify CD6, IRF8 and TNFRSF1A as new multiple sclerosis susceptibility loci. Nat Genet 2009;41:776–82. doi:10.1038/ng.401. Disclosure of Interest None declared

https://ard.bmj.com/content/annrheumdis/76/Suppl_2/549.1.full.pdf

FRI0180 Multiple sclerosis risk-alleles study in patients with demyelinating side effects on anti tnf alpha therapy

Effet des concentrations sériques résiduelles d’anti-TNF et d’anticorps anti-médicaments (ADAb) sur l’efficacité thérapeutique à court terme après switch vers un autre anti-TNF dans la polyarthrite rhumatoïde et la spondyloarthrite axiale ☆

Corinne Miceli-Richard

Papers

Réponse spécifique T anti-Epstein-Barr virus et traitements par méthotrexate et anti-TNFα chez les patients atteints de rhumatismes inflammatoires chroniques

Le syndrome de Blau

Characteristics of patients with difficult-to-treat rheumatoid arthritis in a French single-centre hospital.

FRI0180 Multiple sclerosis risk-alleles study in patients with demyelinating side effects on anti tnf alpha therapy

Effet des concentrations sériques résiduelles d’anti-TNF et d’anticorps anti-médicaments (ADAb) sur l’efficacité thérapeutique à court terme après switch vers un autre anti-TNF dans la polyarthrite rhumatoïde et la spondyloarthrite axiale ☆