Aung T, Ozaki M, Lee MC, Schlötzer-Schrehardt U, Thorleifsson G, Mizoguchi T, Igo RP, Haripriya A, Williams SE, Astakhov YS, Orr AC, Burdon KP, Nakano S, Mori K, Abu-Amero K, Hauser M, Li Z, Prakadeeswari G, Bailey JCN, Cherecheanu AP, Kang JH, Nelson S, Hayashi K, Manabe S-I, Kazama S, Zarnowski T, Inoue K, Irkec M, Coca-Prados M, Sugiyama K, Järvelä I, Schlottmann P, Lerner FS, Lamari H, Nilgün Y, Bikbov M, Park KH, Cha SC, Yamashiro K, Zenteno JC, Jonas JB, Kumar RS, Perera SA, Chan ASY, Kobakhidze N, George R, Vijaya L, Do T, Edward DP, de Juan Marcos L, Pakravan M, Moghimi S, Ideta R, Bach-Holm D, Kappelgaard P, Wirostko B, Thomas S, Gaston D, Bedard K, Greer WL, Yang Z, Chen X, Huang L, Sang J, Jia H, Jia L, Qiao C, Zhang H, Liu X, Zhao B, Wang Y-X, Xu L, Leruez S, Reynier P, Chichua G, Tabagari S, Uebe S, Zenkel M, Berner D, Mossböck G, Weisschuh N, Hoja U, Welge-Luessen U-C, Mardin C, Founti P, Chatzikyriakidou A, Pappas T, Anastasopoulos E, Lambropoulos A, Ghosh A, Shetty R, Porporato N, Saravanan V, Venkatesh R, Shivkumar C, Kalpana N, Sarangapani S, Kanavi MR, Beni AN, Yazdani S, Lashay A, Naderifar H, Khatibi N, Fea A, Lavia C, Dallorto L, Rolle T, Frezzotti P, Paoli D, Salvi E, Manunta P, Mori Y, Miyata K, Higashide T, Chihara E, Ishiko S, Yoshida A, Yanagi M, Kiuchi Y, Ohashi T, Sakurai T, Sugimoto T, Chuman H, Aihara M, Inatani M, Miyake M, Gotoh N, Matsuda F, Yoshimura N, Ikeda Y, Ueno M, Sotozono C, Jeoung JW, Sagong M, Park KH, Ahn J, Cruz-Aguilar M, Ezzouhairi SM, Rafei A, Chong YF, Ng XY, Goh SR, Chen Y, Yong VHK, Khan MI, Olawoye OO, Ashaye AO, Ugbede I, Onakoya A, Kizor-Akaraiwe N, Teekhasaenee C, Suwan Y, Supakontanasan W, Okeke S, Uche NJ, Asimadu I, Ayub H, Akhtar F, Kosior-Jarecka E, Lukasik U, Lischinsky I, Castro V, Grossmann RP, Megevand GS, Roy S, Dervan E, Silke E, Rao A, Sahay P, Fornero P, Cuello O, Sivori D, Zompa T, Mills RA, Souzeau E, Mitchell P, Wang JJ, Hewitt AW, Coote M, Crowston JG, Astakhov SY, Akopov EL, Emelyanov A, Vysochinskaya V, Kazakbaeva G, Fayzrakhmanov R, Al-Obeidan SA, Owaidhah O, Aljasim LA, Chowbay B, Foo JN, Soh RQ, Sim KS, Xie Z, Cheong AWO, Mok SQ, Soo HM, Chen XY, Peh SQ, Heng KK, Husain R, Ho S-L, Hillmer AM, Cheng C-Y, Escudero-Domínguez FA, González-Sarmiento R, Martinon-Torres F, Salas A, Pathanapitoon K, Hansapinyo L, Wanichwecharugruang B, Kitnarong N, Sakuntabhai A, Nguyn HX, Nguyn GTT, Nguyn TV, Zenz W, Binder A, Klobassa DS, Hibberd ML, Davila S, Herms S, Nöthen MM, Moebus S, Rautenbach RM, Ziskind A, Carmichael TR, Ramsay M, Álvarez L, García M, González-Iglesias H, Rodríguez-Calvo PP, Cueto LF-V, Oguz Ç, Tamcelik N, Atalay E, Batu B, Aktas D, Kasım B, Wilson RM, Coleman AL, Liu Y, Challa P, Herndon L, Kuchtey RW, Kuchtey J, Curtin K, Chaya CJ, Crandall A, Zangwill LM, Wong TY, Nakano M, Kinoshita S, den Hollander AI, Vesti E, Fingert JH, Lee RK, Sit AJ, Shingleton BJ, Wang N, Cusi D, Qamar R, Kraft P, Pericak-Vance MA, Raychaudhuri S, Heegaard S, Kivelä T, Reis A, Kruse FE, Weinreb RN, Pasquale LR, Haines JL, Thorsteinsdottir U, Jonasson F, Allingham RR, Milea D, Ritch R, Kubota T, Tashiro K, Vithana EN, Micheal S, Topouzis F, Craig JE, Dubina M, Sundaresan P, Stefansson K, Wiggs JL, Pasutto F, Khor CC. Genetic association study of exfoliation syndrome identifies a protective rare variant at LOXL1 and five new susceptibility loci. Nat Genet 2017;49(7):993-1004.Abstract
Exfoliation syndrome (XFS) is the most common known risk factor for secondary glaucoma and a major cause of blindness worldwide. Variants in two genes, LOXL1 and CACNA1A, have previously been associated with XFS. To further elucidate the genetic basis of XFS, we collected a global sample of XFS cases to refine the association at LOXL1, which previously showed inconsistent results across populations, and to identify new variants associated with XFS. We identified a rare protective allele at LOXL1 (p.Phe407, odds ratio (OR) = 25, P = 2.9 × 10(-14)) through deep resequencing of XFS cases and controls from nine countries. A genome-wide association study (GWAS) of XFS cases and controls from 24 countries followed by replication in 18 countries identified seven genome-wide significant loci (P < 5 × 10(-8)). We identified association signals at 13q12 (POMP), 11q23.3 (TMEM136), 6p21 (AGPAT1), 3p24 (RBMS3) and 5q23 (near SEMA6A). These findings provide biological insights into the pathology of XFS and highlight a potential role for naturally occurring rare LOXL1 variants in disease biology.
Sparks JA, Barbhaiya M, Karlson EW, Ritter SY, Raychaudhuri S, Corrigan CC, Lu F, Selhub J, Chasman DI, Paynter NP, Ridker PM, Solomon DH. Investigating methotrexate toxicity within a randomized double-blinded, placebo-controlled trial: Rationale and design of the Cardiovascular Inflammation Reduction Trial-Adverse Events (CIRT-AE) Study. Semin Arthritis Rheum 2017;Abstract
BACKGROUND: The role of low dose methotrexate (LDM) in potential serious toxicities remains unclear despite its common use. Prior observational studies investigating LDM toxicity compared LDM to other active drugs. Prior placebo-controlled clinical trials of LDM in inflammatory conditions were not large enough to investigate toxicity. The Cardiovascular Inflammation Reduction Trial (CIRT) is an ongoing NIH-funded, randomized, double-blind, placebo-controlled trial of LDM in the secondary prevention of cardiovascular disease. We describe here the rationale and design of the CIRT-Adverse Events (CIRT-AE) ancillary study which aims to investigate adverse events within CIRT. DESIGN: CIRT will randomize up to 7000 participants with cardiovascular disease and no systemic rheumatic disease to either LDM (target dose: 15-20mg/week) or placebo for an average follow-up period of 3-5 years; subjects in both treatment arms receive folic acid 1mg daily for 6 days each week. The primary endpoints of CIRT include recurrent cardio vascular events, incident diabetes, and all-cause mortality, and the ancillary CIRT-AE study has been designed to adjudicate other clinically important adverse events including hepatic, gastrointestinal, respiratory, hematologic, infectious, mucocutaneous, oncologic, renal, neurologic, and musculoskeletal outcomes. Methotrexate polyglutamate levels and genome-wide single nucleotide polymorphisms will be examined for association with adverse events. SUMMARY: CIRT-AE will comprehensively evaluate potential LDM toxicities among subjects with cardiovascular disease within the context of a large, ongoing, double-blind, placebo-controlled trial. This information may lead to a personalized approach to monitoring LDM in clinical practice.
Karnes JH, Bastarache L, Shaffer CM, Gaudieri S, Xu Y, Glazer AM, Mosley JD, Zhao S, Raychaudhuri S, Mallal S, Ye Z, Mayer JG, Brilliant MH, Hebbring SJ, Roden DM, Phillips EJ, Denny JC. Phenome-wide scanning identifies multiple diseases and disease severity phenotypes associated with HLA variants. Sci Transl Med 2017;9(389)Abstract
Although many phenotypes have been associated with variants in human leukocyte antigen (HLA) genes, the full phenotypic impact of HLA variants across all diseases is unknown. We imputed HLA genomic variation from two populations of 28,839 and 8431 European ancestry individuals and tested association of HLA variation with 1368 phenotypes. A total of 104 four-digit and 92 two-digit HLA allele phenotype associations were significant in both discovery and replication cohorts, the strongest being HLA-DQB1*03:02 and type 1 diabetes. Four previously unidentified associations were identified across the spectrum of disease with two- and four-digit HLA alleles and 10 with nonsynonymous variants. Some conditions associated with multiple HLA variants and stronger associations with more severe disease manifestations were identified. A comprehensive, publicly available catalog of clinical phenotypes associated with HLA variation is provided. Examining HLA variant disease associations in this large data set allows comprehensive definition of disease associations to drive further mechanistic insights.
Budu-Aggrey A, Bowes J, Stuart PE, Zawistowski M, Tsoi LC, Nair R, Jadon DR, McHugh N, Korendowych E, Elder JT, Barton A, Raychaudhuri S. A rare coding allele in IFIH1 is protective for psoriatic arthritis. Ann Rheum Dis 2017;76(7):1321-1324.Abstract
OBJECTIVES: Psoriatic arthritis (PsA) is an inflammatory arthritis associated with psoriasis. While many common risk alleles have been reported for association with PsA as well as psoriasis, few rare coding alleles have yet been identified. METHODS: To identify rare coding variation associated with PsA risk or protection, we genotyped 41 267 variants with the exome chip and investigated association within an initial cohort of 1980 PsA cases and 5913 controls. Genotype data for an independent cohort of 2234 PsA cases and 5708 controls was also made available, allowing for a meta-analysis to be performed with the discovery dataset. RESULTS: We identified an association with the rare variant rs35667974 (p=2.39x10(-6), OR=0.47), encoding an Ile923Val amino acid change in the IFIH1 gene protein product. The association was reproduced in our independent cohort, which reached a high level of significance on meta-analysis with the discovery and replication datasets (p=4.67x10(-10)). We identified a strong association with IFIH1 when performing multiple-variant analysis (p=6.77x10(-6)), and found evidence of independent effects between the rare allele and the common PsA variant at the same locus. CONCLUSION: For the first time, we report a rare coding allele in IFIH1 to be protective for PsA. This rare allele has also been identified to have the same direction of effect on type I diabetes and psoriasis. While this association further supports existing evidence for IFIH1 as a causal gene for PsA, mechanistic studies will need to be pursued to confirm that IFIH1 is indeed causal.
Terao C, Kawaguchi T, Dieude P, Varga J, Kuwana M, Hudson M, Kawaguchi Y, Matucci-Cerinic M, Ohmura K, Riemekasten G, Kawasaki A, Airo P, Horita T, Oka A, Hachulla E, Yoshifuji H, Caramaschi P, Hunzelmann N, Baron M, Atsumi T, Hassoun P, Torii T, Takahashi M, Tabara Y, Shimizu M, Tochimoto A, Ayuzawa N, Yanagida H, Furukawa H, Tohma S, Hasegawa M, Fujimoto M, Ishikawa O, Yamamoto T, Goto D, Asano Y, Jinnin M, Endo H, Takahashi H, Takehara K, Sato S, Ihn H, Raychaudhuri S, Liao K, Gregersen P, Tsuchiya N, Riccieri V, Melchers I, Valentini G, Cauvet A, Martinez M, Mimori T, Matsuda F, Allanore Y. Transethnic meta-analysis identifies GSDMA and PRDM1 as susceptibility genes to systemic sclerosis. Ann Rheum Dis 2017;76(6):1150-1158.Abstract
OBJECTIVES: Systemic sclerosis (SSc) is an autoimmune disease characterised by skin and systemic fibrosis culminating in organ damage. Previous genetic studies including genome-wide association studies (GWAS) have identified 12 susceptibility loci satisfying genome-wide significance. Transethnic meta-analyses have successfully expanded the list of susceptibility genes and deepened biological insights for other autoimmune diseases. METHODS: We performed transethnic meta-analysis of GWAS in the Japanese and European populations, followed by a two-staged replication study comprising a total of 4436 cases and 14 751 controls. Associations between significant single nuclear polymorphisms (SNPs) and neighbouring genes were evaluated. Enrichment analysis of H3K4Me3, a representative histone mark for active promoter was conducted with an expanded list of SSc susceptibility genes. RESULTS: We identified two significant SNP in two loci, GSDMA and PRDM1, both of which are related to immune functions and associated with other autoimmune diseases (p=1.4×10(-10) and 6.6×10(-10), respectively). GSDMA also showed a significant association with limited cutaneous SSc. We also replicated the associations of previously reported loci including a non-GWAS locus, TNFAIP3. PRDM1 encodes BLIMP1, a transcription factor regulating T-cell proliferation and plasma cell differentiation. The top SNP in GSDMA was a missense variant and correlated with gene expression of neighbouring genes, and this could explain the association in this locus. We found different human leukocyte antigen (HLA) association patterns between the two populations. Enrichment analysis suggested the importance of CD4-naïve primary T cell. CONCLUSIONS: GSDMA and PRDM1 are associated with SSc. These findings provide enhanced insight into the genetic and biological basis of SSc.
Rao DA, Gurish MF, Marshall JL, Slowikowski K, Fonseka CY, Liu Y, Donlin LT, Henderson LA, Wei K, Mizoguchi F, Teslovich NC, Weinblatt ME, Massarotti EM, Coblyn JS, Helfgott SM, Lee YC, Todd DJ, Bykerk VP, Goodman SM, Pernis AB, Ivashkiv LB, Karlson EW, Nigrovic PA, Filer A, Buckley CD, Lederer JA, Raychaudhuri S, Brenner MB. Pathologically expanded peripheral T helper cell subset drives B cells in rheumatoid arthritis. Nature 2017;542(7639):110-114.Abstract
CD4(+) T cells are central mediators of autoimmune pathology; however, defining their key effector functions in specific autoimmune diseases remains challenging. Pathogenic CD4(+) T cells within affected tissues may be identified by expression of markers of recent activation. Here we use mass cytometry to analyse activated T cells in joint tissue from patients with rheumatoid arthritis, a chronic immune-mediated arthritis that affects up to 1% of the population. This approach revealed a markedly expanded population of PD-1(hi)CXCR5(-)CD4(+) T cells in synovium of patients with rheumatoid arthritis. However, these cells are not exhausted, despite high PD-1 expression. Rather, using multidimensional cytometry, transcriptomics, and functional assays, we define a population of PD-1(hi)CXCR5(-) 'peripheral helper' T (TPH) cells that express factors enabling B-cell help, including IL-21, CXCL13, ICOS, and MAF. Like PD-1(hi)CXCR5(+) T follicular helper cells, TPH cells induce plasma cell differentiation in vitro through IL-21 secretion and SLAMF5 interaction (refs 3, 4). However, global transcriptomics highlight differences between TPH cells and T follicular helper cells, including altered expression of BCL6 and BLIMP1 and unique expression of chemokine receptors that direct migration to inflamed sites, such as CCR2, CX3CR1, and CCR5, in TPH cells. TPH cells appear to be uniquely poised to promote B-cell responses and antibody production within pathologically inflamed non-lymphoid tissues.
Cui J, Diogo D, Stahl EA, Canhao H, Mariette X, Greenberg JD, Okada Y, Pappas DA, Fulton RS, Tak PP, Nurmohamed MT, Lee A, Larson DE, Kurreeman F, Deluca TL, O'Laughlin M, Fronick CC, Fulton LL, Mardis ER, van der Horst-Bruinsma IE, Wolbink G-J, Gregersen PK, Kremer JM, Crusius BJA, de Vries N, Huizinga TWJ, Fonseca JE, Miceli-Richard C, Karlson EW, Coenen MJ, Barton A, Plenge RM, Raychaudhuri S. Brief Report: The Role of Rare Protein-Coding Variants in Anti-Tumor Necrosis Factor Treatment Response in Rheumatoid Arthritis. Arthritis Rheumatol 2017;69(4):735-741.Abstract
OBJECTIVE: In many rheumatoid arthritis (RA) patients, disease is controlled with anti-tumor necrosis factor (anti-TNF) biologic therapies. However, in a significant number of patients, the disease fails to respond to anti-TNF therapy. We undertook the present study to examine the hypothesis that rare and low-frequency genetic variants might influence response to anti-TNF treatment. METHODS: We sequenced the coding region of 750 genes in 1,094 RA patients of European ancestry who were treated with anti-TNF. After quality control, 690 genes were included in the analysis. We applied single-variant association and gene-based association tests to identify variants associated with anti-TNF treatment response. In addition, given the key mechanistic role of TNF, we performed gene set analyses of 27 TNF pathway genes. RESULTS: We identified 14,420 functional variants, of which 6,934 were predicted as nonsynonymous 2,136 of which were further predicted to be "damaging." Despite the fact that the study was well powered, no single variant or gene showed study-wide significant association with change in the outcome measures disease activity or European League Against Rheumatism response. Intriguingly, we observed 3 genes, of 27 with nominal signals of association (P < 0.05), that were involved in the TNF signaling pathway. However, when we performed a rigorous gene set enrichment analysis based on association P value ranking, we observed no evidence of enrichment of association at genes involved in the TNF pathway (Penrichment  = 0.15, based on phenotype permutations). CONCLUSION: Our findings suggest that rare and low-frequency protein-coding variants in TNF signaling pathway genes or other genes do not contribute substantially to anti-TNF treatment response in patients with RA.
Pouget JG, Gonçalves VF, Spain SL, Finucane HK, Raychaudhuri S, Kennedy JL, Knight J. Genome-Wide Association Studies Suggest Limited Immune Gene Enrichment in Schizophrenia Compared to 5 Autoimmune Diseases. Schizophr Bull 2016;42(5):1176-84.Abstract
There has been intense debate over the immunological basis of schizophrenia, and the potential utility of adjunct immunotherapies. The major histocompatibility complex is consistently the most powerful region of association in genome-wide association studies (GWASs) of schizophrenia and has been interpreted as strong genetic evidence supporting the immune hypothesis. However, global pathway analyses provide inconsistent evidence of immune involvement in schizophrenia, and it remains unclear whether genetic data support an immune etiology per se. Here we empirically test the hypothesis that variation in immune genes contributes to schizophrenia. We show that there is no enrichment of immune loci outside of the MHC region in the largest genetic study of schizophrenia conducted to date, in contrast to 5 diseases of known immune origin. Among 108 regions of the genome previously associated with schizophrenia, we identify 6 immune candidates (DPP4, HSPD1, EGR1, CLU, ESAM, NFATC3) encoding proteins with alternative, nonimmune roles in the brain. While our findings do not refute evidence that has accumulated in support of the immune hypothesis, they suggest that genetically mediated alterations in immune function may not play a major role in schizophrenia susceptibility. Instead, there may be a role for pleiotropic effects of a small number of immune genes that also regulate brain development and plasticity. Whether immune alterations drive schizophrenia progression is an important question to be addressed by future research, especially in light of the growing interest in applying immunotherapies in schizophrenia.
Cassa CA, Smith SE, Docken W, Hoffman E, McLaughlin H, Chun S, Leshchiner I, Miraoui H, Raychaudhuri S, Frank NY, Wilson BJ, Sunyaev SR, Maas RL, Vuzman D. An argument for early genomic sequencing in atypical cases: a WISP3 variant leads to diagnosis of progressive pseudorheumatoid arthropathy of childhood. Rheumatology (Oxford) 2016;55(3):586-9.
Gusev A, Shi H, Kichaev G, Pomerantz M, Li F, Long HW, Ingles SA, Kittles RA, Strom SS, Rybicki BA, Nemesure B, Isaacs WB, Zheng W, Pettaway CA, Yeboah ED, Tettey Y, Biritwum RB, Adjei AA, Tay E, Truelove A, Niwa S, Chokkalingam AP, John EM, Murphy AB, Signorello LB, Carpten J, Leske CM, Wu S-Y, Hennis AJM, Neslund-Dudas C, Hsing AW, Chu L, Goodman PJ, Klein EA, Witte JS, Casey G, Kaggwa S, Cook MB, Stram DO, Blot WJ, Eeles RA, Easton D, Kote-Jarai Z, Al Olama AA, Benlloch S, Muir K, Giles GG, Southey MC, Fitzgerald LM, Gronberg H, Wiklund F, Aly M, Henderson BE, Schleutker J, Wahlfors T, Tammela TLJ, Nordestgaard BG, Key TJ, Travis RC, Neal DE, Donovan JL, Hamdy FC, Pharoah P, Pashayan N, Khaw K-T, Stanford JL, Thibodeau SN, McDonnell SK, Schaid DJ, Maier C, Vogel W, Luedeke M, Herkommer K, Kibel AS, Cybulski C, Wokolorczyk D, Kluzniak W, Cannon-Albright L, Teerlink C, Brenner H, Dieffenbach AK, Arndt V, Park JY, Sellers TA, Lin H-Y, Slavov C, Kaneva R, Mitev V, Batra J, Spurdle A, Clements JA, Teixeira MR, Pandha H, Michael A, Paulo P, Maia S, Kierzek A, Conti DV, Albanes D, Berg C, Berndt SI, Campa D, Crawford DE, Diver RW, Gapstur SM, Gaziano MJ, Giovannucci E, Hoover R, Hunter DJ, Johansson M, Kraft P, Le Marchand L, Lindström S, Navarro C, Overvad K, Riboli E, Siddiq A, Stevens VL, Trichopoulos D, Vineis P, Yeager M, Trynka G, Raychaudhuri S, Schumacher FR, Price AL, Freedman ML, Haiman CA, Pasaniuc B. Atlas of prostate cancer heritability in European and African-American men pinpoints tissue-specific regulation. Nat Commun 2016;7:10979.Abstract
Although genome-wide association studies have identified over 100 risk loci that explain ∼33% of familial risk for prostate cancer (PrCa), their functional effects on risk remain largely unknown. Here we use genotype data from 59,089 men of European and African American ancestries combined with cell-type-specific epigenetic data to build a genomic atlas of single-nucleotide polymorphism (SNP) heritability in PrCa. We find significant differences in heritability between variants in prostate-relevant epigenetic marks defined in normal versus tumour tissue as well as between tissue and cell lines. The majority of SNP heritability lies in regions marked by H3k27 acetylation in prostate adenoc7arcinoma cell line (LNCaP) or by DNaseI hypersensitive sites in cancer cell lines. We find a high degree of similarity between European and African American ancestries suggesting a similar genetic architecture from common variation underlying PrCa risk. Our findings showcase the power of integrating functional annotation with genetic data to understand the genetic basis of PrCa.
Frisell T, Hellgren K, Alfredsson L, Raychaudhuri S, Klareskog L, Askling J. Familial aggregation of arthritis-related diseases in seropositive and seronegative rheumatoid arthritis: a register-based case-control study in Sweden. Ann Rheum Dis 2016;75(1):183-9.Abstract
OBJECTIVES: Our objective was to estimate the risk of developing rheumatoid arthritis (RA) associated with a family history of non-RA arthritis-related diseases. This familial co-aggregation is of clinical interest since it is often encountered when assessing family history of RA specifically, but also informative on the genetic overlap between these diseases. Since anticitrullinated peptide antibodies/rheumatoid factor (RF)-positive and RF-negative RA have both specific and shared genetic factors, the familial co-aggregation was assessed separately for seropositive and seronegative disease. METHODS: Nested case-control study in prospectively recorded Swedish total population data. The Multi-Generation Register identified first-degree relatives. RA and arthritis-related diseases were ascertained through the nationwide patient register. RA serology was based on International Classification of Diseases tenth revision coded diagnoses, mainly reflecting RF. Familial risks were calculated using conditional logistic regression. Results were replicated using the Swedish rheumatology register. RESULTS: Familial co-aggregation was found between RA and every studied arthritis-related disease, but the magnitude varied widely, from juvenile idiopathic arthritis (JIA) (seropositive RA OR=3.98 (3.01 to 5.26); seronegative RA OR=5.70 (3.47 to 9.36)) to osteoarthritis (seropositive RA OR=1.03 (1.00 to 1.06); seronegative RA OR=1.05 (1.00 to 1.09)). The familial co-aggregation pattern of non-RA arthritis-related diseases was overall similar for seropositive and seronegative RA. Among those with family history of RA, relatives' other arthritis-related diseases conferred little or no additional risk. CONCLUSIONS: Although family history of several arthritis-related diseases may be useful to predict RA (eg, lupus and JIA), others (eg, osteoarthritis and arthralgia) are less useful. Seropositive and seronegative RA had rather similar familial co-aggregation patterns with arthritis-related diseases, suggesting that the two RA subsets are similar in the genetic factors that overlap with these diseases.
Gutierrez-Achury J, Zorro MM, Ricaño-Ponce I, Zhernakova DV, Diogo D, Raychaudhuri S, Franke L, Trynka G, Wijmenga C, Zhernakova A. Functional implications of disease-specific variants in loci jointly associated with coeliac disease and rheumatoid arthritis. Hum Mol Genet 2016;25(1):180-90.Abstract
Hundreds of genomic loci have been associated with a significant number of immune-mediated diseases, and a large proportion of these associated loci are shared among traits. Both the molecular mechanisms by which these loci confer disease susceptibility and the extent to which shared loci are implicated in a common pathogenesis are unknown. We therefore sought to dissect the functional components at loci shared between two autoimmune diseases: coeliac disease (CeD) and rheumatoid arthritis (RA). We used a cohort of 12 381 CeD cases and 7827 controls, and another cohort of 13 819 RA cases and 12 897 controls, all genotyped with the Immunochip platform. In the joint analysis, we replicated 19 previously identified loci shared by CeD and RA and discovered five new non-HLA loci shared by CeD and RA. Our fine-mapping results indicate that in nine of 24 shared loci the associated variants are distinct in the two diseases. Using cell-type-specific histone markers, we observed that loci which pointed to the same variants in both diseases were enriched for marks of promoters active in CD14+ and CD34+ immune cells (P < 0.001), while loci pointing to distinct variants in one of the two diseases showed enrichment for marks of more specialized cell types, like CD4+ regulatory T cells in CeD (P < 0.0001) compared with Th17 and CD15+ in RA (P = 0.0029).
Yarwood A, Viatte S, Okada Y, Plenge R, Yamamoto K, Barton A, Symmons D, Raychaudhuri S, Klareskog L, Gregersen P, Worthington J, Eyre S. Loci associated with N-glycosylation of human IgG are not associated with rheumatoid arthritis: a Mendelian randomisation study. Ann Rheum Dis 2016;75(1):317-20.Abstract
OBJECTIVES: A recent study identified 16 genetic variants associated with N-glycosylation of human IgG. Several of the genomic regions where these single nucleotide polymorphisms (SNPs) reside have also been associated with autoimmune disease (AID) susceptibility, suggesting there may be pleiotropy (genetic sharing) between loci controlling both N-glycosylation and AIDs. We investigated this by testing variants associated with levels of IgG N-glycosylation for association with rheumatoid arthritis (RA) susceptibility using a Mendelian randomisation study, and testing a subset of these variants in a less well-powered study of treatment response and severity. METHODS: SNPs showing association with IgG N-glycosylation were analysed for association with RA susceptibility in 14 361 RA cases and 43 923 controls. Five SNPs were tested for association with response to anti-tumour necrosis factor (TNF) therapy in 1081 RA patient samples and for association with radiological disease severity in 342 patients. RESULTS: Only one SNP (rs9296009) associated with N-glycosylation showed an association (p=6.92×10(-266)) with RA susceptibility, although this was due to linkage disequilibrium with causal human leukocyte antigen (HLA) variants. Four regions of the genome harboured SNPs associated with both traits (shared loci); although statistical analysis indicated that the associations observed for the two traits are independent. No SNPs showed association with response to anti-TNF therapy. One SNP rs12342831 was modestly associated with Larsen score (p=0.05). CONCLUSIONS: In a large, well-powered cohort of RA patients, we show SNPs driving levels of N-glycosylation have no association with RA susceptibility, indicating colocalisation of associated SNPs are not necessarily indicative of a shared genetic background or a role for glycosylation in disease susceptibility.
van der Harst P, van Setten J, Verweij N, Vogler G, Franke L, Maurano MT, Wang X, Mateo Leach I, Eijgelsheim M, Sotoodehnia N, Hayward C, Sorice R, Meirelles O, Lyytikäinen L-P, Polašek O, Tanaka T, Arking DE, Ulivi S, Trompet S, Müller-Nurasyid M, Smith AV, Dörr M, Kerr KF, Magnani JW, del Greco M F, Zhang W, Nolte IM, Silva CT, Padmanabhan S, Tragante V, Esko T, Abecasis GR, Adriaens ME, Andersen K, Barnett P, Bis JC, Bodmer R, Buckley BM, Campbell H, Cannon MV, Chakravarti A, Chen LY, Delitala A, Devereux RB, Doevendans PA, Dominiczak AF, Ferrucci L, Ford I, Gieger C, Harris TB, Haugen E, Heinig M, Hernandez DG, Hillege HL, Hirschhorn JN, Hofman A, Hubner N, Hwang S-J, Iorio A, Kähönen M, Kellis M, Kolcic I, Kooner IK, Kooner JS, Kors JA, Lakatta EG, Lage K, Launer LJ, Levy D, Lundby A, Macfarlane PW, May D, Meitinger T, Metspalu A, Nappo S, Naitza S, Neph S, Nord AS, Nutile T, Okin PM, Olsen JV, Oostra BA, Penninger JM, Pennacchio LA, Pers TH, Perz S, Peters A, Pinto YM, Pfeufer A, Pilia MG, Pramstaller PP, Prins BP, Raitakari OT, Raychaudhuri S, Rice KM, Rossin EJ, Rotter JI, Schafer S, Schlessinger D, Schmidt CO, Sehmi J, Silljé HHW, Sinagra G, Sinner MF, Slowikowski K, Soliman EZ, Spector TD, Spiering W, Stamatoyannopoulos JA, Stolk RP, Strauch K, Tan S-T, Tarasov KV, Trinh B, Uitterlinden AG, van den Boogaard M, van Duijn CM, van Gilst WH, Viikari JS, Visscher PM, Vitart V, Völker U, Waldenberger M, Weichenberger CX, Westra H-J, Wijmenga C, Wolffenbuttel BH, Yang J, Bezzina CR, Munroe PB, Snieder H, Wright AF, Rudan I, Boyer LA, Asselbergs FW, van Veldhuisen DJ, Stricker BH, Psaty BM, Ciullo M, Sanna S, Lehtimäki T, Wilson JF, Bandinelli S, Alonso A, Gasparini P, Jukema WJ, Kääb S, Gudnason V, Felix SB, Heckbert SR, de Boer RA, Newton-Cheh C, Hicks AA, Chambers JC, Jamshidi Y, Visel A, Christoffels VM, Isaacs A, Samani NJ, de Bakker PIW. 52 Genetic Loci Influencing Myocardial Mass. J Am Coll Cardiol 2016;68(13):1435-1448.Abstract
BACKGROUND: Myocardial mass is a key determinant of cardiac muscle function and hypertrophy. Myocardial depolarization leading to cardiac muscle contraction is reflected by the amplitude and duration of the QRS complex on the electrocardiogram (ECG). Abnormal QRS amplitude or duration reflect changes in myocardial mass and conduction, and are associated with increased risk of heart failure and death. OBJECTIVES: This meta-analysis sought to gain insights into the genetic determinants of myocardial mass. METHODS: We carried out a genome-wide association meta-analysis of 4 QRS traits in up to 73,518 individuals of European ancestry, followed by extensive biological and functional assessment. RESULTS: We identified 52 genomic loci, of which 32 are novel, that are reliably associated with 1 or more QRS phenotypes at p < 1 × 10(-8). These loci are enriched in regions of open chromatin, histone modifications, and transcription factor binding, suggesting that they represent regions of the genome that are actively transcribed in the human heart. Pathway analyses provided evidence that these loci play a role in cardiac hypertrophy. We further highlighted 67 candidate genes at the identified loci that are preferentially expressed in cardiac tissue and associated with cardiac abnormalities in Drosophila melanogaster and Mus musculus. We validated the regulatory function of a novel variant in the SCN5A/SCN10A locus in vitro and in vivo. CONCLUSIONS: Taken together, our findings provide new insights into genes and biological pathways controlling myocardial mass and may help identify novel therapeutic targets.
Ellinghaus D, Jostins L, Spain SL, Cortes A, Bethune J, Han B, Park YR, Raychaudhuri S, Pouget JG, Hübenthal M, Folseraas T, Wang Y, Esko T, Metspalu A, Westra H-J, Franke L, Pers TH, Weersma RK, Collij V, D'Amato M, Halfvarson J, Jensen AB, Lieb W, Degenhardt F, Forstner AJ, Hofmann A, Schreiber S, Mrowietz U, Juran BD, Lazaridis KN, Brunak S, Dale AM, Trembath RC, Weidinger S, Weichenthal M, Ellinghaus E, Elder JT, Barker JNWN, Andreassen OA, McGovern DP, Karlsen TH, Barrett JC, Parkes M, Brown MA, Franke A. Analysis of five chronic inflammatory diseases identifies 27 new associations and highlights disease-specific patterns at shared loci. Nat Genet 2016;48(5):510-8.Abstract
We simultaneously investigated the genetic landscape of ankylosing spondylitis, Crohn's disease, psoriasis, primary sclerosing cholangitis and ulcerative colitis to investigate pleiotropy and the relationship between these clinically related diseases. Using high-density genotype data from more than 86,000 individuals of European ancestry, we identified 244 independent multidisease signals, including 27 new genome-wide significant susceptibility loci and 3 unreported shared risk loci. Complex pleiotropy was supported when contrasting multidisease signals with expression data sets from human, rat and mouse together with epigenetic and expressed enhancer profiles. The comorbidities among the five immune diseases were best explained by biological pleiotropy rather than heterogeneity (a subgroup of cases genetically identical to those with another disease, possibly owing to diagnostic misclassification, molecular subtypes or excessive comorbidity). In particular, the strong comorbidity between primary sclerosing cholangitis and inflammatory bowel disease is likely the result of a unique disease, which is genetically distinct from classical inflammatory bowel disease phenotypes.
Okada Y, Suzuki A, Ikari K, Terao C, Kochi Y, Ohmura K, Higasa K, Akiyama M, Ashikawa K, Kanai M, Hirata J, Suita N, Teo Y-Y, Xu H, Bae S-C, Takahashi A, Momozawa Y, Matsuda K, Momohara S, Taniguchi A, Yamada R, Mimori T, Kubo M, Brown MA, Raychaudhuri S, Matsuda F, Yamanaka H, Kamatani Y, Yamamoto K. Contribution of a Non-classical HLA Gene, HLA-DOA, to the Risk of Rheumatoid Arthritis. Am J Hum Genet 2016;99(2):366-74.Abstract
Despite the progress in human leukocyte antigen (HLA) causal variant mapping, independent localization of major histocompatibility complex (MHC) risk from classical HLA genes is challenging. Here, we conducted a large-scale MHC fine-mapping analysis of rheumatoid arthritis (RA) in a Japanese population (6,244 RA cases and 23,731 controls) population by using HLA imputation, followed by a multi-ethnic validation study including east Asian and European populations (n = 7,097 and 23,149, respectively). Our study identified an independent risk of a synonymous mutation at HLA-DOA, a non-classical HLA gene, on anti-citrullinated protein autoantibody (ACPA)-positive RA risk (p = 1.4 × 10(-9)), which demonstrated a cis-expression quantitative trait loci (cis-eQTL) effect on HLA-DOA expression. Trans-ethnic comparison revealed different linkage disequilibrium (LD) patterns in HLA-DOA and HLA-DRB1, explaining the observed HLA-DOA variant risk heterogeneity among ethnicities, which was most evident in the Japanese population. Although previous HLA fine-mapping studies have identified amino acid polymorphisms of the classical HLA genes as driving genetic susceptibility to disease, our study additionally identifies the dosage contribution of a non-classical HLA gene to disease etiology. Our study contributes to the understanding of HLA immunology in human diseases and suggests the value of incorporating additional ancestry in MHC fine-mapping.
Hinks A, Bowes J, Cobb J, Ainsworth HC, Marion MC, Comeau ME, Sudman M, Han B, Becker ML, Bohnsack JF, de Bakker PIW, Haas JP, Hazen M, Lovell DJ, Nigrovic PA, Nordal E, Punnaro M, Rosenberg AM, Rygg M, Smith SL, Wise CA, Videm V, Wedderburn LR, Yarwood A, Yeung RSM, Prahalad S, Langefeld CD, Raychaudhuri S, Thompson SD, Thomson W. Fine-mapping the MHC locus in juvenile idiopathic arthritis (JIA) reveals genetic heterogeneity corresponding to distinct adult inflammatory arthritic diseases. Ann Rheum Dis 2016;76(4):765-772.Abstract
OBJECTIVES: Juvenile idiopathic arthritis (JIA) is a heterogeneous group of diseases, comprising seven categories. Genetic data could potentially be used to help redefine JIA categories and improve the current classification system. The human leucocyte antigen (HLA) region is strongly associated with JIA. Fine-mapping of the region was performed to look for similarities and differences in HLA associations between the JIA categories and define correspondences with adult inflammatory arthritides. METHODS: Dense genotype data from the HLA region, from the Immunochip array for 5043 JIA cases and 14 390 controls, were used to impute single-nucleotide polymorphisms, HLA classical alleles and amino acids. Bivariate analysis was performed to investigate genetic correlation between the JIA categories. Conditional analysis was used to identify additional effects within the region. Comparison of the findings with those in adult inflammatory arthritic diseases was performed. RESULTS: We identified category-specific associations and have demonstrated for the first time that rheumatoid factor (RF)-negative polyarticular JIA and oligoarticular JIA are genetically similar in their HLA associations. We also observe that each JIA category potentially has an adult counterpart. The RF-positive polyarthritis association at HLA-DRB1 amino acid at position 13 mirrors the association in adult seropositive rheumatoid arthritis (RA). Interestingly, the combined oligoarthritis and RF-negative polyarthritis dataset shares the same association with adult seronegative RA. CONCLUSIONS: The findings suggest the value of using genetic data in helping to classify the categories of this heterogeneous disease. Mapping JIA categories to adult counterparts could enable shared knowledge of disease pathogenesis and aetiology and facilitate transition from paediatric to adult services.
Li Z, Xia Y, Feng L-N, Chen J-R, Li H-M, Cui J, Cai Q-Q, Sim KS, Nairismägi M-L, Laurensia Y, Meah WY, Liu W-S, Guo Y-M, Chen L-Z, Feng Q-S, Pang CP, Chen LJ, Chew SH, Ebstein RP, Foo JN, Liu J, Ha J, Khoo LP, Chin ST, Zeng Y-X, Aung T, Chowbay B, Diong CP, Zhang F, Liu Y-H, Tang T, Tao M, Quek R, Mohamad F, Tan SY, Teh BT, Ng SB, Chng WJ, Ong CK, Okada Y, Raychaudhuri S, Lim ST, Tan W, Peng R-J, Khor CC, Bei J-X. Genetic risk of extranodal natural killer T-cell lymphoma: a genome-wide association study. Lancet Oncol 2016;17(9):1240-7.Abstract
BACKGROUND: Extranodal natural killer T-cell lymphoma (NKTCL), nasal type, is a rare and aggressive malignancy that occurs predominantly in Asian and Latin American populations. Although Epstein-Barr virus infection is a known risk factor, other risk factors and the pathogenesis of NKTCL are not well understood. We aimed to identify common genetic variants affecting individual risk of NKTCL. METHODS: We did a genome-wide association study of 189 patients with extranodal NKTCL, nasal type (WHO classification criteria; cases) and 957 controls from Guangdong province, southern China. We validated our findings in four independent case-control series, including 75 cases from Guangdong province and 296 controls from Hong Kong, 65 cases and 983 controls from Guangdong province, 125 cases and 1110 controls from Beijing (northern China), and 60 cases and 2476 controls from Singapore. We used imputation and conditional logistic regression analyses to fine-map the associations. We also did a meta-analysis of the replication series and of the entire dataset. FINDINGS: Associations exceeding the genome-wide significance threshold (p<5 × 10(-8)) were seen at 51 single-nucleotide polymorphisms (SNPs) mapping to the class II MHC region on chromosome 6, with rs9277378 (located in HLA-DPB1) having the strongest association with NKTCL susceptibility (p=4·21 × 10(-19), odds ratio [OR] 1·84 [95% CI 1·61-2·11] in meta-analysis of entire dataset). Imputation-based fine-mapping across the class II MHC region suggests that four aminoacid residues (Gly84-Gly85-Pro86-Met87) in near-complete linkage disequilibrium at the edge of the peptide-binding groove of HLA-DPB1 could account for most of the association between the rs9277378*A risk allele and NKTCL susceptibility (OR 2·38, p value for haplotype 2·32 × 10(-14)). This association is distinct from MHC associations with Epstein-Barr virus infection. INTERPRETATION: To our knowledge, this is the first time that a genetic variant conferring an NKTCL risk is noted at genome-wide significance. This finding underlines the importance of HLA-DP antigen presentation in the pathogenesis of NKTCL. FUNDING: Top-Notch Young Talents Program of China, Special Support Program of Guangdong, Specialized Research Fund for the Doctoral Program of Higher Education (20110171120099), Program for New Century Excellent Talents in University (NCET-11-0529), National Medical Research Council of Singapore (TCR12DEC005), Tanoto Foundation Professorship in Medical Oncology, New Century Foundation Limited, Ling Foundation, Singapore National Cancer Centre Research Fund, and the US National Institutes of Health (1R01AR062886, 5U01GM092691-04, and 1R01AR063759-01A1).
Prins BP, Abbasi A, Wong A, Vaez A, Nolte I, Franceschini N, Stuart PE, Guterriez Achury J, Mistry V, Bradfield JP, Valdes AM, Bras J, Shatunov A, Lu C, Han B, Raychaudhuri S, Bevan S, Mayes MD, Tsoi LC, Evangelou E, Nair RP, Grant SFA, Polychronakos C, Radstake TRD, van Heel DA, Dunstan ML, Wood NW, Al-Chalabi A, Dehghan A, Hakonarson H, Markus HS, Elder JT, Knight J, Arking DE, Spector TD, Koeleman BPC, van Duijn CM, Martin J, Morris AP, Weersma RK, Wijmenga C, Munroe PB, Perry JRB, Pouget JG, Jamshidi Y, Snieder H, Alizadeh BZ. Investigating the Causal Relationship of C-Reactive Protein with 32 Complex Somatic and Psychiatric Outcomes: A Large-Scale Cross-Consortium Mendelian Randomization Study. PLoS Med 2016;13(6):e1001976.Abstract
BACKGROUND: C-reactive protein (CRP) is associated with immune, cardiometabolic, and psychiatric traits and diseases. Yet it is inconclusive whether these associations are causal. METHODS AND FINDINGS: We performed Mendelian randomization (MR) analyses using two genetic risk scores (GRSs) as instrumental variables (IVs). The first GRS consisted of four single nucleotide polymorphisms (SNPs) in the CRP gene (GRSCRP), and the second consisted of 18 SNPs that were significantly associated with CRP levels in the largest genome-wide association study (GWAS) to date (GRSGWAS). To optimize power, we used summary statistics from GWAS consortia and tested the association of these two GRSs with 32 complex somatic and psychiatric outcomes, with up to 123,865 participants per outcome from populations of European ancestry. We performed heterogeneity tests to disentangle the pleiotropic effect of IVs. A Bonferroni-corrected significance level of less than 0.0016 was considered statistically significant. An observed p-value equal to or less than 0.05 was considered nominally significant evidence for a potential causal association, yet to be confirmed. The strengths (F-statistics) of the IVs were 31.92-3,761.29 and 82.32-9,403.21 for GRSCRP and GRSGWAS, respectively. CRP GRSGWAS showed a statistically significant protective relationship of a 10% genetically elevated CRP level with the risk of schizophrenia (odds ratio [OR] 0.86 [95% CI 0.79-0.94]; p < 0.001). We validated this finding with individual-level genotype data from the schizophrenia GWAS (OR 0.96 [95% CI 0.94-0.98]; p < 1.72 × 10-6). Further, we found that a standardized CRP polygenic risk score (CRPPRS) at p-value thresholds of 1 × 10-4, 0.001, 0.01, 0.05, and 0.1 using individual-level data also showed a protective effect (OR < 1.00) against schizophrenia; the first CRPPRS (built of SNPs with p < 1 × 10-4) showed a statistically significant (p < 2.45 × 10-4) protective effect with an OR of 0.97 (95% CI 0.95-0.99). The CRP GRSGWAS showed that a 10% increase in genetically determined CRP level was significantly associated with coronary artery disease (OR 0.88 [95% CI 0.84-0.94]; p < 2.4 × 10-5) and was nominally associated with the risk of inflammatory bowel disease (OR 0.85 [95% CI 0.74-0.98]; p < 0.03), Crohn disease (OR 0.81 [95% CI 0.70-0.94]; p < 0.005), psoriatic arthritis (OR 1.36 [95% CI 1.00-1.84]; p < 0.049), knee osteoarthritis (OR 1.17 [95% CI 1.01-1.36]; p < 0.04), and bipolar disorder (OR 1.21 [95% CI 1.05-1.40]; p < 0.007) and with an increase of 0.72 (95% CI 0.11-1.34; p < 0.02) mm Hg in systolic blood pressure, 0.45 (95% CI 0.06-0.84; p < 0.02) mm Hg in diastolic blood pressure, 0.01 ml/min/1.73 m2 (95% CI 0.003-0.02; p < 0.005) in estimated glomerular filtration rate from serum creatinine, 0.01 g/dl (95% CI 0.0004-0.02; p < 0.04) in serum albumin level, and 0.03 g/dl (95% CI 0.008-0.05; p < 0.009) in serum protein level. However, after adjustment for heterogeneity, neither GRS showed a significant effect of CRP level (at p < 0.0016) on any of these outcomes, including coronary artery disease, nor on the other 20 complex outcomes studied. Our study has two potential limitations: the limited variance explained by our genetic instruments modeling CRP levels in blood and the unobserved bias introduced by the use of summary statistics in our MR analyses. CONCLUSIONS: Genetically elevated CRP levels showed a significant potentially protective causal relationship with risk of schizophrenia. We observed nominal evidence at an observed p < 0.05 using either GRSCRP or GRSGWAS-with persistence after correction for heterogeneity-for a causal relationship of elevated CRP levels with psoriatic osteoarthritis, rheumatoid arthritis, knee osteoarthritis, systolic blood pressure, diastolic blood pressure, serum albumin, and bipolar disorder. These associations remain yet to be confirmed. We cannot verify any causal effect of CRP level on any of the other common somatic and neuropsychiatric outcomes investigated in the present study. This implies that interventions that lower CRP level are unlikely to result in decreased risk for the majority of common complex outcomes.
Wagner EK, Raychaudhuri S, Villalonga MB, Java A, Triebwasser MP, Daly MJ, Atkinson JP, Seddon JM. Mapping rare, deleterious mutations in Factor H: Association with early onset, drusen burden, and lower antigenic levels in familial AMD. Sci Rep 2016;6:31531.Abstract
The genetic architecture of age-related macular degeneration (AMD) involves numerous genetic variants, both common and rare, in the coding region of complement factor H (CFH). While these variants explain high disease burden in some families, they fail to explain the pathology in all. We selected families whose AMD was unexplained by known variants and performed whole exome sequencing to probe for other rare, highly penetrant variants. We identified four rare loss-of-function variants in CFH associated with AMD. Missense variant CFH 1:196646753 (C192F) segregated perfectly within a family characterized by advanced AMD and drusen temporal to the macula. Two families, each comprising a pair of affected siblings with extensive extramacular drusen, carried essential splice site variant CFH 1:196648924 (IVS6+1G>A) or missense variant rs139360826 (R175P). In a fourth family, missense variant rs121913058 (R127H) was associated with AMD. Most carriers had early onset bilateral advanced AMD and extramacular drusen. Carriers tended to have low serum Factor H levels, especially carriers of the splice variant. One missense variant (R127H) has been previously shown not to be secreted. The two other missense variants were produced recombinantly: compared to wild type, one (R175P) had no functional activity and the other (C192F) had decreased secretion.