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1.  Erratum: Crowdsourced assessment of common genetic contribution to predicting anti-TNF treatment response in rheumatoid arthritis 
Sieberts, Solveig K. | Zhu, Fan | García-García, Javier | Stahl, Eli | Pratap, Abhishek | Pandey, Gaurav | Pappas, Dimitrios | Aguilar, Daniel | Anton, Bernat | Bonet, Jaume | Eksi, Ridvan | Fornés, Oriol | Guney, Emre | Li, Hongdong | Marín, Manuel Alejandro | Panwar, Bharat | Planas-Iglesias, Joan | Poglayen, Daniel | Cui, Jing | Falcao, Andre O. | Suver, Christine | Hoff, Bruce | Balagurusamy, Venkat S. K. | Dillenberger, Donna | Neto, Elias Chaibub | Norman, Thea | Aittokallio, Tero | Ammad-ud-din, Muhammad | Azencott, Chloe-Agathe | Bellón, Víctor | Boeva, Valentina | Bunte, Kerstin | Chheda, Himanshu | Cheng, Lu | Corander, Jukka | Dumontier, Michel | Goldenberg, Anna | Gopalacharyulu, Peddinti | Hajiloo, Mohsen | Hidru, Daniel | Jaiswal, Alok | Kaski, Samuel | Khalfaoui, Beyrem | Khan, Suleiman Ali | Kramer, Eric R. | Marttinen, Pekka | Mezlini, Aziz M. | Molparia, Bhuvan | Pirinen, Matti | Saarela, Janna | Samwald, Matthias | Stoven, Véronique | Tang, Hao | Tang, Jing | Torkamani, Ali | Vert, Jean-Phillipe | Wang, Bo | Wang, Tao | Wennerberg, Krister | Wineinger, Nathan E. | Xiao, Guanghua | Xie, Yang | Yeung, Rae | Zhan, Xiaowei | Zhao, Cheng | Greenberg, Jeff | Kremer, Joel | Michaud, Kaleb | Barton, Anne | Coenen, Marieke | Mariette, Xavier | Miceli, Corinne | Shadick, Nancy | Weinblatt, Michael | de Vries, Niek | Tak, Paul P. | Gerlag, Danielle | Huizinga, Tom W. J. | Kurreeman, Fina | Allaart, Cornelia F. | Bridges Jr., S. Louis | Criswell, Lindsey | Moreland, Larry | Klareskog, Lars | Saevarsdottir, Saedis | Padyukov, Leonid | Gregersen, Peter K. | Friend, Stephen | Plenge, Robert | Stolovitzky, Gustavo | Oliva, Baldo | Guan, Yuanfang | Mangravite, Lara M.
Nature Communications  2016;7:13205.
doi:10.1038/ncomms13205
PMCID: PMC5062501  PMID: 27721464
2.  A method to decipher pleiotropy by detecting underlying heterogeneity driven by hidden subgroups applied to autoimmune and neuropsychiatric diseases 
Nature genetics  2016;48(7):803-810.
There is growing evidence of shared risk alleles between complex traits (pleiotropy), including autoimmune and neuropsychiatric diseases. This might be due to sharing between all individuals (whole-group pleiotropy), or a subset of individuals within a genetically heterogeneous cohort (subgroup heterogeneity). BUHMBOX is a well-powered statistic distinguishing between these two situations using genotype data. We observed a shared genetic basis between 11 autoimmune diseases and type 1 diabetes (T1D, p<10−4), and 11 autoimmune diseases and rheumatoid arthritis (RA, p<10−3). This sharing was not explained by subgroup heterogeneity (corrected pBUHMBOX>0.2, 6,670 T1D cases and 7,279 RA cases). Genetic sharing between seronegative and seropostive RA (p<10−9) had significant evidence of subgroup heterogeneity, suggesting a subgroup of seropositive-like cases within seronegative cases (pBUHMBOX=0.008, 2,406 seronegative RA cases). We also observed a shared genetic basis between major depressive disorder (MDD) and schizophrenia (p<10−4) that was not explained by subgroup heterogeneity (pBUHMBOX=0.28 in 9,238 MDD cases).
doi:10.1038/ng.3572
PMCID: PMC4925284  PMID: 27182969
3.  Molecular signatures in systemic lupus erythematosus: distinction between disease flare and infection 
Lupus Science & Medicine  2016;3(1):e000159.
doi:10.1136/lupus-2016-000159
PMCID: PMC5133406  PMID: 27933197
Systemic Lupus Erythematosus; infection; interferon signature; flare; gene expression
4.  New data and an old puzzle: the negative association between schizophrenia and rheumatoid arthritis 
Lee, S Hong | Byrne, Enda M | Hultman, Christina M | Kähler, Anna | Vinkhuyzen, Anna AE | Ripke, Stephan | Andreassen, Ole A | Frisell, Thomas | Gusev, Alexander | Hu, Xinli | Karlsson, Robert | Mantzioris, Vasilis X | McGrath, John J | Mehta, Divya | Stahl, Eli A | Zhao, Qiongyi | Kendler, Kenneth S | Sullivan, Patrick F | Price, Alkes L | O’Donovan, Michael | Okada, Yukinori | Mowry, Bryan J | Raychaudhuri, Soumya | Wray, Naomi R | Byerley, William | Cahn, Wiepke | Cantor, Rita M | Cichon, Sven | Cormican, Paul | Curtis, David | Djurovic, Srdjan | Escott-Price, Valentina | Gejman, Pablo V | Georgieva, Lyudmila | Giegling, Ina | Hansen, Thomas F | Ingason, Andrés | Kim, Yunjung | Konte, Bettina | Lee, Phil H | McIntosh, Andrew | McQuillin, Andrew | Morris, Derek W | Nöthen, Markus M | O’Dushlaine, Colm | Olincy, Ann | Olsen, Line | Pato, Carlos N | Pato, Michele T | Pickard, Benjamin S | Posthuma, Danielle | Rasmussen, Henrik B | Rietschel, Marcella | Rujescu, Dan | Schulze, Thomas G | Silverman, Jeremy M | Thirumalai, Srinivasa | Werge, Thomas | Agartz, Ingrid | Amin, Farooq | Azevedo, Maria H | Bass, Nicholas | Black, Donald W | Blackwood, Douglas H R | Bruggeman, Richard | Buccola, Nancy G | Choudhury, Khalid | Cloninger, Robert C | Corvin, Aiden | Craddock, Nicholas | Daly, Mark J | Datta, Susmita | Donohoe, Gary J | Duan, Jubao | Dudbridge, Frank | Fanous, Ayman | Freedman, Robert | Freimer, Nelson B | Friedl, Marion | Gill, Michael | Gurling, Hugh | De Haan, Lieuwe | Hamshere, Marian L | Hartmann, Annette M | Holmans, Peter A | Kahn, René S | Keller, Matthew C | Kenny, Elaine | Kirov, George K | Krabbendam, Lydia | Krasucki, Robert | Lawrence, Jacob | Lencz, Todd | Levinson, Douglas F | Lieberman, Jeffrey A | Lin, Dan-Yu | Linszen, Don H | Magnusson, Patrik KE | Maier, Wolfgang | Malhotra, Anil K | Mattheisen, Manuel | Mattingsdal, Morten | McCarroll, Steven A | Medeiros, Helena | Melle, Ingrid | Milanova, Vihra | Myin-Germeys, Inez | Neale, Benjamin M | Ophoff, Roel A | Owen, Michael J | Pimm, Jonathan | Purcell, Shaun M | Puri, Vinay | Quested, Digby J | Rossin, Lizzy | Ruderfer, Douglas | Sanders, Alan R | Shi, Jianxin | Sklar, Pamela | St. Clair, David | Stroup, T Scott | Van Os, Jim | Visscher, Peter M | Wiersma, Durk | Zammit, Stanley | Bridges, S Louis | Choi, Hyon K | Coenen, Marieke JH | de Vries, Niek | Dieud, Philippe | Greenberg, Jeffrey D | Huizinga, Tom WJ | Padyukov, Leonid | Siminovitch, Katherine A | Tak, Paul P | Worthington, Jane | De Jager, Philip L | Denny, Joshua C | Gregersen, Peter K | Klareskog, Lars | Mariette, Xavier | Plenge, Robert M | van Laar, Mart | van Riel, Piet
Background: A long-standing epidemiological puzzle is the reduced rate of rheumatoid arthritis (RA) in those with schizophrenia (SZ) and vice versa. Traditional epidemiological approaches to determine if this negative association is underpinned by genetic factors would test for reduced rates of one disorder in relatives of the other, but sufficiently powered data sets are difficult to achieve. The genomics era presents an alternative paradigm for investigating the genetic relationship between two uncommon disorders.
Methods: We use genome-wide common single nucleotide polymorphism (SNP) data from independently collected SZ and RA case-control cohorts to estimate the SNP correlation between the disorders. We test a genotype X environment (GxE) hypothesis for SZ with environment defined as winter- vs summer-born.
Results: We estimate a small but significant negative SNP-genetic correlation between SZ and RA (−0.046, s.e. 0.026, P = 0.036). The negative correlation was stronger for the SNP set attributed to coding or regulatory regions (−0.174, s.e. 0.071, P = 0.0075). Our analyses led us to hypothesize a gene-environment interaction for SZ in the form of immune challenge. We used month of birth as a proxy for environmental immune challenge and estimated the genetic correlation between winter-born and non-winter born SZ to be significantly less than 1 for coding/regulatory region SNPs (0.56, s.e. 0.14, P  = 0.00090).
Conclusions: Our results are consistent with epidemiological observations of a negative relationship between SZ and RA reflecting, at least in part, genetic factors. Results of the month of birth analysis are consistent with pleiotropic effects of genetic variants dependent on environmental context.
doi:10.1093/ije/dyv136
PMCID: PMC4881824  PMID: 26286434
Schizophrenia; rheumatoid arthritis; genetic relationship; pleiotropy
5.  Crowdsourced assessment of common genetic contribution to predicting anti-TNF treatment response in rheumatoid arthritis 
Sieberts, Solveig K. | Zhu, Fan | García-García, Javier | Stahl, Eli | Pratap, Abhishek | Pandey, Gaurav | Pappas, Dimitrios | Aguilar, Daniel | Anton, Bernat | Bonet, Jaume | Eksi, Ridvan | Fornés, Oriol | Guney, Emre | Li, Hongdong | Marín, Manuel Alejandro | Panwar, Bharat | Planas-Iglesias, Joan | Poglayen, Daniel | Cui, Jing | Falcao, Andre O. | Suver, Christine | Hoff, Bruce | Balagurusamy, Venkat S. K. | Dillenberger, Donna | Neto, Elias Chaibub | Norman, Thea | Aittokallio, Tero | Ammad-ud-din, Muhammad | Azencott, Chloe-Agathe | Bellón, Víctor | Boeva, Valentina | Bunte, Kerstin | Chheda, Himanshu | Cheng, Lu | Corander, Jukka | Dumontier, Michel | Goldenberg, Anna | Gopalacharyulu, Peddinti | Hajiloo, Mohsen | Hidru, Daniel | Jaiswal, Alok | Kaski, Samuel | Khalfaoui, Beyrem | Khan, Suleiman Ali | Kramer, Eric R. | Marttinen, Pekka | Mezlini, Aziz M. | Molparia, Bhuvan | Pirinen, Matti | Saarela, Janna | Samwald, Matthias | Stoven, Véronique | Tang, Hao | Tang, Jing | Torkamani, Ali | Vert, Jean-Phillipe | Wang, Bo | Wang, Tao | Wennerberg, Krister | Wineinger, Nathan E. | Xiao, Guanghua | Xie, Yang | Yeung, Rae | Zhan, Xiaowei | Zhao, Cheng | Greenberg, Jeff | Kremer, Joel | Michaud, Kaleb | Barton, Anne | Coenen, Marieke | Mariette, Xavier | Miceli, Corinne | Shadick, Nancy | Weinblatt, Michael | de Vries, Niek | Tak, Paul P. | Gerlag, Danielle | Huizinga, Tom W. J. | Kurreeman, Fina | Allaart, Cornelia F. | Louis Bridges Jr., S. | Criswell, Lindsey | Moreland, Larry | Klareskog, Lars | Saevarsdottir, Saedis | Padyukov, Leonid | Gregersen, Peter K. | Friend, Stephen | Plenge, Robert | Stolovitzky, Gustavo | Oliva, Baldo | Guan, Yuanfang | Mangravite, Lara M.
Nature Communications  2016;7:12460.
Rheumatoid arthritis (RA) affects millions world-wide. While anti-TNF treatment is widely used to reduce disease progression, treatment fails in ∼one-third of patients. No biomarker currently exists that identifies non-responders before treatment. A rigorous community-based assessment of the utility of SNP data for predicting anti-TNF treatment efficacy in RA patients was performed in the context of a DREAM Challenge (http://www.synapse.org/RA_Challenge). An open challenge framework enabled the comparative evaluation of predictions developed by 73 research groups using the most comprehensive available data and covering a wide range of state-of-the-art modelling methodologies. Despite a significant genetic heritability estimate of treatment non-response trait (h2=0.18, P value=0.02), no significant genetic contribution to prediction accuracy is observed. Results formally confirm the expectations of the rheumatology community that SNP information does not significantly improve predictive performance relative to standard clinical traits, thereby justifying a refocusing of future efforts on collection of other data.
Rheumatoid arthritis patients respond differently to anti-TNF treatment. Using community-based challenge, the authors show that currently available data does not reveal meaningful genetic predictors of response to anti-TNF therapy, thus confirming clinical observations.
doi:10.1038/ncomms12460
PMCID: PMC4996969  PMID: 27549343
6.  GWAS implicates a role for quantitative immune traits and threshold effects in risk for human autoimmune disorders 
Current opinion in immunology  2012;24(5):538-543.
Genome wide association studies in human autoimmune disorders has provided a long list of alleles with rather modest degrees of risk. A large fraction of these associations are likely due to either quantitative differences in gene expression or amino acid changes that regulate quantitative aspects of the immune response. While functional studies are still lacking for most of these associations, we present examples of autoimmune disease risk alleles that influence quantitative changes in lymphocyte activation, cytokine signaling and dendritic cell function. The analysis of immune quantitative traits associated with autoimmune loci is clearly going to be an important component of understanding the pathogenesis of autoimmunity. This will require both new and more efficient ways of characterizing the normal immune system, as well as large population resources with which genotype-phenotype correlations can be convincingly demonstrated. Future development of new therapies will depend on understanding the mechanistic underpinnings of immune regulation by these new risk loci.
doi:10.1016/j.coi.2012.09.003
PMCID: PMC4758732  PMID: 23026397
7.  Double-Blind Randomized Placebo-Controlled Trial of the Effect of Vitamin D3 on the Interferon Signature in Patients with Systemic Lupus Erythematosus 
Objective
Vitamin D modulates the immune response and blocks induction of an interferon signature by SLE sera. We investigated the effects of vitamin D supplementation on the IFN signature in SLE patients.
Methods
57 SLE patients with stable, inactive disease, a serum 25OH vitamin D (25OHD) ≤20ng/ml, elevated anti-DNA antibodies and an IFN signature (determined by measurement of 3 interferon responsive genes) were randomized into a 12 week double-blind placebo controlled trial of 0, 2000IU or 4000IU of vitamin D3. An IFN signature response required a 50% reduction in expression of 1 gene or a 25% decrease in 2 genes. Disease activity, adverse events and endocrine effects were assessed.
Results
Baseline characteristics of the 3 treatment groups were similar. No subjects receiving placebo repleted (achieved 25OHD levels ≥30ng/ml) compared to 16 of 33 subjects receiving vitamin D3. The percent of subjects achieving an IFN signature response did not differ between treatment groups. Moreover, there was no difference in the IFN signature response in vitamin D deficient versus repleted subjects. Modular microarray analysis of a subset (n=40) revealed no changes in any modules including the IFN-inducible module between any treatment group, nor when comparing expression data from vitamin D repleted to persistently deficient subjects. Vitamin D3 was well-tolerated with no safety concerns.
Conclusions
Vitamin D3 supplementation up to 4000IU daily was safe and well-tolerated but failed to diminish the IFN signature in vitamin D deficient SLE patients. Higher 25OHD levels sustained for longer duration may be required to affect immunological outcomes.
doi:10.1002/art.39108
PMCID: PMC4732716  PMID: 25777546
Vitamin D3; SLE; interferon signature
8.  Modular Analysis of Peripheral Blood Gene Expression in Rheumatoid Arthritis Captures Reproducible Gene Expression Changes in TNF Responders 
Objective
To establish whether the analysis of whole blood gene expression can be useful in predicting or monitoring response to anti-TNF therapy in RA.
Methods
Whole blood RNA (PAXgene) was obtained at baseline and 14 weeks on three independent cohorts with a combined total of 250 patients with rheumatoid arthritis beginning anti-TNF therapy. We employed an approach to gene expression analysis that is based on gene expression “modules”.
Results
Good and Moderate Responders by EULAR criteria exhibited highly significant and consistent changes in multiple gene expression modules using a hyper geometric analysis after 14 weeks of therapy. Strikingly, non responders exhibited very little change in any modules, despite exposure to TNF blockade. These patterns of change were highly consistent across all three cohorts, indicating that immunological changes after TNF treatment are specific to the combination of both drug exposure and responder status. In contrast, modular patterns of gene expression did not exhibit consistent differences between responders and non-responders at baseline in the three cohorts.
Conclusions
These data provide evidence that using gene expression modules related to inflammatory disease may provide a valuable method for objective monitoring of the response of RA patients who are treated with TNF inhibitors.
doi:10.1002/art.38947
PMCID: PMC4476407  PMID: 25371395
9.  Genome-wide Association Study Identifies HLA 8.1 Ancestral Haplotype Alleles as Major Genetic Risk Factors for Myositis Phenotypes 
Genes and immunity  2015;16(7):470-480.
Autoimmune muscle diseases (myositis) comprise a group of complex phenotypes influenced by genetic and environmental factors. To identify genetic risk factors in patients of European ancestry, we conducted a genome-wide association study (GWAS) of the major myositis phenotypes in a total of 1710 cases, which included 705 adult dermatomyositis; 473 juvenile dermatomyositis; 532 polymyositis; and 202 adult dermatomyositis, juvenile dermatomyositis or polymyositis patients with anti-histidyl tRNA synthetase (anti-Jo-1) autoantibodies, and compared them with 4724 controls. Single-nucleotide polymorphisms showing strong associations (P < 5 × 10−8) in GWAS were identified in the major histocompatibility complex (MHC) region for all myositis phenotypes together, as well as for the four clinical and autoantibody phenotypes studied separately. Imputation and regression analyses found that alleles comprising the human leukocyte antigen (HLA) 8.1 ancestral haplotype (AH8.1) defined essentially all the genetic risk in the phenotypes studied. Although the HLA DRB1*03:01 allele showed slightly stronger associations with adult and juvenile dermatomyositis, and HLA B*08:01 with polymyositis and anti-Jo-1 autoantibody-positive myositis, multiple alleles of AH8.1 were required for the full risk effects. Our findings establish that alleles of the AH8.1haplotype comprise the primary genetic risk factors associated with the major myositis phenotypes in geographically diverse Caucasian populations.
doi:10.1038/gene.2015.28
PMCID: PMC4840953  PMID: 26291516
polymyositis; dermatomyositis; adult; juvenile; anti-Jo-1 autoantibodies; HLA 8.1 ancestral haplotype
10.  Widespread non-additive and interaction effects within HLA loci modulate the risk of autoimmune diseases 
Nature genetics  2015;47(9):1085-1090.
Human leukocyte antigen (HLA) genes confer strong risk for autoimmune diseases on a log-additive scale. Here we speculated that differences in autoantigen binding repertoires between a heterozygote’s two expressed HLA variants may result in additional non-additive risk effects. We tested non-additive disease contributions of classical HLA alleles in patients and matched controls for five common autoimmune diseases: rheumatoid arthritis (RA, Ncases=5,337), type 1 diabetes (T1D, Ncases=5,567), psoriasis vulgaris (Ncases=3,089), idiopathic achalasia (Ncases=727), and celiac disease (Ncases=11,115). In four out of five diseases, we observed highly significant non-additive dominance effects (RA: P=2.5×1012; T1D: P=2.4×10−10; psoriasis: P=5.9×10−6; celiac disease: P=1.2×10−87). In three of these diseases, the dominance effects were explained by interactions between specific classical HLA alleles (RA: P=1.8×10−3; T1D: P=8.6×1027; celiac disease: P=6.0×10−100). These interactions generally increased disease risk and explained moderate but significant fractions of phenotypic variance (RA: 1.4%, T1D: 4.0%, and celiac disease: 4.1%, beyond a simple additive model).
doi:10.1038/ng.3379
PMCID: PMC4552599  PMID: 26258845
Autoimmunity; complex diseases; MHC; HLA; genetic architecture; non-additive effects; interactions
11.  HLA-DRB1 rheumatoid arthritis risk in African Americans at multiple levels: Hierarchical classification systems, amino acid positions and residues 
Objective
To evaluate African American rheumatoid arthritis HLA-DRB1 genetic risk by three validated allele classification systems, and by amino acid position and residue. To compare the genetic risk between African American and European ancestries.
Methods
Four-digit HLA-DRB1 genotyping was performed on 561 autoantibody-positive African American cases and 776 African American controls. Association analysis was performed on Tezenas du Montcel (TdM); de Vries (DV); and Mattey classification system alleles and separately by amino acid position and individual residues.
Results
TdM S2 and S3P alleles were associated with RA (odds ratios (95% CI) 2.8 (2.0, 3.9) and 2.1 (1.7, 2.7), respectively). The DV (P-value=3.2 x 10−12) and Mattey (P-value=6.5 x 10−13) system alleles were both protective in African Americans. Amino acid position 11 (permutation P-value < 0.00001) accounted for nearly all variability explained by HLA-DRB1, although conditional analysis demonstrated that position 57 was also significant (0.01<= permutation P-val <=0.05). The valine and aspartic acid residues at position 11 conferred the highest risk for RA in African Americans.
Conclusion
With some exceptions, the genetic risk conferred by HLA-DRB1 in African Americans is similar to European ancestry at multiple levels: classification system (e.g., TdM), amino acid position (e.g. 11) and residue (Val 11). Unlike that reported from European ancestry, amino acid position 57 was associated with RA in African Americans, but positions 71 and 74 were not. Asp11 (OR = 1 in European ancestry) corresponds to the four digit classical allele, *09:01, also a risk allele for RA in Koreans.
doi:10.1002/art.38855
PMCID: PMC4273668  PMID: 25524867
12.  A role for non-coding variation in schizophrenia 
Cell reports  2014;9(4):1417-1429.
SUMMARY
A large portion of common variant loci associated with genetic risk for schizophrenia reside within non-coding sequence of unknown function. Here, we demonstrate promoter and enhancer enrichment in schizophrenia variants associated with expression quantitative trait loci (eQTL). The enrichment is greater when functional annotations derived from human brain are used relative to peripheral tissues. Regulatory trait concordance analysis ranked genes within schizophrenia genome-wide significant loci for a potential functional role, based on co-localization of a risk SNP, eQTL and regulatory element sequence. We identified potential physical interactions of non-contiguous proximal and distal regulatory elements. This was verified in prefrontal cortex and induced pluripotent stem cell-derived neurons for the L-type calcium channel (CACNA1C) risk locus. Our findings point to a functional link between schizophrenia-associated non-coding SNPs and 3-dimensional genome architecture associated with chromosomal loopings and transcriptional regulation in the brain.
doi:10.1016/j.celrep.2014.10.015
PMCID: PMC4255904  PMID: 25453756
13.  Genome-Wide Association Study of Late-Onset Myasthenia Gravis: Confirmation of TNFRSF11A and Identification of ZBTB10 and Three Distinct HLA Associations 
Molecular Medicine  2015;21(1):769-781.
To investigate the genetics of late-onset myasthenia gravis (LOMG), we conducted a genome-wide association study imputation of >6 million single nucleotide polymorphisms (SNPs) in 532 LOMG cases (anti–acetylcholine receptor [AChR] antibody positive; onset age ≥50 years) and 2,128 controls matched for sex and population substructure. The data confirm reported TNFRSF11A associations (rs4574025, P = 3.9 × 10−7, odds ratio [OR] 1.42) and identify a novel candidate gene, ZBTB10, achieving genome-wide significance (rs6998967, P = 8.9 × 10−10, OR 0.53). Several other SNPs showed suggestive significance including rs2476601 (P = 6.5 × 10−6, OR 1.62) encoding the PTPN22 R620W variant noted in early-onset myasthenia gravis (EOMG) and other autoimmune diseases. In contrast, EOMG-associated SNPs in TNIP1 showed no association in LOMG, nor did other loci suggested for EOMG. Many SNPs within the major histocompatibility complex (MHC) region showed strong associations in LOMG, but with smaller effect sizes than in EOMG (highest OR ~2 versus ~6 in EOMG). Moreover, the strongest associations were in opposite directions from EOMG, including an OR of 0.54 for DQA1*05:01 in LOMG (P = 5.9 × 10−12) versus 2.82 in EOMG (P = 3.86 × 10−45). Association and conditioning studies for the MHC region showed three distinct and largely independent association peaks for LOMG corresponding to (a) MHC class II (highest attenuation when conditioning on DQA1), (b) HLA-A and (c) MHC class III SNPs. Conditioning studies of human leukocyte antigen (HLA) amino acid residues also suggest potential functional correlates. Together, these findings emphasize the value of subgrouping myasthenia gravis patients for clinical and basic investigations and imply distinct predisposing mechanisms in LOMG.
doi:10.2119/molmed.2015.00232
PMCID: PMC4749491  PMID: 26562150
14.  Studies on ageing and the severity of radiographic joint damage in rheumatoid arthritis 
Introduction
The western population is ageing. It is unknown whether age at diagnosis affects the severity of Rheumatoid Arthritis (RA), we therefore performed the present study.
Method
1,875 RA-patients (7,219 radiographs) included in five European and North-American cohorts (Leiden-EAC, Wichita, Umeå, Groningen and Lund) were studied on associations between age at diagnosis and joint damage severity. In 698 Leiden RA-patients with 7-years follow-up it was explored if symptom duration, anti-citrullinated-peptide-antibodies (ACPA), swollen joint count (SJC) and C-reactive-protein (CRP) mediated the association of age with joint damage. Fifty-six other RA-patients of the EAC-cohort underwent baseline MRIs of wrist, MCP and MTP-joints; MRI-inflammation (RAMRIS-synovitis plus bone marrow edema) was also evaluated in mediation analyses. Linear regression and multivariate normal regression models were used.
Results
Analysis on the five cohorts and the Leiden-EAC separately revealed 1.026-fold and 1.034-fold increase of radiographic joint damage per year increase in age (β=1.026, 1.034, both p<0.001); this effect was present at baseline and persisted over time. Age correlated stronger with baseline erosion-scores compared to joint space narrowing (JSN)-scores (r=0.38 versus 0.29). Symptom duration, ACPA, SJC and CRP did not mediate the association of age with joint damage severity. Age was significantly associated with the MRI-inflammation-score after adjusting for CRP and SJC (β=1.018, p=0.027). The association of age with joint damage (β=1.032, p=0.004) decreased after also including the MRI-inflammation-score (β=1.025, p=0.021), suggesting partial mediation.
Conclusion
RA-patients presenting at higher age have more severe joint damage; this might be partially explained by more severe MRI-detected inflammation at higher age.
Electronic supplementary material
The online version of this article (doi:10.1186/s13075-015-0740-0) contains supplementary material, which is available to authorized users.
doi:10.1186/s13075-015-0740-0
PMCID: PMC4547419  PMID: 26299443
15.  Genome-wide meta-analysis in alopecia areata resolves HLA associations and reveals two new susceptibility loci 
Nature communications  2015;6:5966.
Alopecia areata (AA) is a prevalent autoimmune disease with ten known susceptibility loci. Here we perform the first meta-analysis in AA by combining data from two genome-wide association studies (GWAS), and replication with supplemented ImmunoChip data for a total of 3,253 cases and 7,543 controls. The strongest region of association is the MHC, where we fine-map 4 independent effects, all implicating HLA-DR as a key etiologic driver. Outside the MHC, we identify two novel loci that exceed statistical significance, containing ACOXL/BCL2L11(BIM) (2q13); GARP (LRRC32) (11q13.5), as well as a third nominally significant region SH2B3(LNK)/ATXN2 (12q24.12). Candidate susceptibility gene expression analysis in these regions demonstrates expression in relevant immune cells and the hair follicle. We integrate our results with data from seven other autoimmune diseases and provide insight into the alignment of AA within these disorders. Our findings uncover new molecular pathways disrupted in AA, including autophagy/apoptosis, TGFß/Tregs and JAK kinase signaling, and support the causal role of aberrant immune processes in AA.
doi:10.1038/ncomms6966
PMCID: PMC4451186  PMID: 25608926
16.  Absolute pitch exhibits phenotypic and genetic overlap with synesthesia 
Human Molecular Genetics  2013;22(10):2097-2104.
Absolute pitch (AP) and synesthesia are two uncommon cognitive traits that reflect increased neuronal connectivity and have been anecdotally reported to occur together in an individual. Here we systematically evaluate the occurrence of synesthesia in a population of 768 subjects with documented AP. Out of these 768 subjects, 151 (20.1%) reported synesthesia, most commonly with color. These self-reports of synesthesia were validated in a subset of 21 study subjects, using an established methodology. We further carried out combined linkage analysis of 53 multiplex families with AP and 36 multiplex families with synesthesia. We observed a peak NPL LOD = 4.68 on chromosome 6q, as well as evidence of linkage on chromosome 2, using a dominant model. These data establish the close phenotypic and genetic relationship between AP and synesthesia. The chromosome 6 linkage region contains 73 genes; several leading candidate genes involved in neurodevelopment were investigated by exon resequencing. However, further studies will be required to definitively establish the identity of the causative gene(s) in the region.
doi:10.1093/hmg/ddt059
PMCID: PMC4707203  PMID: 23406871
17.  High-Density Genotyping of Immune Loci in Koreans and Europeans Identifies Eight New Rheumatoid Arthritis Risk Loci 
Objective
A highly polygenic etiology and high degree of allele-sharing between ancestries have been well-elucidated in genetic studies of rheumatoid arthritis. Recently, the high-density genotyping array Immunochip for immune disease loci identified 14 new rheumatoid arthritis risk loci among individuals of European ancestry. Here, we aimed to identify new rheumatoid arthritis risk loci using Korean-specific Immunochip data.
Methods
We analyzed Korean rheumatoid arthritis case-control samples using the Immunochip and GWAS array to search for new risk alleles of rheumatoid arthritis with anti-citrullinated peptide antibodies. To increase power, we performed a meta-analysis of Korean data with previously published European Immunochip and GWAS data, for a total sample size of 9,299 Korean and 45,790 European case-control samples.
Results
We identified 8 new rheumatoid arthritis susceptibility loci (TNFSF4, LBH, EOMES, ETS1–FLI1, COG6, RAD51B, UBASH3A and SYNGR1) that passed a genome-wide significance threshold (p<5×10−8), with evidence for three independent risk alleles at 1q25/TNFSF4. The risk alleles from the 7 new loci except for the TNFSF4 locus (monomorphic in Koreans), together with risk alleles from previously established RA risk loci, exhibited a high correlation of effect sizes between ancestries. Further, we refined the number of SNPs that represent potentially causal variants through a trans-ethnic comparison of densely genotyped SNPs.
Conclusion
This study demonstrates the advantage of dense-mapping and trans-ancestral analysis for identification of potentially causal SNPs. In addition, our findings support the importance of T cells in the pathogenesis and the fact of frequent overlap of risk loci among diverse autoimmune diseases.
doi:10.1136/annrheumdis-2013-204749
PMCID: PMC4467986  PMID: 24532676
Rheumatoid arthritis; Gene polymorphism; Anti-CCP
18.  Risk for Myasthenia Gravis maps to 151Pro→ Ala change in TNIP1 and to HLA-B*08 
Annals of neurology  2012;72(6):927-935.
Objective
The objective of this study is to comprehensively define the genetic basis of Early Onset Myasthenia Gravis.
Methods
We have carried out a two-stage genome-wide association study on a total of 649 North European EOMG patients. Cases were matched 1:4 with controls of European ancestry. We performed imputation and conditional analyses across the major histocompatibility complex, as well as in the top regions of association outside the HLA region.
Results
We observed the strongest association in the HLA class I region at rs7750641 (p = 1.2 × 10−92, OR = 6.25). By imputation and conditional analyses, HLA-B*08 proves to be the major associated allele (p = 2.87 × 10−113, OR = 6.41). In addition to the expected association with PTPN22 (rs2476601, OR =1.71, p = 8.2 ×10−10), an imputed coding variant (rs2233290) at position 151 (Pro→Ala) in the TNFAIP3-interacting protein 1, TNIP1, confers even stronger risk than PTPN22 (OR = 1.91, p = 3.2 × 10−10).
Interpretation
The association at TNIP1 in EOMG implies disease mechanisms involving ubiquitin-dependent dysregulation of NF-κB signaling. The localization of the major HLA signal to the HLA-B*08 allele suggests that CD8+ T-cells may play a key role in disease initiation or pathogenesis.
doi:10.1002/ana.23691
PMCID: PMC3535539  PMID: 23055271
19.  A Genome-Wide Association Study Identifies IL23R as an Inflammatory Bowel Disease Gene 
Science (New York, N.Y.)  2006;314(5804):1461-1463.
The inflammatory bowel diseases Crohn's disease and ulcerative colitis are common, chronic disorders that cause abdominal pain, diarrhea, and gastrointestinal bleeding. To identify genetic factors that might contribute to these disorders, we performed a genome-wide association study. We found a highly significant association between Crohn's disease and the IL23R gene on chromosome 1p31, which encodes a subunit of the receptor for the proinflammatory cytokine interleukin-23. An uncommon coding variant (rs11209026, c.1142G>A, p.Arg381Gln) confers strong protection against Crohn's disease, and additional noncoding IL23R variants are independently associated. Replication studies confirmed IL23R associations in independent cohorts of patients with Crohn's disease or ulcerative colitis. These results and previous studies on the proinflammatory role of IL-23 prioritize this signaling pathway as a therapeutic target in inflammatory bowel disease.
doi:10.1126/science.1135245
PMCID: PMC4410764  PMID: 17068223
20.  TYK2 Protein-Coding Variants Protect against Rheumatoid Arthritis and Autoimmunity, with No Evidence of Major Pleiotropic Effects on Non-Autoimmune Complex Traits 
PLoS ONE  2015;10(4):e0122271.
Despite the success of genome-wide association studies (GWAS) in detecting a large number of loci for complex phenotypes such as rheumatoid arthritis (RA) susceptibility, the lack of information on the causal genes leaves important challenges to interpret GWAS results in the context of the disease biology. Here, we genetically fine-map the RA risk locus at 19p13 to define causal variants, and explore the pleiotropic effects of these same variants in other complex traits. First, we combined Immunochip dense genotyping (n = 23,092 case/control samples), Exomechip genotyping (n = 18,409 case/control samples) and targeted exon-sequencing (n = 2,236 case/controls samples) to demonstrate that three protein-coding variants in TYK2 (tyrosine kinase 2) independently protect against RA: P1104A (rs34536443, OR = 0.66, P = 2.3x10-21), A928V (rs35018800, OR = 0.53, P = 1.2x10-9), and I684S (rs12720356, OR = 0.86, P = 4.6x10-7). Second, we show that the same three TYK2 variants protect against systemic lupus erythematosus (SLE, Pomnibus = 6x10-18), and provide suggestive evidence that two of the TYK2 variants (P1104A and A928V) may also protect against inflammatory bowel disease (IBD; Pomnibus = 0.005). Finally, in a phenome-wide association study (PheWAS) assessing >500 phenotypes using electronic medical records (EMR) in >29,000 subjects, we found no convincing evidence for association of P1104A and A928V with complex phenotypes other than autoimmune diseases such as RA, SLE and IBD. Together, our results demonstrate the role of TYK2 in the pathogenesis of RA, SLE and IBD, and provide supporting evidence for TYK2 as a promising drug target for the treatment of autoimmune diseases.
doi:10.1371/journal.pone.0122271
PMCID: PMC4388675  PMID: 25849893
21.  Expression of Blimp-1 in Dendritic Cells Modulates the Innate Inflammatory Response in Dextran Sodium Sulfate–Induced Colitis 
Molecular Medicine  2015;20(1):707-719.
A single nucleotide polymorphism of PRDM1, the gene encoding Blimp-1, is strongly associated with inflammatory bowel disease. Here, we demonstrate that Blimp-1 in CD103+ dendritic cells (DCs) critically contributes to the regulation of macrophage homeostasis in the colon. Dextran sodium sulfate (DSS)-exposed Blimp-1cko mice with a deletion of Blimp-1 in CD103+ DCs and CD11chi macrophages exhibited severe inflammatory symptoms, pronounced weight loss, high mortality, robust infiltration of neutrophils in epithelial regions of the colon, an increased expression of proinflammatory cytokines and a significant decrease in CD103+ DCs in the colon compared with DSS exposed wild-type (WT) mice. Purified colonic macrophages from Blimp-1cko mice expressed increased levels of matrix metalloproteinase 8, 9 and 12 mRNA. WT macrophages cocultured with colonic DCs but not bone marrow–derived DCs from Blimp-1cko produced increased matrix metalloproteinases in an interleukin (IL)-1β– and IL-6–dependent manner. Treatment of Blimp-1cko mice with anti–IL-1β and anti–IL-6 abrogated the exaggerated clinical response. Overall, these data demonstrate that Blimp-1 expression in DCs can alter an innate inflammatory response by modulating the activation of myeloid cells. This is a novel mechanism of contribution of Blimp-1 for the pathogenesis of inflammatory bowel diseases, implicating another therapeutic target for the development of inflammatory bowel disease.
doi:10.2119/molmed.2014.00231
PMCID: PMC4398669  PMID: 25826676
22.  A genetic study on C5-TRAF1 and progression of joint damage in rheumatoid arthritis 
Introduction
The severity of joint damage progression in rheumatoid arthritis (RA) is heritable. Several genetic variants have been identified, but together explain only part of the total genetic effect. Variants in Interleukin-6 (IL-6), Interleukin-10 (IL-10), C5-TRAF1, and Fc-receptor-like-3 (FCRL3) have been described to associate with radiographic progression, but results of different studies were incongruent. We aimed to clarify associations of these variants with radiographic progression by evaluating six independent cohorts.
Methods
In total 5,895 sets of radiographs of 2,493 RA-patients included in six different independent datasets from the Netherlands, Sweden, Spain and North-America were studied in relation to rs1800795 (IL-6), rs1800896 (IL-10), rs2900180 (C5-TRAF1) and rs7528684 (FCRL3). Associations were tested in the total RA-populations and in anti-citrullinated peptide antibodies (ACPA)-positive and ACPA-negative subgroups per cohort, followed by meta-analyses. Furthermore, the associated region C5-TRAF1 was fine-mapped in the ACPA-negative Dutch RA-patients.
Results
No associations were found for rs1800795 (IL-6), rs1800896 (IL-10) and rs7528684 (FCRL3) in the total RA-population and after stratification for ACPA. Rs2900180 in C5-TRAF1 was associated with radiographic progression in the ACPA-negative population (P-value meta-analysis = 5.85 × 10−7); the minor allele was associated with more radiographic progression. Fine-mapping revealed a region of 66Kb that was associated; the lowest P-value was for rs7021880 in TRAF1. The P-value for rs7021880 in meta-analysis was 6.35 × 10−8. Previous studies indicate that the region of rs7021880 was associated with RNA expression of TRAF1 and C5.
Conclusion
Variants in IL-6, IL-10 and FCRL3 were not associated with radiographic progression. Rs2900180 in C5-TRAF1 and linked variants in a 66Kb region were associated with radiographic progression in ACPA-negative RA.
Electronic supplementary material
The online version of this article (doi:10.1186/s13075-014-0514-0) contains supplementary material, which is available to authorized users.
doi:10.1186/s13075-014-0514-0
PMCID: PMC4318544  PMID: 25566937
23.  Relationship between air pollution and positivity of RA-related autoantibodies in individuals without established RA: a report on SERA 
Annals of the rheumatic diseases  2013;72(12):10.1136/annrheumdis-2012-202949.
Introduction
Studies suggest that respiratory exposures including smoking, proximity to traffic and air pollution might be associated with development of rheumatoid arthritis (RA). RA-related autoantibodies are predictive of the development of RA.
Objective
We evaluated the relationship between RA-related autoantibodies and exposure to particulate matter (PM), a measure of air pollution of interest to health, in individuals without RA.
Methods
The Studies of the Etiology of Rheumatoid Arthritis (SERA) is a multicentre study following first-degree relatives (FDRs) of a proband with RA. FDRs are without the 1987 ACR (American College of Rheumatology) classifiable RA at enrolment and are followed for the development of RA-related autoimmunity. RA-related autoantibody outcomes as well as tender and swollen joint outcomes were assessed. Exposure to PM was assigned using ambient air pollution monitoring data and interpolated with inverse distance weighting spatial analyses using Geographic Information Systems. PM exposures were linked to FDR’s residential zip codes.
Results
RA-related autoantibodies as well as tender or swollen joints are not associated with ambient PM concentrations.
Discussion
While other respiratory exposures may be associated with increased risk of RA, our data suggest that ambient PM is not associated with autoantibodies and joint signs among individuals without RA, but at increased risk of developing RA.
doi:10.1136/annrheumdis-2012-202949
PMCID: PMC3818364  PMID: 23572338
24.  Genome-wide Association Study of Dermatomyositis Reveals Genetic Overlap with other Autoimmune Disorders 
Arthritis and rheumatism  2013;65(12):3239-3247.
Objective
To identify new genetic associations with juvenile and adult dermatomyositis (DM).
Methods
We performed a genome-wide association study (GWAS) of adult and juvenile DM patients of European ancestry (n = 1178) and controls (n = 4724). To assess genetic overlap with other autoimmune disorders, we examined whether 141 single nucleotide polymorphisms (SNPs) outside the major histocompatibility complex (MHC) locus, and previously associated with autoimmune diseases, predispose to DM.
Results
Compared to controls, patients with DM had a strong signal in the MHC region consisting of GWAS-level significance (P < 5x10−8) at 80 genotyped SNPs. An analysis of 141 non-MHC SNPs previously associated with autoimmune diseases showed that three SNPs linked with three genes were associated with DM, with a false discovery rate (FDR) < 0.05. These genes were phospholipase C like 1 (PLCL1, rs6738825, FDR=0.00089), B lymphoid tyrosine kinase (BLK, rs2736340, FDR=0.00031), and chemokine (C-C motif) ligand 21 (CCL21, rs951005, FDR=0.0076). None of these genes was previously reported to be associated with DM.
Conclusion
Our findings confirm the MHC as the major genetic region associated with DM and indicate that DM shares non-MHC genetic features with other autoimmune diseases, suggesting the presence of additional novel risk loci. This first identification of autoimmune disease genetic predispositions shared with DM may lead to enhanced understanding of pathogenesis and novel diagnostic and therapeutic approaches.
doi:10.1002/art.38137
PMCID: PMC3934004  PMID: 23983088
dermatomyositis; adult; juvenile; shared autoimmunity genes
25.  Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci 
Nature genetics  2010;42(6):508-514.
To identify novel genetic risk factors for rheumatoid arthritis (RA), we conducted a genome-wide association study (GWAS) meta-analysis of 5,539 autoantibody positive RA cases and 20,169 controls of European descent, followed by replication in an independent set of 6,768 RA cases and 8,806 controls. Of 34 SNPs selected for replication, 7 novel RA risk alleles were identified at genome-wide significance (P<5×10−8) in analysis of all 41,282 samples. The associated SNPs are near genes of known immune function, including IL6ST, SPRED2, RBPJ, CCR6, IRF5, and PXK. We also refined the risk alleles at two established RA risk loci (IL2RA and CCL21) and confirmed the association at AFF3. These new associations bring the total number of confirmed RA risk loci to 31 among individuals of European ancestry. An additional 11 SNPs replicated at P<0.05, many of which are validated autoimmune risk alleles, suggesting that most represent bona fide RA risk alleles.
doi:10.1038/ng.582
PMCID: PMC4243840  PMID: 20453842

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