A Replication Study of the Association between Rheumatoid Arthritis and Deletion of the Late Cornified Envelope Genes LCE3B and LCE3C

OBJECTIVE: Two recent studies, in a Spanish and a Chinese population, point to an association between rheumatoid arthritis (RA) risk and the deletion of the Late Cornified Envelope (LCE) 3B and 3C genes (LCE3C_LCE3B-del), a known risk factor for psoriasis. We aimed to replicate these studies in a large Dutch cohort. METHODS: 1039 RA cases and 759 controls were genotyped for LCE3C_LCE3B-del. Association analysis was performed for the complete cohort and after stratification for the serologic markers anti-cyclic citrullinated peptide and rheumatoid factor. A meta-analysis was performed combining our data with the Spanish and Chinese datasets, resulting in an analysis including 2466 RA cases and 2438 controls. RESULTS: In the Dutch cohort we did not observe a significant association of LCE3C_LCE3B-del (p = 0.093) with RA risk. A stratified analysis for the serologic positive and negative group did not show an association between the genetic variant and disease risk, either. The meta-analysis, however, confirmed a significant association (p<0.0001, OR = 1.31, 95% confidence interval 1.16-1.47). CONCLUSION: Our meta-analysis confirms the association of the LCE3 deletion with RA, suggesting that LCE3C_LCE3B-del is a common risk factor for (auto)immune diseases

Genetics of inflammatory bowel disease: beyond NOD2

The study of the genetic underpinnings of inflammatory bowel disease has made great progress since the identification of NOD2 as a major susceptibility gene. Novel genotyping and sequencing technologies have led to the discovery of 242 common susceptibility loci, 45 of which have been fine-mapped to statistically conclusive causal variants; 50 genes associated with very-early-onset inflammatory disease have been identified. The evolving genetic architecture of inflammatory bowel disease has deepened our understanding of its pathogenesis through identification of major disease associated pathways-knowledge that has the potential to indicate novel drug targets or markers for personalised medicine. However, many causal variants have yet to be identified, and a large proportion of missing heritability still needs to be accounted for. In addition, the medical and scientific communities are probably not yet fully harnessing the power of these genetic discoveries.publisher: Elsevier articletitle: Genetics of inflammatory bowel disease: beyond NOD2 journaltitle: The Lancet Gastroenterology & Hepatology articlelink: http://dx.doi.org/10.1016/S2468-1253(16)30111-X content_type: article copyright: © 2017 Elsevier Ltd. All rights reserved.status: publishe

Genetic mapping of cell type specificity for complex traits

Single-cell RNA sequencing (scRNA-seq) data allows to create cell type specific transcriptome profiles. Such profiles can be aligned with genome-wide association studies (GWASs) to implicate cell type specificity of the traits. Current methods typically rely only on a small subset of available scRNA-seq datasets, and integrating multiple datasets is hampered by complex batch effects. Here we collated 43 publicly available scRNA-seq datasets. We propose a 3-step workflow with conditional analyses within and between datasets, circumventing batch effects, to uncover associations of traits with cell types. Applying this method to 26 traits, we identify independent associations of multiple cell types. These results lead to starting points for follow-up functional studies aimed at gaining a mechanistic understanding of these traits. The proposed framework as well as the curated scRNA-seq datasets are made available via an online platform, FUMA, to facilitate rapid evaluation of cell type specificity by other researchers

Author Correction: Genetic mapping of cell type specificity for complex traits (Nature Communications, (2019), 10, 1, (3222), 10.1038/s41467-019-11181-1)

The original version of this Article contained an error in Fig. 5 and Supplementary Fig. 12, in which the colours of the bar plots at the top of the heatmaps were incorrectly given, leading to incorrect mapping of the plots to the corresponding dataset based on the dataset legend. The correct version of Fig. 5 is. (Figure Presented.)

Pharmacogenetics of disease-modifying antirheumatic drugs in rheumatoid arthritis: towards personalized medicine

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Author Correction:A global overview of pleiotropy and genetic architecture in complex traits

In the version of this article originally published, the captions of Fig. 1e,f were incorrectly swapped. The error has been corrected in the HTML and PDF versions of the article

Meta-analyses of association of the <i>LCE3C_LCE3B</i> deletion with RA in the Spanish, Chinese and Dutch cohort.

<p>Number of controls in the Spanish, Chinese and Dutch studies is 978, 681 and 779 respectively. The number of controls in the meta-analysis is 2438. <i>LCE3C_LCE3B</i> deletion: deletion of the <i>LCE3B</i> and <i>LCE3C</i> gene; del: deletion; CCP−: patients negative for anti cyclic citrullinated peptide; CCP+: patients positive for anti-cyclic citrullinated peptide; RF−: patients negative for rheumatoid factor; RF+ patients positive for rheumatoid factor. OR: odds ratio; L95: left border 95% confidence interval. R95: right border 95% confidence interval. I² (p): measure for heterogeneity and p-value of the chi-square test for heterogeneity.</p

No association of the <i>LCE3C_LCE3B</i> deletion with RA in the Dutch cohort.

<p><i>LCE3C_LCE3B</i> deletion: deletion of the <i>LCE3B</i> and <i>LCE3C</i> gene; del: deletion; CCP−: patients negative for anti cyclic citrullinated peptide; CCP+: patients positive for anti-cyclic citrullinated peptide; RF−: patients negative for rheumatoid factor; RF+ patients positive for rheumatoid factor. OR: odds ratio; 95% CI: 95% confidence interval.</p

Demographics of the rheumatoid arthritis cohort.

<p>Numbers are depicted as n(%) or mean ± standard deviation. Data available for ^#686, ^##717, ^###952, ^####451 patients. RA: rheumatoid arthritis; CCP: anti-cyclic citrullinated peptide; RF: rheumatoid factor.</p