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Genome-wide association studies (GWAS) have identified hundreds of loci associated with Crohns disease (CD), however, as with all complex diseases, deriving pathogenic mechanisms from these non-coding GWAS discoveries has been challenging. To complement GWAS and better define actionable biological targets, we analysed sequenced data from more than 30,000 CD patients and 80,000 population controls. We observe rare coding variants in established CD susceptibility genes as well as ten genes where coding variation directly implicates the gene in disease risk for the first time.

BACKGROUND AND AIMS: Polygenic risk scores (PRS) may soon be used to predict inflammatory bowel disease (IBD) risk in prevention efforts. We leveraged exome-sequence and single nucleotide polymorphism (SNP) array data from 29,358 individuals in the multiethnic, randomly ascertained health system-based BioMe biobank to define effects of common and rare IBD variants on disease prediction and pathophysiology. METHODS: PRS were calculated from European, African American, and Ashkenazi Jewish (AJ) reference case-control studies, and a meta-GWAS run using all three association datasets. PRS were then combined using regression to assess which combination of scores best predicted IBD status in European, AJ, Hispanic, and African American cohorts in BioMe. Additionally, rare variants were assessed in genes associated with very early-onset IBD (VEO-IBD), by estimating genetic penetrance in each BioMe population. RESULTS: Combining risk scores based on association data from distinct ancestral populations improved IBD prediction for every population in BioMe and significantly improved prediction among European ancestry UK Biobank individuals. Lower predictive power for non-Europeans was observed, reflecting in part substantially lower African IBD case-control reference sizes. We replicated associations for two VEO-IBD genes, ADAM17 and LRBA, with high dominant model penetrance in BioMe. Autosomal recessive LRBA risk alleles are associated with severe, early-onset autoimmunity; we show that heterozygous carriage of an African-predominant LRBA protein-altering allele is associated with significantly decreased LRBA and CTLA-4 expression with T-cell activation. CONCLUSIONS: Greater genetic diversity in African populations improves prediction across populations, and generalizes some VEO-IBD genes. Increasing African American IBD case-collections should be prioritized to reduce health disparities and enhance pathophysiological insight.

BACKGROUND & AIMS: Anti-tumor necrosis factor (anti-TNF) therapies are the most widely used biologic drugs for treating immune-mediated diseases, but repeated administration can induce the formation of anti-drug antibodies. The ability to identify patients at increased risk for development of anti-drug antibodies would facilitate selection of therapy and use of preventative strategies.METHODS: We performed a genome-wide association study to identify variants associated with time to development of anti-drug antibodies in a discovery cohort of 1240 biologic-naïve patients with Crohn's disease starting infliximab or adalimumab therapy. Immunogenicity was defined as an anti-drug antibody titer ≥10 AU/mL using a drug-tolerant enzyme-linked immunosorbent assay. Significant association signals were confirmed in a replication cohort of 178 patients with inflammatory bowel disease.RESULTS: The HLA-DQA1*05 allele, carried by approximately 40% of Europeans, significantly increased the rate of immunogenicity (hazard ratio [HR], 1.90; 95% confidence interval [CI], 1.60-2.25; P = 5.88 × 10-13). The highest rates of immunogenicity, 92% at 1 year, were observed in patients treated with infliximab monotherapy who carried HLA-DQA1*05; conversely the lowest rates of immunogenicity, 10% at 1 year, were observed in patients treated with adalimumab combination therapy who did not carry HLA-DQA1*05. We confirmed this finding in the replication cohort (HR, 2.00; 95% CI, 1.35-2.98; P = 6.60 × 10-4). This association was consistent for patients treated with adalimumab (HR, 1.89; 95% CI, 1.32-2.70) or infliximab (HR, 1.92; 95% CI, 1.57-2.33), and for patients treated with anti-TNF therapy alone (HR, 1.75; 95% CI, 1.37-2.22) or in combination with an immunomodulator (HR, 2.01; 95% CI, 1.57-2.58).CONCLUSIONS: In an observational study, we found a genome-wide significant association between HLA-DQA1*05 and the development of antibodies against anti-TNF agents. A randomized controlled biomarker trial is required to determine whether pretreatment testing for HLA-DQA1*05 improves patient outcomes by helping physicians select anti-TNF and combination therapies. ClinicalTrials.gov ID: NCT03088449.

Background Genome-wide association studies (GWASs) have identified >200 genomic regions associated with IBD. These signals are mainly driven by common variants in noncoding regions, making it a challenge to extract biological insight. Targeted sequencing of genes in these regions has successfully identified putative causal variants, often rarer and independent of the initial GWAS hit. These coding variants have led to more direct functional experiments demonstrating causal mechanisms for at least ten genes. Methods To further rare variant-based discovery, we pursued large-scale exome sequencing of more than 30,000 Crohn's disease (CD) cases and population controls from more than 20 centers in the International IBD Genetics Consortium. Sequencing was performed at the Broad Institute using both Nextera (11,125 CD cases) and TWIST (7,442 CD cases) exome captures - and at the Sanger Institute (whole genomes 6,404 CD cases and Agilent exome 3,848 CD cases). Further replication was performed with a sample of 4,359 cases from Kiel sequenced at Regeneron. In each technical experiment, a comparable or larger number of sequenced controls were available for genetic association analysis. Results We conducted meta-analysis of two exome captures at the Broad Institute. To expand on GWAS, we focused on rare and low-frequency coding variants between 0.01% and 10% and estimated roughly 85% of all protein coding variants in this frequency range are reliably analyzed in both exome captures. 119 variants (figure below) were identified with p Conclusion These findings provide novel launch points for mechanistic studies that will further our understanding of disease pathogenesis. For example, SDF2L1 (R161H) flags a gene not previously implicated in IBD but which is reported to regulate feeding-induced ER stress, with a series of CRISPR screens identifying it as an essential regulator of ER homeostasis. Download : Download high-res image (141KB) Download : Download full-size image Effect size versus frequency for significant low frequency coding variants (credit: Hailiang Huang)

SummaryBackgroundAnti-tumour necrosis factor (anti-TNF) therapies are the most widely used biologic therapies for treating immune-mediated diseases. Their efficacy is significantly reduced by the development of anti-drug antibodies which can lead to treatment failure and adverse reactions. The biological mechanisms underlying antibody development are unknown but the ability to identify subjects at higher risk would have significant clinical benefits.MethodsThe PANTS cohort consists of Crohn’s disease patients recruited prior to first administration of anti-TNF, with serial measurements of anti-drug antibody titres. We performed a genome-wide association study across 1240 individuals from this cohort to identify genetic variants associated with anti-drug antibody development.FindingsThe Human Leukocyte Antigen allele, HLA-DQA1*05, carried by approximately 40% of Europeans, significantly increased the rate of anti-drug antibody development (hazard ratio [HR], 1.90; 95% confidence interval [CI], 1.60 to 2.25; P=5.88×10-13). This association was consistent for patients treated with adalimumab (HR, 1.89; 95% CI, 1.32 to 2.70) and infliximab (HR, 1.92; 95% CI, 1.57 to 2.33), and for patients treated with mono-(HR, 1.75; 95% CI, 1.37 to 2.22) or combination therapy with immunomodulators (HR, 2.0; 95% CI, 1.57 to 2.58).InterpretationHLA-DQA1*05 is significantly associated with an increased rate of anti-drug antibody formation in patients with Crohn’s disease treated with infliximab and adalimumab. Pre-treatment HLA-DQA1*05 genetic testing may help personalise the choice of anti-TNF therapy and allow the targeted use of immunomodulator therapy to minimise risk and maximise response.

Background Immunogenicity to anti-TNF therapy is a major cause of loss of response, treatment discontinuation and hypersensitivity reactions and currently cannot be predicted prior to treatment. A number of factors have been associated with the risk of immunogenicity, but knowledge of the cellular and molecular mechanisms remain limited. Our aim was to investigate genetic susceptibility to immunogenicity. Methods The PANTS (Personalised Anti-TNF Therapy in Crohn’s disease) study is a 3 year prospective observational UK-wide study investigating primary non-response, loss of response and adverse drug reactions to the anti-TNF drugs infliximab and adalimumab. Anti-drug antibodies (ADAs) were measured serially at trough using the IDKmonitor total ADAb ELISA assay. Immunogenicity was defined as (a) ADA titre ≥10 AU/ml and (b) ADA titre ≥10 AU/ml with no detectable drug. A genome-wide association study (GWAS) was carried out on imputed genotype data using a Cox proportional hazards model incorporating the anti-TNF used and presence of concomitant immunomodulator as covariates (SurvivalGWAS_SV v1.3.1). Results After quality control, we had genotype data for 1284 patients followed prospectively for a minimum of 12 months since starting anti-TNF therapy. Using a Cox proportional hazards model and an immunogenicity definition of ADAs titre ≥10 AU/ml we identified a genome-wide association on chromosome 6 (top SNP rs74291249 with p=5.6 × 10−13). We imputed the HLA alleles at 2- and 4-digit resolution using the HIBAG package and demonstrated that this signal was driven by HLA-DQA1*05 for both infliximab and adalimumab. No additive effect of having two DQA1*05 was seen. Figures 1 and 2 show immunogenicity-free survival stratified by HLA-DQA1*05 genotype and concomitant immunomodulators at baseline. Conclusion We have demonstrated that immunogenicity to anti-TNF is determined by HLA variants. Pre-treatment genetic testing might allow the use of individual risk profiles and targeted use of immunomodulatory therapies to deliver more durable, safe and cost-effective anti-TNF therapy.

Genome-wide association studies (GWASs) have revolutionized human disease genetics by discovering tens of thousands of associations between common variants and complex diseases. In parallel, huge technological advances in DNA sequencing have made it possible to measure and analyze rare variation in populations. This review considers these two stories and how they have come together. We first review the history of GWASs and sequencing. We then consider how to understand the biological mechanisms that drive signals of strong association in the absence of rare-variant studies. We describe how rare-variant studies complement these approaches and highlight both data generation and statistical challenges in their interpretation. Finally, we consider how certain special study designs, such as those for families and isolated populations, fit in this paradigm.

We introduce NetworKit, an open-source software package for analyzing the structure of large complex networks. Appropriate algorithmic solutions are required to handle increasingly common large graph data sets containing up to billions of connections. We describe the methodology applied to develop scalable solutions to network analysis problems, including techniques like parallelization, heuristics for computationally expensive problems, efficient data structures, and modular software architecture. Our goal for the software is to package results of our algorithm engineering efforts and put them into the hands of domain experts. NetworKit is implemented as a hybrid combining the kernels written in C++ with a Python front end, enabling integration into the Python ecosystem of tested tools for data analysis and scientific computing. The package provides a wide range of functionality (including common and novel analytics algorithms and graph generators) and does so via a convenient interface. In an experimental comparison with related software, NetworKit shows the best performance on a range of typical analysis tasks., 21 pages