Genetic architecture differences between pediatric and adult-onset inflammatory bowel diseases in the Polish population

Background & Aims: Most inflammatory bowel diseases (IBDs) are classic polygenic disorders represented by common alleles. However, multiple determinants of very early-onset IBD characterized by a more extensive disease course remain largely unknown. The present study aimed to define the genetic architecture of pediatric and adult-onset IBDs in the Polish population. Results: Of 82 SNPs validated/replicated for association with IBD, a novel BRD2 (rs1049526) association was found in both pediatric (OR= 2.35) and adult (OR= 2.66) patients. Thirty SNPs were shared between pediatric and adult patients; 22 and 30 were unique to adult-onset and pediatric-onset IBD, respectively. WES identified numerous rare/infrequent, potentially deleterious variants in IBD-associated or innate immunity-associated genes. Both groups of variants were over-represented in affected children. Two highly deleterious homozygous variants, HLA-DRB1 c.565_566insC and NCF4 p.Arg8Trp, were found in two affected children, and WAS p.Glu131Lys was found in one child and one adult patient. Conclusions: Our GWAS revealed differences in the polygenic architecture of pediatric- and adult-onset IBD. A significant accumulation of rare/low frequency deleterious variants in affected children suggests a contribution by yet unexplained genetic components. A total of 1495 patients were recruited at Gastroenterology Departments at different Polish hospitals, including 761 patients with Crohn’s disease (CD; 424 pediatric), 734 patients with ulcerative colitis (UC; 390 pediatric), and 934 healthy controls. Allelotyping employed a pooled-DNA sample-based genome-wide association study (GWAS) and was validated by individual genotyping. Whole exome sequencing (WES) was performed on 44 IBD patients diagnosed before 6 years of age, 45 patients diagnosed after 40 years of age, and 18 healthy controls. Please note that no data processing was applied and thus only theta values from unprocessed file were provided in the 'Matrix_signal_intensities.txt' file. The main reason for not normalizing the data was that it was derived from pooled samples. Sample pools were of different sizes, some were mixed sex. Data normalization algorithms were in general optimized for genotype calling (which is impossible for these samples), and thus may introduce possible artifact introduction. Thus "the less the better" approach was made with the data analysis. PCA hasn't revealed any alarming stratification. Raw theta values were used as an input for Student's t-test. Clusters of significant probes were selected for validation in individual patients.