68 species and virulence factors from the virulence factors database (VFDB)), (2) the immune epitope database (IEDB),24 (3) proteins from allergen databases and (4) bacteriophages. Leveraging the rich metadata available for this deeply phenotyped cohort (including imputed genotypes, gut microbiota shotgun sequencing, clinical blood tests (immune, metabolic and autoimmune markers), family information, lifestyle and self-reported diseases and allergy questionnaires) alongside the PhIP-Seq data allowed us to establish key genetic and environmental factors shaping the human antibody epitope repertoire. Materials and Methods Lead contact Further information and requests for resources should be directed to the Lead Contact, Alexandra Zhernakova (a.zhernakova@umcg.nl). Material availability A list of antibody-bound peptides enriched in LLD participants is publicly available on the bioRxiv preprint server: https://doi.org/10.1101/2021.12.07.471553. Data and code availability https://github.com/GRONINGEN-MICROBIOME-CENTRE/Phip-Seq_LLD-IBD. Cohort information Lifelines is a multi-disciplinary prospective population-based cohort study examining, in a unique three-generation design, the health and health-related behaviors of 167,729 individuals living in the North of the Netherlands. It employs a broad range of investigative procedures to assess the biomedical, socio-demographic, behavioral, physical and psychological factors that contribute to the health and disease of the general population, with a special focus on multi-morbidity and complex genetics.25 We collected data from the subcohort LLD22 (58% female, mean age 45.04 years, mean BMI 25.26, 12% obese participants with BMI > 30). Approval from institutional ethics review is available under reference number M12.113965. In this study, we used a subset of LLD (n = 1,437, 57% female, mean age 44.5 years) with available information including anthropometrics, blood parameters and self-assessed questionnaires about health and lifestyle. The autoantibody panels for anti-CCP and CTD-ratio and anti-SSA were originally described in26 and,27 respectively. The 1000IBD cohort is a large, prospective observational cohort study based in Groningen, the Netherlands, aiming to biologically and clinically characterize patients with inflammatory bowel disease (IBD) who are included at the outpatient IBD clinic of the University Medical Center Groningen (UMCG).28 Detailed phenotypic data and multi-omics profiles have been generated for over 1,000 included patients with IBD, enrolled from 2007 onwards. Antibody-bound peptide repertoires (PhIP-Seq profiles) were generated for 497 patients included in the 1000IBD cohort (median age 39 years, 63% females, median BMI 24.7 kg/m2), of which 256 patients were diagnosed with Crohn’s disease, 207 with ulcerative colitis and 34 with an undetermined type of IBD (IBD-U). Ethical approval for participation in the 1000IBD cohort has been granted by the Chapter 3
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