The inflammatory bowel diseases (IBD) Crohn’s disease and ulcerative colitis are common causes of morbidity in children and young adults in the western world. Here we report the results of a genome-wide association study in early-onset IBD involving 3,426 affected individuals and 11,963 genetically matched controls recruited through international collaborations in Europe and North America, thereby extending the results from a previous study of 1,011 individuals with early-onset IBD1. We have identified five new regions associated with early-onset IBD susceptibility, including 16p11 near the cytokine gene IL27 (rs8049439, P = 2.41 × 10−9), 22q12 (rs2412973, P = 1.55 × 10−9), 10q22 (rs1250550, P = 5.63 × 10−9), 2q37 (rs4676410, P = 3.64 × 10−8) and 19q13.11 (rs10500264, P = 4.26 × 10−10). Our scan also detected associations at 23 of 32 loci previously implicated in adult-onset Crohn’s disease and at 8 of 17 loci implicated in adult-onset ulcerative colitis, highlighting the close pathogenetic relationship between early- and adult-onset IBD.

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Data availabilitySummary statistics generated by COVID-19 Host Genetics Initiative are available online (https://www.covid19hg.org/results/r6/). The analyses described here use the freeze 6 data. The COVID-19 Host Genetics Initiative continues to regularly release new data freezes. Summary statistics for samples from individuals of non-European ancestry are not currently available owing to the small individual sample sizes of these groups, but the results for 23 loci lead variants are reported in Supplementary Table 3. Individual-level data can be requested directly from the authors of the contributing studies, listed in Supplementary Table 1.

SUMMARYRare deletions and duplications of genomic segments, collectively known as rare copy number variants (rCNVs), contribute to a broad spectrum of human diseases. To date, most disease-association studies of rCNVs have focused on recognized genomic disorders or on the impact of haploinsufficiency caused by deletions. By comparison, our understanding of duplications in disease remains rudimentary as very few individual genes are known to be triplosensitive (i.e., duplication intolerant). In this study, we meta-analyzed rCNVs from 753,994 individuals across 30 primarily neurological disease phenotypes to create a genome-wide catalog of rCNV association statistics across disorders. We discovered 114 rCNV-disease associations at 52 distinct loci surpassing genome-wide significance (P=3.72×10−6), 42% of which involve duplications. Using Bayesian fine-mapping methods, we further prioritized 38 novel triplosensitive disease genes (e.g., GMEB2 in brain abnormalities), including three known haploinsufficient genes that we now reveal as bidirectionally dosage sensitive (e.g., ANKRD11 in growth abnormalities). By integrating our results with prior literature, we found that disease-associated rCNV segments were enriched for genes constrained against damaging coding variation and identified likely dominant driver genes for about one-third (32%) of rCNV segments based on de novo mutations from exome sequencing studies of developmental disorders. However, while the presence of constrained driver genes was a common feature of many pathogenic large rCNVs across disorders, most of the rCNVs showing genome-wide significant association were incompletely penetrant (mean odds ratio=11.6) and we also identified two examples of noncoding disease-associated rCNVs (e.g., intronic CADM2 deletions in behavioral disorders). Finally, we developed a statistical model to predict dosage sensitivity for all genes, which defined 3,006 haploinsufficient and 295 triplosensitive genes where the effect sizes of rCNVs were comparable to deletions of genes constrained against truncating mutations. These dosage sensitivity scores classified disease genes across molecular mechanisms, prioritized pathogenic de novo rCNVs in children with autism, and revealed features that distinguished haploinsufficient and triplosensitive genes, such as insulation from other genes and local cis-regulatory complexity. Collectively, the cross-disorder rCNV maps and metrics derived in this study provide the most comprehensive assessment of dosage sensitive genomic segments and genes in disease to date and set the foundation for future studies of dosage sensitivity throughout the human genome.

The eMERGE Consortium* , * The advancement of precision medicine requires new methods to coordinate and deliver genetic data from heterogeneous sources to physicians and patients. The eMERGE III Network enrolled >25,000 participants from biobank and prospective cohorts of predominantly healthy individuals for clinical genetic testing to determine clinically actionable findings. The network developed protocols linking together the 11 participant collection sites and 2 clinical genetic testing laboratories. DNA capture panels targeting 109 genes were used for testing of DNA and sample collection, data generation, interpretation, reporting, delivery, and storage were each harmonized. A compliant and secure network enabled ongoing review and reconciliation of clinical interpretations, while maintaining communication and data sharing between clinicians and investigators. A total of 202 individuals had positive diagnostic findings relevant to the indication for testing and 1,294 had additional/secondary findings of medical significance deemed to be returnable, establishing data return rates for other testing endeavors. This study accomplished integration of structured genomic results into multiple electronic health record (EHR) systems, setting the stage for clinical decision support to enable genomic medicine. Further, the established processes enable different sequencing sites to harmonize technical and interpretive aspects of sequencing tests, a critical achievement toward global standardization of genomic testing. The eMERGE protocols and tools are available for widespread dissemination.