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Here the authors provide an explanation for 95% of examined predicted loss of function variants found in disease-associated haploinsufficient genes in the Genome Aggregation Database (gnomAD), underscoring the power of the presented analysis to minimize false assignments of disease risk.

Polygenic scores for body mass index and obesity constructed using data from 5 million people with different ancestries were associated with distinct weight gain trajectories from early childhood to adulthood.

Mark Daly, Manuel Rivas and colleagues used next-generation sequencing to study the coding exons of 56 genes from regions previously associated with Crohn's disease. Follow-up analyses in independent case-control series confirmed association of many newly discovered rare variants with disease risk.

A large genome-wide association study of more than 5 million individuals reveals that 12,111 single-nucleotide polymorphisms account for nearly all the heritability of height attributable to common genetic variants.

A genome-wide association meta-analysis study of blood lipid levels in roughly 1.6 million individuals demonstrates the gain of power attained when diverse ancestries are included to improve fine-mapping and polygenic score generation, with gains in locus discovery related to sample size.

Richard Duerr and colleagues present a genome-wide association study of ulcerative colitis. They identify new risk loci on chromosomes 1p36 and 12q15.

Inflammatory bowel disease (IBD) is highly prevalent among the Ashkenazi Jewish population. Here, the authors identify novel IBD-associated variants and genes, validated by transcriptomic and phenome-wide associations.

John Rioux, Andre Franke, Tom Karlsen and colleagues perform a fine-mapping study of the HLA region in Crohn's disease and ulcerative colitis. They identify a primary role for HLA-DRB1*01:03 in both diseases and find evidence of heterozygous advantage in protection against ulcerative colitis.

Genome-wide association analyses across individuals of East Asian and European ancestries identify new risk loci for inflammatory bowel diseases. A polygenic risk score derived from the combined datasets shows improved prediction accuracy.

Large-scale sequence-based analyses identify novel risk variants and susceptibility genes for Crohn’s disease, and implicate mesenchymal cell-mediated intestinal homeostasis in disease etiology.

Miles Parkes and colleagues report results of a large genome-wide association meta-analysis and replication study for Crohn's disease. They identify 30 new susceptibility loci for this inflammatory bowel disease and implicate several interesting candidate genes in disease pathogenesis.

Results of fine-mapping 94 inflammatory bowel disease loci using high-density genotyping in 67,852 individuals and several new fine-mapping methods.

A strategy for inferring phase for rare variant pairs is applied to exome sequencing data for 125,748 individuals from the Genome Aggregation Database (gnomAD). This resource will aid interpretation of rare co-occurring variants in the context of recessive disease.

The Inflammatory Bowel Disease Multi’omics Database includes longitudinal data encompassing a multitude of analyses of stool, blood and biopsies of more than 100 individuals, and provides a comprehensive description of host and microbial activities in inflammatory bowel diseases.

While hundreds of loci are linked with inflammatory bowel diseases (IBDs), the functional consequences of the associated variants remain unclear. Here, the authors screened in ulcerative colitis (UC) patients’ genomes for protein-truncating variants near IBD loci, and identify a protein truncating variant in RNF186to be protective against UC.

A genomic constraint map for the human genome constructed using data from 76,156 human genomes from the Genome Aggregation Database shows that non-coding constrained regions are enriched for regulatory elements and variants associated with complex diseases and traits.

David Ellinghaus and colleagues report a combined association analysis of five chronic inflammatory diseases. They identify 27 new associations and highlight disease-specific association patterns at shared susceptibility loci.

Exome sequencing data from 60,706 people of diverse geographic ancestry is presented, providing insight into genetic variation across populations, and illuminating the relationship between DNA variants and human disease.

Analysis of paired metagenomes and metatranscriptomes associated with patients with inflammatory bowel disease (IBD) and non-IBD controls over time provides some insights into microbial community variation and potential pathways influencing IBD symptoms.

Multi-nucleotide variants (MNV) are genetic variants in close proximity of each other on the same haplotype whose functional impact is difficult to predict if they reside in the same codon. Here, Wang et al. use the gnomAD dataset to assemble a catalogue of MNVs and estimate their global mutation rate.

Upstream open reading frames (uORFs), located in 5’ untranslated regions, are regulators of downstream protein translation. Here, Whiffin et al. use the genomes of 15,708 individuals in the Genome Aggregation Database (gnomAD) to systematically assess the deleteriousness of variants creating or disrupting uORFs.

A catalogue of predicted loss-of-function variants in 125,748 whole-exome and 15,708 whole-genome sequencing datasets from the Genome Aggregation Database (gnomAD) reveals the spectrum of mutational constraints that affect these human protein-coding genes.

A large empirical assessment of sequence-resolved structural variants from 14,891 genomes across diverse global populations in the Genome Aggregation Database (gnomAD) provides a reference map for disease-association studies, population genetics, and diagnostic screening.

We are moving towards an era of disease categorization beyond Crohn's disease and ulcerative colitis to a more robust definition of a spectrum of IBD subtypes. This Review outlines some of the genetic, clinical, biochemical, serological, and microbiome data that could be used for risk stratification and treatment selection in clinically meaningful subgroups of patients.

A novel variant annotation metric that quantifies the level of expression of genetic variants across tissues is validated in the Genome Aggregation Database (gnomAD) and is shown to improve rare variant interpretation.

Glycan research holds great promise in the development of biomarkers, and might highlight targets for novel therapeutics in IBD. This Review introduces the main characteristics of glycosylation, and the roles of glycans in health and disease are also briefly presented. The authors subsequently describe in detail the current body of glycobiology literature in relation to IBD and conclude with proposed strategies for further glycan research.

Epigenetic perturbations may be an important factor in diseases where both genes and environment play a role. Here, Ventham and colleagues show that DNA methylation changes in inflammatory bowel disease are related to the underlying genotype, and are associated with cell-specific changes to gene expression.

Mark Seielstad and colleagues report results of a large genome-wide association and replication study of ulcerative colitis. The work identifies several new risk loci for this disease and provides further insight into the shared pathogenesis of ulcerative colitis and Crohn's disease.

Kyuyoung Song and colleagues report the results of a two-stage association study of thiopurine-induced early leukopenia in individuals undergoing treatment for Crohn's disease. They find a missense variant in NUDT15 associated with substantially higher risk of developing this life-threatening complication to thiopurine therapy.

A meta-analysis of previous genome-wide association studies of Crohn’s disease and ulcerative colitis, the two most common forms of inflammatory bowel disease, with a combined total of more than 75,000 cases and controls, finds that most loci contribute to both phenotypes and other immune-mediated disorders.

John Rioux and colleagues report results of a large genome-wide association meta-analysis and follow-up study of ulcerative colitis. They identify 29 new risk loci for this inflammatory disease and show that many risk loci are shared between ulcerative colitis and Crohn's disease.

Most of the more than 200 known genetic risk loci for inflammatory bowel disease (IBD) reside in regulatory regions. Here, the authors provide eQTL datasets for six circulating immune cell types and ileal, colonic and rectal biopsies to map regulatory modules and identify potential causative genes for IBD.

Structural variants in more than 17,000 human genomes are mapped and characterized using whole-genome sequencing, showing how this type of variation contributes to rare deleterious coding and noncoding alleles.

Hakon Hakonarson and colleagues report the discovery of five new regions associated with susceptibility to early-onset inflammatory bowel disease. They also identify multiple loci previously implicated in the etiology of adult-onset Crohn's disease and/or ulcerative colitis as risk factors for early-onset forms of these diseases.

Analysis of predicted loss-of-function variants from 125,748 human exomes and 15,708 whole genomes in the Genome Aggregation Database (gnomAD) provides a roadmap for human ‘knockout’ studies and a guide for future research into disease biology and drug-target selection.

In this Expert Recommendation, Uhlig and colleagues review the therapeutic landscape for monogenic inflammatory bowel disease and propose recommendations for standardized reporting of clinical outcomes.

Analysis of large genomic datasets, including gnomAD, reveals that partial LRRK2 loss of function is not strongly associated with diseases, serving as an example of how human genetics can be leveraged for target validation in drug discovery.

The STORMS tool provides guidance for concise and complete reporting of microbiome studies to facilitate manuscript preparation, peer review, reader comprehension of publications, and comparative analysis of published results.

The biological effects of cytokines in intestinal homeostasis and disease occur as a result of JAK–STAT signalling. This Review describes the current understanding of JAK–STAT signalling in intestinal homeostasis and inflammatory bowel disease as well as the rationale for therapeutically targeting this pathway.