Defining the Dimensions of Diversity to Promote Inclusion in the Digital Era of Health Care: A Lexicon.

The pandemic provided a stark reminder of the inequities faced by populations historically marginalized by the health care system and accelerated the adoption of digital health technologies to drive innovation. Digital health technologies' purported promises to reduce inefficiencies and costs, improve access and health outcomes, and empower patients add a new level of urgency to health equity. As conventional medicine shifts toward digital medicine, we have the opportunity to intentionally develop and deploy digital health technologies with an inclusion focus. The first step is ensuring that the multiple dimensions of diversity are captured. We propose a lexicon that encompasses elements critical for implementing an inclusive approach to advancing health care quality and health services research in the digital era.

Factors influencing the clinical adoption of quantitative gait analysis technology with a focus on clinical efficacy and clinician perspectives: A scoping review.

INTRODUCTION: Quantitative gait analysis (QGA) has the potential to support clinician decision-making. However, it is not yet widely accepted in practice. Evidence for clinical efficacy (i.e., efficacy and effectiveness), as well as a users' perspective on using the technology in clinical practice (e.g., ease of use and usefulness) can help impact their widespread adoption. OBJECTIVE: To synthesize the literature on the clinical efficacy and clinician perspectives on the use of gait analysis technologies in the clinical care of adult populations. METHODS: This scoping review followed the Joanna Briggs Institute (JBI) methodology for scoping reviews. We included peer-reviewed and gray literature (i.e., conference abstracts). A search was conducted in MEDLINE (Ovid), CENTRAL (Ovid), EMBASE (Ovid), CINAHL (EBSCO) and SPORTDiscus (EBSCO). Included full-text studies were critically appraised using the JBI critical appraisal tools. RESULTS: A total of 15 full-text studies and two conference abstracts were included in this review. Results suggest that QGA technologies can influence decision-making with some evidence to suggest their role in improving patient outcomes. The main barrier to ease of use was a clinician's lack of data expertise, and main facilitator was receiving support from staff. Barriers to usefulness included challenges finding suitable reference data and data accuracy, while facilitators were enhancing patient care and supporting clinical decision-making. SIGNIFICANCE: This review is the first step to understanding how QGA technologies can optimize clinical practice. Many gaps in the literature exist and reveal opportunities to improve the clinical adoption of gait analysis technologies. Further research is needed in two main areas: 1) examining the clinical efficacy of gait analysis technologies and 2) gathering clinician perspectives using a theoretical model like the Technology Acceptance Model to guide study design. Results will inform research aimed at evaluating, developing, or implementing these technologies. FUNDING: This work was supported by the Walter and Maria Schroeder Institute for Brain Innovation and Recovery and AGE-WELL Graduate Student Award in Technology and Aging [2021,2022].

The retrograde IFT dynein is required for normal function of diverse mechanosensory cilia in Drosophila.

Introduction: Cilia biogenesis relies on intraflagellar transport (IFT), a conserved transport mechanism which functions bi-directionally to bring protein complexes to the growing ciliary tip and recycle signaling and transport proteins between the cilium and cell body. In Drosophila, anterograde IFT is critical for assembly of sensory cilia in the neurons of both chordotonal (ch) organs, which have relatively long ciliary axonemes, and external sensory (es) organs, which have short axonemal segments with microtubules in distal sensory segments forming non-axonemal bundles. We previously isolated the beethoven (btv) mutant in a mutagenesis screen for auditory mutants. Although many btv mutant flies are deaf, some retain a small residual auditory function as determined both by behavior and by auditory electrophysiology. Results: Here we molecularly characterize the btv gene and demonstrate that it encodes the IFT-associated dynein-2 heavy chain Dync2h1. We also describe morphological changes in Johnston's organ as flies age to 30 days, and we find that morphological and electrophysiological phenotypes in this ch organ of btv mutants become more severe with age. We show that NompB protein, encoding the conserved IFT88 protein, an IFT complex B component, fails to be cleared from chordotonal cilia in btv mutants, instead accumulating in the distorted cilia. In macrochaete bristles, a class of es organ, btv mutants show a 50% reduction in mechanoreceptor potentials. Discussion: Thus, the btv-encoded Dync2h1 functions as the retrograde IFT motor in the assembly of long ciliary axonemes in ch organs and is also important for normal function of the short ciliary axonemes in es organs.

Building the Business Case for an Inclusive Approach to Digital Health Measurement With a Web App (Market Opportunity Calculator): Instrument Development Study.

BACKGROUND: The use of digital health measurement tools has grown substantially in recent years. However, there are concerns that the promised benefits from these products will not be shared equitably. Underserved populations, such as those with lower education and income, racial and ethnic minorities, and those with disabilities, may find such tools poorly suited for their needs. Because underserved populations shoulder a disproportionate share of the US disease burden, they also represent a substantial share of digital health companies' target markets. Incorporating inclusive principles into the product development process can help ensure that the resulting tools are broadly accessible and effective. In this context, inclusivity not only maximizes societal benefit but also leads to greater commercial success. OBJECTIVE: A critical element in fostering inclusive product development is building the business case for why it is worthwhile. The Digital Health Measurement Collaborative Community (DATAcc) Market Opportunity Calculator was developed as an open-access resource to enable digital health measurement product developers to build a business case for incorporating inclusive practices into their research and development processes. METHODS: The DATAcc Market Opportunity Calculator combines data on population demographics and disease prevalence and health status from the US Census Bureau and the US Centers for Disease Control and Prevention (CDC). Together, these data are used to calculate the share of US adults with specific conditions (eg, diabetes) falling into various population segments along key "inclusion vectors" (eg, race and ethnicity). RESULTS: A free and open resource, the DATAcc Market Opportunity Calculator can be accessed from the DATAcc website. Users first select the target health condition addressed by their product, and then an inclusion vector to segment the patient population. The calculator displays each segment as a share of the overall US adult population and its share specifically among adults with the target condition, quantifying the importance of underserved patient segments to the target market. The calculator also estimates the value of improvements to product inclusivity by modeling the downstream impact on the accessible market size. For example, simplifying prompts on a hypertension-focused product to make it more accessible for adults with lower educational attainment is shown by the calculator to increase the target market by 2 million people and the total addressable market opportunity by US $200 million. CONCLUSIONS: Digital health measurement is still in its infancy. Now is the time to establish a precedent for inclusive product development to maximize societal benefit and build sustainable commercial returns. The Market Opportunity Calculator can help build the business case for "why"-showing how inclusivity can translate to financial opportunity. Once the decision has been made to pursue inclusive design, other components of the broader DATAcc toolkit for inclusive product development can support the "how."

Factors Influencing the Clinical Adoption of Quantitative Gait Analysis Technologies for Adult Patient Populations With a Focus on Clinical Efficacy and Clinician Perspectives: Protocol for a Scoping Review.

BACKGROUND: Quantitative gait analysis can support clinical decision-making. These analyses can be performed using wearable sensors, nonwearable sensors, or a combination of both. However, to date, they have not been widely adopted in clinical practice. Technology adoption literature has highlighted the clinical efficacy of technology and the users' perspective on the technology (eg, ease of use and usefulness) as some factors that influence their widespread adoption. OBJECTIVE: To assist with the clinical adoption of quantitative gait technologies, this scoping review will synthesize the literature on their clinical efficacy and clinician perspectives on their use in the clinical care of adult patient populations. METHODS: This scoping review protocol follows the Joanna Briggs Institute methodology for scoping reviews. The review will include both peer-reviewed and gray literature (ie, conference abstracts) regarding the clinical efficacy of quantitative gait technologies and clinician perspectives on their use in the clinical care of adult patient populations. A comprehensive search strategy was created in MEDLINE (Ovid), which was then translated to 4 other databases: CENTRAL (Ovid), Embase (Ovid), CINAHL (EBSCO), and SPORTDiscus (EBSCO). The title and abstract screening, full-text review, and data extraction of relevant articles will be performed independently by 2 reviewers, with a third reviewer involved to support the resolution of conflicts. Data will be analyzed using content analysis and summarized in tabular and diagram formats. RESULTS: A search of relevant articles will be conducted in all 5 databases, and through hand-searching in Google Scholar and PEDro, including articles published up until December 2022. The research team plans to submit the final scoping review for publication in a peer-reviewed journal in 2023. CONCLUSIONS: The findings of this review will be presented at clinical science conferences and published in a peer-reviewed journal. This review will inform future studies designed to develop, evaluate, or implement quantitative gait analysis technologies in clinical practice. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/39767.

Virtual Accessible Bilingual Conference Planning: The Parks Accessibility Conference.

Virtual events have become more popular recently, and while these events have the potential to be inclusive to a broader range of attendees, there is limited information available on how to plan and deliver a virtual, accessible, and bilingual event. The objective of this paper is to share how our team planned and delivered a virtual conference that was fully bilingual and accessible to individuals with disabilities by incorporating closed captions, sign language interpretation, language interpretation (audio), regularly scheduled breaks, and a multi-sensory experience. We describe our approaches to planning the conference, such as including individuals with disabilities in decision-making, selecting virtual conference platforms, captioners, and interpreters, and how we incorporated a multi-sensory experience. The paper also summarizes feedback we received from our attendees using a post-conference evaluation survey and our team's reflections on positive aspects of the conference and opportunities for improvement. We conclude by providing a set of practical recommendations that we feel may be helpful to others planning virtual accessible bilingual conferences in the future.

A Survey of the Challenges Faced by Individuals with Disabilities and Unpaid Caregivers during the COVID-19 Pandemic.

The COVID-19 pandemic negatively affected many individuals. In particular, it is likely that individuals with disabilities and unpaid caregivers were disproportionately affected, however, its exact impact is largely unknown. The primary objective of this work was to identify challenges faced by individuals with disabilities and unpaid caregivers. A secondary objective was to identify potential solutions to the major challenges experienced by both populations. Two surveys were administered online to individuals with disabilities and unpaid caregivers, respectively between September 2020 and January 2021. We used an inductive thematic analysis within an interpretivist paradigm to analyze survey responses. A total of 111 survey responses were collected amongst both surveys. Separate thematic maps were created for individuals with disabilities and unpaid caregivers, and maps were drawn to compare challenges. Potential solutions to mitigate the challenges experienced by both populations include revising financial assistance programs and improving awareness of support programs that are available.

Wearable fitness tracker use in federally qualified health center patients: strategies to improve the health of all of us using digital health devices.

As the use of connected devices rises, an understanding of how digital health technologies can be used for equitable healthcare across diverse communities is needed. We surveyed 1007 adult patients at six Federally Qualified Health Centers regarding wearable fitness trackers. Findings indicate the majority interest in having fitness trackers. Barriers included cost and lack of information, revealing that broad digital health device adoption requires education, investment, and high-touch methods.

Evacuation solutions for individuals with functional limitations in the built environment: a scoping review protocol.

BACKGROUND: Whether due to aging, disability, injury, or other circumstances, an increasing number of Canadians experience functional limitations that reduce their ability to participate in activities of daily life. While the built environment has become increasingly accessible, existing Canadian evacuation guidelines lack comprehensive strategies for evacuating individuals with functional limitations from buildings during emergencies. To inform guideline revisions, a map of existing solutions for evacuating such individuals is required. Therefore, this scoping review aims to provide an account of solutions that have been reported to safely evacuate individuals with functional limitations from the built environment. METHODS: We will conduct a scoping review using the Arksey and O'Malley methodological framework. To identify potentially relevant studies, comprehensive searches (from January 2002 onwards) of the CINAHL, Ei Compendex, Inspec, Embase, MEDLINE, KCI, RSCI, SciELO CI, Web of Science Collection, and Scopus databases will be performed. Using a set of inclusion and exclusion criteria, two reviewers will independently (1) classify identified studies as relevant, irrelevant, or maybe relevant by evaluating their titles and abstracts and (2) classify the relevant and maybe relevant studies as included or excluded by evaluating their full-text. From each included study, data on publication information, study purpose, methodological details, evacuation information, and outcomes will be extracted using a set of data extraction items. We will present a numerical summary of the key characteristics of the included studies. For each evacuation activity, reported evacuation solutions will be summarized, and citations provided for functional limitations that are targeted by a given evacuation solution. To inform Canadian evacuation guideline revisions, we will tabulate evacuation activities common to different types of buildings and emergencies. DISCUSSION: To our knowledge, this will be the first scoping review to identify the state and use of solutions for evacuating individuals with functional limitations from the built environment. Identifying solutions that enable all individuals to safely evacuate from different types of buildings will allow us to inform recommendations for the revision of evacuation guidelines in Canada and other jurisdictions. The findings of this scoping review will be published in a peer-reviewed journal, presented at relevant conferences, and made publicly available on the internet. SYSTEMATIC REVIEW REGISTRATION: Open Science Framework: osf.io/jefgy.

Evaluating Primary Care Providers' Readiness for Delivering Genetic and Genomic Services to Underserved Populations.

INTRODUCTION: Increased genomics knowledge and access are advancing precision medicine and care delivery. With the translation of precision medicine across health care, genetics and genomics will play a greater role in primary care services. Health disparities and inadequate representation of racial and ethnically diverse groups threaten equitable access for those historically underserved. Health provider awareness, knowledge, and perceived importance are important determinants of the utilization of genomic applications. METHODS: We evaluated the readiness of primary care providers at a Federally Qualified Health Center, the Community Health Center, Inc. (CHCI) for delivering genetic and genomic testing to underserved populations. Online survey questions focused on providers' education and training in basic and clinical genetics, familiarity with current genetic tests, and needs for incorporating genetics and genomics into their current practice. RESULTS: Fifty of 77 (65%) primary care providers responded to the survey. Less than half received any training in basic or clinical genetics (40%), were familiar with specific genetic tests (36%), or felt confident with collecting family health history (44%), and 70% believed patients would benefit from genetic testing. CONCLUSION: Despite knowledge gaps, respondents recognized the value and need to bring these services to their patients, though would like more education on applying genetics and genomics into their practice, and more training about discussing risk factors associated with race or ethnicity. We provide further evidence of the need for educational resources and standardized guidelines for providers caring for underserved populations to optimize appropriate use and referral of genetic and genomic services and to reduce disparities in care.

Zebrafish modeling of intestinal injury, bacterial exposures and medications defines epithelial in vivo responses relevant to human inflammatory bowel disease.

Genome-wide association studies have identified over 200 genomic loci associated with inflammatory bowel disease (IBD). High-effect risk alleles define key roles for genes involved in bacterial response and innate defense. More high-throughput in vivo systems are required to rapidly evaluate therapeutic agents. We visualize, in zebrafish, the effects on epithelial barrier function and intestinal autophagy of one-course and repetitive injury. Repetitive injury induces increased mortality, impaired recovery of intestinal barrier function, failure to contain bacteria within the intestine and impaired autophagy. Prostaglandin E2 (PGE2) administration protected against injury by enhancing epithelial barrier function and limiting systemic infection. Effects of IBD therapeutic agents were defined: mesalamine showed protective features during injury, whereas 6-mercaptopurine displayed marked induction of autophagy during recovery. Given the highly conserved nature of innate defense in zebrafish, it represents an ideal model system with which to test established and new IBD therapies targeted to the epithelial barrier.This article has an associated First Person interview with the first author of the paper.

A Pleiotropic Missense Variant in SLC39A8 Is Associated With Crohn's Disease and Human Gut Microbiome Composition.

BACKGROUND & AIMS: Genome-wide association studies have identified 200 inflammatory bowel disease (IBD) loci, but the genetic architecture of Crohn's disease (CD) and ulcerative colitis remain incompletely defined. Here, we aimed to identify novel associations between IBD and functional genetic variants using the Illumina ExomeChip (San Diego, CA). METHODS: Genotyping was performed in 10,523 IBD cases and 5726 non-IBD controls. There were 91,713 functional single-nucleotide polymorphism loci in coding regions analyzed. A novel identified association was replicated further in 2 independent cohorts. We further examined the association of the identified single-nucleotide polymorphism with microbiota from 338 mucosal lavage samples in the Mucosal Luminal Interface cohort measured using 16S sequencing. RESULTS: We identified an association between CD and a missense variant encoding alanine or threonine at position 391 in the zinc transporter solute carrier family 39, member 8 protein (SLC39A8 alanine 391 threonine, rs13107325) and replicated the association with CD in 2 replication cohorts (combined meta-analysis P = 5.55 × 10(-13)). This variant has been associated previously with distinct phenotypes including obesity, lipid levels, blood pressure, and schizophrenia. We subsequently determined that the CD risk allele was associated with altered colonic mucosal microbiome composition in both healthy controls (P = .009) and CD cases (P = .0009). Moreover, microbes depleted in healthy carriers strongly overlap with those reduced in CD patients (P = 9.24 × 10(-16)) and overweight individuals (P = 6.73 × 10(-16)). CONCLUSIONS: Our results suggest that an SLC39A8-dependent shift in the gut microbiome could explain its pleiotropic effects on multiple complex diseases including CD.

A Frameshift in CSF2RB Predominant Among Ashkenazi Jews Increases Risk for Crohn's Disease and Reduces Monocyte Signaling via GM-CSF.

BACKGROUND & AIMS: Crohn's disease (CD) has the highest prevalence in Ashkenazi Jewish populations. We sought to identify rare, CD-associated frameshift variants of high functional and statistical effects. METHODS: We performed exome sequencing and array-based genotype analyses of 1477 Ashkenazi Jewish individuals with CD and 2614 Ashkenazi Jewish individuals without CD (controls). To validate our findings, we performed genotype analyses of an additional 1515 CD cases and 7052 controls for frameshift mutations in the colony-stimulating factor 2-receptor ß common subunit gene (CSF2RB). Intestinal tissues and blood samples were collected from patients with CD; lamina propria leukocytes were isolated and expression of CSF2RB and granulocyte-macrophage colony-stimulating factor-responsive cells were defined by adenomatous polyposis coli (APC) time-of-flight mass cytometry (CyTOF analysis). Variants of CSF2RB were transfected into HEK293 cells and the expression and functions of gene products were compared. RESULTS: In the discovery cohort, we associated CD with a frameshift mutation in CSF2RB (P = 8.52 × 10(-4)); the finding was validated in the replication cohort (combined P = 3.42 × 10(-6)). Incubation of intestinal lamina propria leukocytes with granulocyte-macrophage colony-stimulating factor resulted in high levels of phosphorylation of signal transducer and activator of transcription (STAT5) and lesser increases in phosphorylation of extracellular signal-regulated kinase and AK straining transforming (AKT). Cells co-transfected with full-length and mutant forms of CSF2RB had reduced pSTAT5 after stimulation with granulocyte-macrophage colony-stimulating factor, compared with cells transfected with control CSF2RB, indicating a dominant-negative effect of the mutant gene. Monocytes from patients with CD who were heterozygous for the frameshift mutation (6% of CD cases analyzed) had reduced responses to granulocyte-macrophage colony-stimulating factor and markedly decreased activity of aldehyde dehydrogenase; activity of this enzyme has been associated with immune tolerance. CONCLUSIONS: In a genetic analysis of Ashkenazi Jewish individuals, we associated CD with a frameshift mutation in CSF2RB. Intestinal monocytes from carriers of this mutation had reduced responses to granulocyte-macrophage colony-stimulating factor, providing an additional mechanism for alterations to the innate immune response in individuals with CD.

Transmembrane channel-like (tmc) gene regulates Drosophila larval locomotion.

Drosophila larval locomotion, which entails rhythmic body contractions, is controlled by sensory feedback from proprioceptors. The molecular mechanisms mediating this feedback are little understood. By using genetic knock-in and immunostaining, we found that the Drosophila melanogaster transmembrane channel-like (tmc) gene is expressed in the larval class I and class II dendritic arborization (da) neurons and bipolar dendrite (bd) neurons, both of which are known to provide sensory feedback for larval locomotion. Larvae with knockdown or loss of tmc function displayed reduced crawling speeds, increased head cast frequencies, and enhanced backward locomotion. Expressing Drosophila TMC or mammalian TMC1 and/or TMC2 in the tmc-positive neurons rescued these mutant phenotypes. Bending of the larval body activated the tmc-positive neurons, and in tmc mutants this bending response was impaired. This implicates TMC's roles in Drosophila proprioception and the sensory control of larval locomotion. It also provides evidence for a functional conservation between Drosophila and mammalian TMCs.

Deep resequencing of GWAS loci identifies rare variants in CARD9, IL23R and RNF186 that are associated with ulcerative colitis.

Genome-wide association studies and follow-up meta-analyses in Crohn's disease (CD) and ulcerative colitis (UC) have recently identified 163 disease-associated loci that meet genome-wide significance for these two inflammatory bowel diseases (IBD). These discoveries have already had a tremendous impact on our understanding of the genetic architecture of these diseases and have directed functional studies that have revealed some of the biological functions that are important to IBD (e.g. autophagy). Nonetheless, these loci can only explain a small proportion of disease variance (~14% in CD and 7.5% in UC), suggesting that not only are additional loci to be found but that the known loci may contain high effect rare risk variants that have gone undetected by GWAS. To test this, we have used a targeted sequencing approach in 200 UC cases and 150 healthy controls (HC), all of French Canadian descent, to study 55 genes in regions associated with UC. We performed follow-up genotyping of 42 rare non-synonymous variants in independent case-control cohorts (totaling 14,435 UC cases and 20,204 HC). Our results confirmed significant association to rare non-synonymous coding variants in both IL23R and CARD9, previously identified from sequencing of CD loci, as well as identified a novel association in RNF186. With the exception of CARD9 (OR = 0.39), the rare non-synonymous variants identified were of moderate effect (OR = 1.49 for RNF186 and OR = 0.79 for IL23R). RNF186 encodes a protein with a RING domain having predicted E3 ubiquitin-protein ligase activity and two transmembrane domains. Importantly, the disease-coding variant is located in the ubiquitin ligase domain. Finally, our results suggest that rare variants in genes identified by genome-wide association in UC are unlikely to contribute significantly to the overall variance for the disease. Rather, these are expected to help focus functional studies of the corresponding disease loci.

Granulocyte-macrophage colony-stimulating factor autoantibodies: a marker of aggressive Crohn's disease.

BACKGROUND: Neutralizing autoantibodies (Abs) against granulocyte-macrophage colony-stimulating factor (GM-CSF Ab) have been associated with stricturing ileal Crohn's disease (CD) in a largely pediatric patient cohort (total 394, adult CD 57). The aim of this study was to examine this association in 2 independent predominantly adult inflammatory bowel disease patient cohorts. METHODS: Serum samples from 742 subjects from the NIDDK IBD Genetics Consortium and 736 subjects from Australia were analyzed for GM-CSF Ab and genetic markers. We conducted multiple regression analysis with backward elimination to assess the contribution of GM-CSF Ab levels and established CD risk alleles and smoking on ileal disease location in the 477 combined CD subjects from both cohorts. We also determined associations of GM-CSF Ab levels with complications requiring surgical intervention in combined CD subjects in both cohorts. RESULTS: Serum samples from patients with CD expressed significantly higher concentrations of GM-CSF Ab when compared with ulcerative colitis or controls in each cohort. Nonsmokers with ileal CD expressed significantly higher GM-CSF Ab concentrations in the Australian cohort (P = 0.002). Elevated GM-CSF Ab, ileal disease location, and disease duration more than 3 years were independently associated with stricturing/penetrating behavior and intestinal resection for CD. CONCLUSIONS: The expression of high GM-CSF Ab is a risk marker for aggressive CD behavior and complications including surgery. Modifying factors include environmental exposure to smoking and genetic risk markers.

Supporting conditional mouse mutagenesis with a comprehensive cre characterization resource.

Full realization of the value of the loxP-flanked alleles generated by the International Knockout Mouse Consortium will require a large set of well-characterized cre-driver lines. However, many cre driver lines display excision activity beyond the intended tissue or cell type, and these data are frequently unavailable to the potential user. Here we describe a high-throughput pipeline to extend characterization of cre driver lines to document excision activity in a wide range of tissues at multiple time points and disseminate these data to the scientific community. Our results show that the majority of cre strains exhibit some degree of unreported recombinase activity. In addition, we observe frequent mosaicism, inconsistent activity and parent-of-origin effects. Together, these results highlight the importance of deep characterization of cre strains, and provide the scientific community with a critical resource for cre strain information.

Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease.

Crohn's disease and ulcerative colitis, the two common forms of inflammatory bowel disease (IBD), affect over 2.5 million people of European ancestry, with rising prevalence in other populations. Genome-wide association studies and subsequent meta-analyses of these two diseases as separate phenotypes have implicated previously unsuspected mechanisms, such as autophagy, in their pathogenesis and showed that some IBD loci are shared with other inflammatory diseases. Here we expand on the knowledge of relevant pathways by undertaking a meta-analysis of Crohn's disease and ulcerative colitis genome-wide association scans, followed by extensive validation of significant findings, with a combined total of more than 75,000 cases and controls. We identify 71 new associations, for a total of 163 IBD loci, that meet genome-wide significance thresholds. Most loci contribute to both phenotypes, and both directional (consistently favouring one allele over the course of human history) and balancing (favouring the retention of both alleles within populations) selection effects are evident. Many IBD loci are also implicated in other immune-mediated disorders, most notably with ankylosing spondylitis and psoriasis. We also observe considerable overlap between susceptibility loci for IBD and mycobacterial infection. Gene co-expression network analysis emphasizes this relationship, with pathways shared between host responses to mycobacteria and those predisposing to IBD.

Deep resequencing of GWAS loci identifies independent rare variants associated with inflammatory bowel disease.

More than 1,000 susceptibility loci have been identified through genome-wide association studies (GWAS) of common variants; however, the specific genes and full allelic spectrum of causal variants underlying these findings have not yet been defined. Here we used pooled next-generation sequencing to study 56 genes from regions associated with Crohn's disease in 350 cases and 350 controls. Through follow-up genotyping of 70 rare and low-frequency protein-altering variants in nine independent case-control series (16,054 Crohn's disease cases, 12,153 ulcerative colitis cases and 17,575 healthy controls), we identified four additional independent risk factors in NOD2, two additional protective variants in IL23R, a highly significant association with a protective splice variant in CARD9 (P < 1 × 10(-16), odds ratio ≈ 0.29) and additional associations with coding variants in IL18RAP, CUL2, C1orf106, PTPN22 and MUC19. We extend the results of successful GWAS by identifying new, rare and probably functional variants that could aid functional experiments and predictive models.