Citations

Abstract Polygenic risk scores (PRSs), which quantify inherited susceptibility to complex traits and diseases, have emerged as valuable tools for risk stratification and precision medicine. Despite their promise, PRS developed on European cohorts often demonstrate substantially reduced predictive accuracy in non-European populations, due to differences in genetic architecture. The disproportionate representation of European ancestry cohorts in genome-wide association studies (GWAS) leads to inequitable deployment of PRS technologies across diverse populations. Here, we introduce PRANA (Polygenic Risk Adaptation via Neural-network Architecture), a deep learning framework that adapts an existing PRS developed on one population to other ancestries. Unlike methods that require large-scale GWAS in the target population, PRANA leverages pre-trained PRS models derived from European cohorts and adapts them using modestly sized cohorts from the target population. We evaluated PRANA on seven complex traits in South Asian, East Asian and Ashkenazi Jewish populations, as well as in selected smaller East Asian subpopulations where the scarcity of training data poses a particular challenge. PRANA mostly improved predictive performance of the baseline PRS models by 5%-20% in terms of effect size (β) and Nagelkerke’s R², and, in most cases, outperformed existing cross-ancestry multi-PRS approaches. These results highlight PRANA as a scalable and practical strategy to reduce disparities in genomic risk prediction and advance the equitable application of PRS in diverse populations.

Abstract Inflammatory bowel diseases (IBD), principally Crohn’s disease (CD) and ulcerative colitis (UC), are common chronic disorders involving inflammation and often progressive tissue damage. Genome-wide association studies have mapped many risk signals, but the causal variants, effector genes and relevant cellular contexts remain difficult to resolve, limiting mechanistic interpretation and therapeutic translation. Here we performed a multi-ancestry GWAS meta-analysis of 125,992 individuals with IBD and more than 1.2 million controls, identifying 619 independent association signals (374 novel) at 420 IBD regions that account for 77–80% of SNP-based heritability. Fine-mapping resolved 81 high-confidence variants, 41 not previously reported. Although most signals were shared between CD and UC, 39% showed IBD subtype specificity, with UC signals showing stronger enrichment in functional annotations from intestinal epithelial, secretory and enteroendocrine cells, and CD showing stronger genetic correlations with circulating inflammatory biomarkers, including C-reactive protein and glycoprotein acetylation. Latent causal modelling supported a causal effect of decreased high-density lipoprotein on CD risk. By integrating bulk and single-cell eQTL and pQTL resources using colocalisation and Mendelian randomisation, together with coding-variant evidence from exome sequencing, we prioritised 664 candidate effector genes across 341 signals, including 390 newly implicated IBD genes, revealing new biological mechanisms and candidate therapeutic targets supported by human genetics.

Abstract Inflammatory bowel disease (IBD) is a chronic immune-mediated disorder of the gastrointestinal tract whose genetic basis is only partly resolved because most risk variants identified by genome-wide association studies (GWAS) lie in non-coding regions, limiting direct gene assignment and biological interpretation 1,2 . Here we analysed whole-exome and whole-genome sequencing data from 86,213 IBD cases and 478,363 controls of European ancestry. We identified 68 IBD genes directly implicated by conditionally independent protein-coding associations across the allele frequency spectrum. Many newly implicated IBD genes are supported by orthogonal genomic or pleiotropic evidence, pointing to disease-related pathways and nominating targets with therapeutic relevance. We further identified allelic series and non-additive effects at key loci such as NOD2 and TYK2. These results show that large-scale sequencing can resolve disease genes and pathways that remain ambiguous from non-coding association alone, providing a more direct route from human genetics to biological insight and therapeutic hypotheses.

BACKGROUND: Among accepted US heart organs, listing centers accept organ offers earliest for White women, followed by Black women, White men, and Black men. Understanding the relationships of center- and geographic-level decisions is necessary to understand waitlist disparities. We sought to determine whether listing center and geography are associated with the first heart organ acceptance by candidate race, since race demographics vary regionally across the United States. METHODS: Using the United Network for Organ Sharing data sets, we identified first organ offers for Black and White candidates listed for heart transplant (October 18, 2018 to September 30, 2024) and compared models with and without listing center effects adjusted for candidate-, donor-, and offer-level variables. RESULTS: Among 20 668 candidates (31.6% Black, 68.4% White, 26.5% women), the adjusted odds of first offer acceptance were lower for Black candidates compared with White candidates (odds ratio, 0.84 [95% CI, 0.76–0.94]; P =0.001) when listing center was not included in the model; but after adjusting for listing center effects, odds were similar by race (odds ratio, 0.98 [95% CI, 0.88–1.10]; P =0.78). There were no clear geographic patterns by center, but centers with lower proportions of Black candidates had higher acceptance rates. CONCLUSIONS: Variability in overall acceptance rate among listing centers explains the lower first offer acceptance for Black compared with White heart candidates. Baseline acceptance rates were linked to the center-level proportion of Black candidates but not geography. Investigation of strategies to systemically improve early acceptance of good heart organs may reduce Black and White disparities in wait time duration.

In adult persons the narcoleptic syndrome consists of narcolepsy proper, cataplexy, sleep paralysis and hypnagogic hallucinations. The characteristics of these phenomena are discussed. The disease is not often recognized in children, although anamnestic evidence suggests that in the majority of patients the onset of the disorder is in childhood or adolescence. Data are presented concerning 16 children in whom narcolepsy was evident. Problems in diagnosis are reviewed and common pitfalls and misinterpretations are discussed. The use of analeptic drugs for treatment is outlined.

Abstract Rare Mendelian disorders affect 300-400 million people globally. Although genetic testing has become widely adopted, gene-specific evidence for tailored variant interpretation remains scattered across resources. We present Gene Portals, a framework for gene-centered multimodal knowledge bases that co-localize expert-harmonized clinical data, functional assays, population variation, structural annotations and gene-specific ACMG/AMP specifications within a single resource. A modular interface integrates this unified evidence with VCEP-refined ACMG specifications to enable automated gene-specific variant classification, infer molecular mechanisms, and support cross-gene analyses. We demonstrate the framework’s utility across five Gene portals spanning eleven neurodevelopmental disorder-associated genes, integrating data from 4,423 individuals with 2,838 unique variants, 36,149 ClinVar submissions, and 1,044 expert-curated molecular readouts. By organizing evidence that is otherwise dispersed across multiple sources into a unified, queryable framework, the SCN, GRIN, CACNA1A, SATB2 and SLC6A1 Gene Portals became widely used community resources and provide an extensible template for standardized rare-disease variant interpretation and mechanism-aware discovery.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Genetic/Familial High-Risk Assessment: Breast, Ovarian, Pancreatic, and Prostate are intended to serve as a resource for health care providers to identify individuals who may benefit from cancer risk assessment and genetic counseling and testing; help guide decisions related to genetic testing; and facilitate a multidisciplinary approach in the comprehensive care of individuals at increased risk for hereditary breast, ovarian, pancreatic, and prostate cancer. The current guidelines focus primarily on assessment of pathogenic and likely pathogenic (P/LP) variants associated with increased risk of breast, ovarian, pancreatic, and prostate cancer and recommended approaches to genetic counseling/testing and care strategies in individuals with these P/LP variants associated with increased risk of these cancers. These NCCN Guidelines Insights summarize the panel’s most recent recommendations regarding screening for prostate cancer and pancreas cancer, as well as testing criteria for nonepithelial ovarian cancer.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Hodgkin lymphoma provide expert, multidisciplinary recommendations for the diagnosis and treatment of Hodgkin lymphoma. The panel convenes annually to update recommendations based on a review of recently published clinical trials. This selection from the NCCN Guidelines for Hodgkin Lymphoma focuses on the management of newly diagnosed and relapsed/refractory classic Hodgkin lymphoma in adults aged 18 to 60 years.

Abstract Background Management of acute cardiogenic shock for post-cardiotomy and post-transplant patients remains challenging. The use of veno-arterial extracorporeal membrane oxygenation (VA-ECMO) for circulatory support is a key intervention, yet the optimal cannulation strategy—central vs. peripheral—remains debated. This study evaluates outcomes associated with each approach to inform clinical decision-making. Methods A retrospective analysis was conducted on 319 patients who received VA-ECMO for CS intraoperatively or within 24 hours postoperatively at Mayo Clinic (2010–2023). Patients were categorized into central (n=241) and peripheral (n=78) ECMO groups. Propensity score (PS) weighting using stabilized inverse probability of treatment weighting was applied to minimize baseline imbalances. Outcomes included in-hospital mortality, bleeding requiring reoperation, limb ischemia, prolonged ventilation (>7 days), and sepsis. Results The median age at ECMO initiation was 68.5 years, with 37.3% female patients. Right ventricular (RV) dysfunction was the predominant indication for ECMO initiation (p<0.001). After PS weighting, no significant difference was observed in in-hospital mortality (49.8% vs. 44.5%, p=0.416) or other major complications between central and peripheral ECMO (see Table 1). Stroke was more frequent in central ECMO (P = 0.159), though not statistically significant. Reoperation for bleeding occurred significantly more often in central ECMO in the unweighted analysis (P = 0.047), but the difference lost statistical significance after weighting (P = 0.071). Renal failure was comparable between groups (P = 0.888). Notably, sternal infection rates were comparable between groups (P=0.921). Acute limb ischemia was more common in the peripheral group (P = 0.209). Limb ischemia associated with central ECMO was not caused by the ECMO cannulas but was instead related to concomitant use of femoral intra-aortic balloon pump. Conclusions After propensity score weighting, analysis showed no significant differences in mortality or complications between central ECMO and peripheral ECMO for post-cardiotomy and post-transplant cardiogenic shock.