- Contribution of autosomal rare and de novo variants to sex differences in autismon February 15, 2025
Autism is four times more prevalent in males than females. To study whether this reflects a difference in genetic predisposition attributed to autosomal rare variants, we evaluated sex differences in effect size of damaging protein-truncating and missense variants on autism predisposition in 47,061 autistic individuals using a liability model with differing thresholds. Given the sex differences in the rates of cognitive impairment among autistic individuals, we also compared effect sizes of […]
- Activation of the imprinted Prader-Willi syndrome locus by CRISPR-based epigenome editingon February 13, 2025
Epigenome editing with DNA-targeting technologies such as CRISPR-dCas9 can be used to dissect gene regulatory mechanisms and potentially treat associated disorders. For example, Prader-Willi syndrome (PWS) results from loss of paternally expressed imprinted genes on chromosome 15q11.2-q13.3, although the maternal allele is intact but epigenetically silenced. Using CRISPR repression and activation screens in human induced pluripotent stem cells (iPSCs), we identified genomic elements that […]
- Low prevalence of CWH43 variants among Finnish and Norwegian idiopathic normal pressure hydrocephalus patients: a cohort-based observational studyon February 13, 2025
CONCLUSIONS: We studied the iNPH-associated CWH43 LOF variants for the first time on a population-scale. Contrary to previously reported findings in smaller cohorts, our study revealed a low prevalence of these variants in the population-scale Finnish iNPH cohort, with no effect on disease risk of iNPH. The prevalence in the Norwegian iNPH cohort was also low compared to previous studies.
- East and South Asian-Specific Blood Pressure Trajectories and Cardiovascular Diseaseon February 12, 2025
CONCLUSIONS: East and South Asian individuals exhibit distinct BP trajectories that age-differentially associate with incident CVD. Disaggregating Asian subgroups may inform tailored hypertension screening and management.
- Research Domain Criteria in NIMH Grants Characterized Using Large Language Modelson February 12, 2025
CONCLUSIONS AND RELEVANCE: In this study of NIMH funding, grants reflecting different RDoC domains differed substantially in their scientific impact in terms of publications, citations, and patent generation. The findings suggest that large language models represent a promising approach to characterizing research proposals at scale, which may be useful in guiding resource allocation to maximize scientific return on investment.
- Whole Genome Sequencing of Pedigrees With High Density of Substance Use and Psychiatric Disorders: A Meeting Reporton February 12, 2025
The National Institute of Drug Abuse convened a panel of scientists with expertise in substance use disorders (SUD) and genetic methodologies primarily to determine the feasibility of performing whole genome sequencing utilizing existing pedigree collections with a high density of SUD and psychiatric disorders. A major focus was on determining if there had been any successes in identifying genetic variants for complex traits in family-based designs. Such information could provide assurance […]
- Characterizing Spin in Psychiatric Clinical Research Literature Using Large Language Modelson February 12, 2025
No abstract
- White matter hyperintensity severity modifies gut metabolite association with cognitive outcomeson February 12, 2025
CONCLUSION: An elevated level of GDCA was associated with worse cognition. WMH severity modified the association between GDCA and cognitive outcomes.
- Instability of high polygenic risk classification and mitigation by integrative scoringon February 12, 2025
Polygenic risk scores (PRS) continue to improve with novel methods and expanding genome-wide association studies. Healthcare and commercial laboratories are increasingly deploying PRS reports to patients, but it is unknown how the classification of high polygenic risk changes across individual PRS. Here, we assess the association and classification performance of cataloged PRS for three complex traits. We chronologically order all trait-related publications (Pub(n)) and identify the single […]
- Evaluating predictors of kinase activity of STK11 variants identified in primary human non-small cell lung cancerson February 11, 2025
Critical evaluation of computational tools for predicting variant effects is important considering their increased use in disease diagnosis and driving molecular discoveries. In the sixth edition of the Critical Assessment of Genome Interpretation (CAGI) challenge, a dataset of 28 STK11 rare variants (27 missense, 1 single amino acid deletion), identified in primary non-small cell lung cancer biopsies, was experimentally assayed to characterize computational methods from four participating […]
- Spatial Correlates of Dementia and Disability After Intracerebral Hemorrhageon February 8, 2025
CONCLUSIONS: Specific distribution of ICH lesions is linked to development of dementia and disability after ICH. These insights have the potential to enhance clinical prognostic models for patients with ICH, facilitating more precise predictions of outcomes based on hemorrhage location.
- Study Finds Most Older Adults Use Digital Health Technologies, Plus Some Surpriseson February 7, 2025
No abstract
- Disease Burden in Female Patients With X-Linked Adrenoleukodystrophyon February 7, 2025
BACKGROUND AND OBJECTIVES: X-linked adrenoleukodystrophy (ALD) is a neurodegenerative disease primarily affecting male patients. Female patients with ALD are also affected in adulthood, yet their disease course and symptom burden remain poorly defined. In this single-site study, we set out to characterize disease burden in female individuals with ALD and identify barriers faced by this patient population.
- A statistical framework for multi-trait rare variant analysis in large-scale whole-genome sequencing studieson February 7, 2025
Large-scale whole-genome sequencing (WGS) studies have improved our understanding of the contributions of coding and noncoding rare variants to complex human traits. Leveraging association effect sizes across multiple traits in WGS rare variant association analysis can improve statistical power over single-trait analysis, and also detect pleiotropic genes and regions. Existing multi-trait methods have limited ability to perform rare variant analysis of large-scale WGS data. We propose...
- Causal Mediation Analysis: A Summary-Data Mendelian Randomization Approachon February 6, 2025
Summary-data Mendelian randomization (MR), a widely used approach in causal inference, has recently attracted attention for improving causal mediation analysis. Two existing methods corresponding to the difference method and product method of linear mediation analysis have been developed to perform MR-based mediation analysis using the inverse-variance weighted method (MR-IVW). Despite these developments, there is still a need for more rigorous, efficient, and precise MR-based mediation...
- Kidney multiome-based genetic scorecard reveals convergent coding and regulatory variantson February 6, 2025
Kidney dysfunction is a major cause of mortality, but its genetic architecture remains elusive. In this study, we conducted a multiancestry genome-wide association study in 2.2 million individuals and identified 1026 (97 previously unknown) independent loci. Ancestry-specific analysis indicated an attenuation of newly identified signals on common variants in European ancestry populations and the power of population diversity for further discoveries. We defined genotype effects on […]
- Whole genome sequencing in early onset advanced heart failureon February 5, 2025
The genetic contributions to early onset heart failure (HF) are incompletely understood. Genetic testing in advanced HF patients undergoing heart transplantation (HTx) may yield clinical benefits, but data is limited. We performed deep-coverage whole genome sequencing (WGS) in 102 Swedish HTx recipients. Gene lists were compiled through a systematic literature review. Variants were prioritized for pathogenicity and classified manually. We also compared polygenic HF risk scores to a...
- Cell Painting for cytotoxicity and mode-of-action analysis in primary human hepatocyteson February 3, 2025
High-throughput, human-relevant approaches for predicting chemical toxicity are urgently needed for better decision-making in human health. Here, we apply image-based profiling (the Cell Painting assay) and two cytotoxicity assays (metabolic and membrane damage readouts) to primary human hepatocytes after exposure to eight concentrations of 1085 compounds that include pharmaceuticals, pesticides, and industrial chemicals with known liver toxicity-related outcomes. Three computational methods...
- Clonal Hematopoiesis and Risk of Heart Failure After Autologous Hematopoietic Cell Transplantation for Lymphomaon February 3, 2025
CONCLUSIONS: CHIP was highly prevalent and associated with risk for HF and nonrelapse mortality after HCT. These findings highlight the role of CHIP as a novel biomarker and potential target for intervention to improve outcomes after autologous HCT.
- Longitudinal Evaluation of Genetic Hypertrophic Cardiomyopathy Penetrance and Transition to Disease in an Academic Biobankon January 31, 2025
No abstract
- Genetic Predisposition to Coronary Artery Disease: Evaluating Statin Therapy in Elder Populations From PROSPERon January 31, 2025
No abstract
- Study Finds People Prefer AI Over Clinician Responses to Questions in the Electronic Medical Recordon January 31, 2025
No abstract
- Characterization of LTBP2 mutation causing mitral valve prolapseon January 30, 2025
CONCLUSION: We report a KO mouse strain with an LTBP2 mutation, demonstrating a valve phenotype, alongside a family with a novel mutation linked to MVP.
- Predicting Atrial Fibrillation After Stroke by Combining Polygenic Risk Scores and Clinical Featureson January 30, 2025
Background: Since treatment with anticoagulants can prevent recurrent strokes, identification of patients at risk for incident AF after stroke is crucial. We aimed to investigate whether the addition of AF polygenic risk scores (PRS) to existing clinical risk predictors could improve prediction of AF after stroke. Methods: Patients diagnosed with ischemic stroke at Massachusetts General Hospital between 2003-2017 were included. Clinical AF risk was estimated using the Re-CHARGE-AF model and...
- Shorter weeknight sleep duration mediates the relationship between earlier adrenarche and depressed mood in adolescentson January 30, 2025
CONCLUSIONS: Maintaining adequate weeknight sleep across adolescent years may mitigate the impact of earlier adrenarche on depressed mood in late adolescence.
- Correction: Assessment and ascertainment in psychiatric molecular genetics: challenges and opportunities for cross-disorder researchon January 28, 2025
No abstract
- Description of STRIVE-ON Study Protocol: Safety and Tolerability of GTX-104 (Nimodipine Injection for IV Infusion) Compared with Oral Nimodipine in Patients Hospitalized for Aneurysmal Subarachnoid Hemorrhage (aSAH): A Prospective, Randomized, Phase III Trial (STRIVE-ON)on January 28, 2025
Oral nimodipine is the only drug approved in North America for patients with aneurysmal subarachnoid hemorrhage (aSAH). However, bioavailability is variable and frequently poor, leading to fluctuations in peak plasma concentrations that cause dose-limiting hypotension. Furthermore, administration is problematic in patients who cannot swallow. An oral liquid formulation exists but causes diarrhea. An intravenous nimodipine formulation (GTX-104) has been developed that has bioavailability...
- AMH protects the ovary from doxorubicin by regulating cell fate and the response to DNA damageon January 28, 2025
Anti-Müllerian hormone (AMH) protects the ovarian reserve from chemotherapy, and this effect is most pronounced with Doxorubicin (DOX). However, DOX toxicity and AMH rescue mechanisms in the ovary have remained unclear. Herein, we characterize the consequences of these treatments in ovarian cell types using scRNAseq. DOX-induced DNA damage activates Tp53 class mediators across ovarian cell types. In the mesenchyme, cotreatment with AMH halts theca progenitor differentiation and reduces […]
- Clonal Hematopoiesis Associates with Prevalent and Incident Cardiometabolic Disease in High-Risk Individualson January 27, 2025
CONCLUSIONS: In high-risk individuals referred for cardiac catheterization, large CHIP and non-DNTM3A CHIP were associated with obesity, prevalent HF, incident CV events. These findings strengthen the importance of CHIP as a biomarker for CV disease and highlight the contributing risk of large CHIP clones and non-DNMT3A CHIP variants.
- Correlates and Consequences of Clonal Hematopoiesis Expansion Rate: A 15-Year Longitudinal Study of 6,986 Womenon January 27, 2025
Clonal hematopoiesis of indeterminate potential (CHIP) is associated with increased mortality and malignancy risk, yet the determinants of clonal expansion remain poorly understood. We performed sequencing at >4,000x depth of coverage for CHIP mutations in 6,986 postmenopausal women from the Women's Health Initiative at two timepoints approximately 15 years apart. Among 3,685 mutations detected at baseline (VAF ≥ 0.5%), 50% progressed to CHIP (VAF ≥ 2%) at follow-up. We confirmed that […]
- Leveraging genetic ancestry continuum information to interpolate PRS for admixed populationson January 27, 2025
The relatively low representation of admixed populations in both discovery and fine-tuning individual-level datasets limits polygenic risk score (PRS) development and equitable clinical translation for admixed populations. Under the assumption that the most informative PRS weight for a homogeneous sample varies linearly in an ancestry continuum space, we introduce a Genetic Distance-assisted PRS Combination Pipeline for Diverse Genetic Ancestries (DiscoDivas) to interpolate a harmonized PRS […]
- Rare variants in PRKCI cause Van der Woude syndrome and other features of peridermopathyon January 27, 2025
Van der Woude syndrome (VWS) is an autosomal dominant disorder characterized by lower lip pits and orofacial clefts (OFCs). With a prevalence of approximately 1 in 35,000 live births, it is the most common form of syndromic clefting and may account for ~2% of all OFCs. The majority of VWS is attributed to genetic variants in IRF6 (~70%) or GRHL3 (~5%), leaving up to 25% of individuals with VWS without a molecular diagnosis. Both IRF6 and GRHL3 function in a transcriptional regulatory network...
- Standardized Measurement of Type 1 Diabetes Polygenic Risk Across Multi-Ancestry Population Cohortson January 27, 2025
Type 1 diabetes (T1D) polygenic risk scores (PRS) are effective tools for discriminating T1D from other diabetes types and predicting T1D risk, with applications in screening and intervention trials. A previously published T1D Genetic Risk Score 2 (GRS2) is widely adopted, but challenges in standardization and accessibility have hindered broader clinical and research utility. To address this, we introduce GRS2x, a standardized and cross-compatible method for accurate T1D PRS calculation,...
- Detailed tandem repeat allele profiling in 1,027 long-read genomes reveals genome-wide patterns of pathogenicityon January 27, 2025
Tandem repeats are a highly polymorphic class of genomic variation that play causal roles in rare diseases but are notoriously difficult to sequence using short-read techniques^(1,2). Most previous studies profiling tandem repeats genome-wide have reduced the description of each locus to the singular value of the length of the entire repetitive locus^(3,4). Here we introduce a comprehensive database of 3.6 billion tandem repeat allele sequences from over one thousand individuals using HiFi...
- Proteomic Profiling of Medullary Thyroid Cancer Identifies CAPN1 as a Key Regulator of NF1 and RET Fueled Growthon January 27, 2025
Background: Medullary thyroid cancer (MTC) is a frequently metastatic tumor of the thyroid that develops from the malignant transformation of C-cells. These tumors most commonly have activating mutations within the RET or RAS proto-oncogenes. Germline mutations within RET result in C-cell hyperplasia, and cause the MTC pre-disposition disorder, multiple endocrine neoplasia, type 2A (MEN2A). Single-agent therapies for MTC, including vandetanib (VAN) and cabozantinib for all MTCs and […]
- Health-Related Behaviors and Risk of Common Age-Related Brain Diseases Across Severities of Genetic Riskon January 27, 2025
No abstract
- A genome-wide atlas of human cell morphologyon January 27, 2025
A key challenge of the modern genomics era is developing empirical data-driven representations of gene function. Here we present the first unbiased morphology-based genome-wide perturbation atlas in human cells, containing three genome-wide genotype-phenotype maps comprising CRISPR-Cas9-based knockouts of >20,000 genes in >30 million cells. Our optical pooled cell profiling platform (PERISCOPE) combines a destainable high-dimensional phenotyping panel (based on Cell Painting) with […]
- Use of the Adaptive Behaviour Dementia Questionnaire in a Down Syndrome Specialty Clinicon January 25, 2025
CONCLUSION: Neither the original ABDQ nor a modified version adequately identified patients with cognitive impairment and/or dementia within the Down syndrome clinical program. The inability to replicate findings from the initial ABDQ validation may be due to differences in setting and format.
- Advancing long-read nanopore genome assembly and accurate variant calling for rare disease detectionon January 25, 2025
More than 50% of families with suspected rare monogenic diseases remain unsolved after whole-genome analysis by short-read sequencing (SRS). Long-read sequencing (LRS) could help bridge this diagnostic gap by capturing variants inaccessible to SRS, facilitating long-range mapping and phasing and providing haplotype-resolved methylation profiling. To evaluate LRS's additional diagnostic yield, we sequenced a rare-disease cohort of 98 samples from 41 families, using nanopore sequencing, […]
- Exploring RNF213 in Ischemic Stroke and Moyamoya Disease: From Cellular Models to Clinical Insightson January 25, 2025
Advances in stroke genetics have highlighted the critical role of rare genetic variants in cerebrovascular diseases, with RNF213 emerging as a key player in ischemic stroke and Moyamoya disease (MMD). Initially identified as the primary susceptibility gene for MMD, RNF213-notably the p.R4810K variant-has been strongly linked to intracranial artery stenosis (ICAS) and various ischemic stroke subtypes, particularly in East Asian populations. This gene encodes an E3 ubiquitin ligase with diverse...
- Synthetic data in generalizable, learning-based neuroimagingon January 24, 2025
Synthetic data have emerged as an attractive option for developing machine-learning methods in human neuroimaging, particularly in magnetic resonance imaging (MRI)-a modality where image contrast depends enormously on acquisition hardware and parameters. This retrospective paper reviews a family of recently proposed methods, based on synthetic data, for generalizable machine learning in brain MRI analysis. Central to this framework is the concept of domain randomization, which involves […]
- Dynamic Importance of Genomic and Clinical Risk for Coronary Artery Disease Over the Life Courseon January 24, 2025
CONCLUSIONS: Genomic and clinical risk factors for CAD display time-varying importance across the lifespan. The study underscores the added value of CAD PRS, particularly among individuals younger than 55 years, for enhancing early risk prediction and prevention strategies. All results are available at https://surbut.github.io/dynamicHRpaper/index.html.
- Characterizing the underlying microangiopathy of deep cerebellar intracerebral hemorrhageon January 24, 2025
INTRODUCTION: While cerebral amyloid angiopathy is likely responsible for intracerebral hemorrhage (ICH) occurring in superficial (grey matter, vermis) cerebellar locations, it is unclear whether hypertensive arteriopathy (HA), the other major cerebral small vessel disease (cSVD), is associated with cerebellar ICH (cICH) in deep (white matter, deep nuclei, cerebellar peduncle) regions. We tested the hypothesis that HA-associated neuroimaging markers are significantly associated with deep cICH...
- Researchers Tested an AI Tool That Drafts Responses to Patient Messages-Here's What They Foundon January 24, 2025
No abstract
- Integrative proteogenomic analysis identifies COL6A3-derived endotrophin as a mediator of the effect of obesity on coronary artery diseaseon January 24, 2025
Obesity strongly increases the risk of cardiometabolic diseases, yet the underlying mediators of this relationship are not fully understood. Given that obesity strongly influences circulating protein levels, we investigated proteins mediating the effects of obesity on coronary artery disease, stroke and type 2 diabetes. By integrating two-step proteome-wide Mendelian randomization, colocalization, epigenomics and single-cell RNA sequencing, we identified five mediators and prioritized […]
- Genome-wide association analysis of composite sleep health scores in 413,904 individualson January 24, 2025
Recent genome-wide association studies (GWASs) of several individual sleep traits have identified hundreds of genetic loci, suggesting diverse mechanisms. Moreover, sleep traits are moderately correlated, so together may provide a more complete picture of sleep health, while illuminating distinct domains. Here we construct novel sleep health scores (SHSs) incorporating five core self-report measures: sleep duration, insomnia symptoms, chronotype, snoring, and daytime sleepiness, using […]
- Maternal-fetal cytokine profiles in acute SARS-CoV-2 "breakthrough" infection after COVID-19 vaccinationon January 23, 2025
CONCLUSION: Vaccination was associated with higher maternal cytokine levels during acute SARS-CoV-2 infection compared to unvaccinated infection, which may reflect vaccine-mediated priming of the immune system. A fetal inflammatory response specific to maternal SARS-CoV-2 infection was not observed.
- Announcing "Technology and Psychiatry" and Expanding Evidence-Based Comments and Reviews in JAMA Psychiatryon January 22, 2025
No abstract
- Hypoxia as a medicineon January 22, 2025
Oxygen is essential for human life, yet a growing body of preclinical research is demonstrating that chronic continuous hypoxia can be beneficial in models of mitochondrial disease, autoimmunity, ischemia, and aging. This research is revealing exciting new and unexpected facets of oxygen biology, but translating these findings to patients poses major challenges, because hypoxia can be dangerous. Overcoming these barriers will require integrating insights from basic science, high-altitude...
- In vivo CRISPR-Cas9 genome editing in mice identifies genetic modifiers of somatic CAG repeat instability in Huntington's diseaseon January 22, 2025
Huntington's disease, one of more than 50 inherited repeat expansion disorders¹, is a dominantly inherited neurodegenerative disease caused by a CAG expansion in HTT². Inherited CAG repeat length is the primary determinant of age of onset, with human genetic studies underscoring that the disease is driven by the CAG length-dependent propensity of the repeat to further expand in the brain^(3-9). Routes to slowing somatic CAG expansion, therefore, hold promise for disease-modifying therapies....
- Genomics yields biological and phenotypic insights into bipolar disorderon January 22, 2025
Bipolar disorder is a leading contributor to the global burden of disease¹. Despite high heritability (60-80%), the majority of the underlying genetic determinants remain unknown². We analysed data from participants of European, East Asian, African American and Latino ancestries (n = 158,036 cases with bipolar disorder, 2.8 million controls), combining clinical, community and self-reported samples. We identified 298 genome-wide significant loci in the multi-ancestry meta-analysis, a […]
- Sex Differences in Long COVIDon January 22, 2025
CONCLUSIONS AND RELEVANCE: In this prospective cohort study of the NIH RECOVER-Adult cohort, female sex was associated with an increased risk of long COVID compared with male sex, and this association was age, pregnancy, and menopausal status dependent. These findings highlight the need to identify biological mechanisms contributing to sex specificity to facilitate risk stratification, targeted drug development, and improved management of long COVID.
- Genomic Drivers of Coronary Artery Disease and Risk of Future Outcomes After Coronary Angiographyon January 21, 2025
CONCLUSIONS AND RELEVANCE: The findings of this study suggest that germline monogenic and polygenic risk are associated with acute coronary syndromes presentation, severity and burden of atherosclerosis, and risk of repeat angiogram, revascularization, and in-stent restenosis. CHIP variant status is associated with incident heart failure and mortality after coronary angiography.
- Diversity and consequences of structural variation in the human genomeon January 21, 2025
The biomedical community is increasingly invested in capturing all genetic variants across human genomes, interpreting their functional consequences and translating these findings to the clinic. A crucial component of this endeavour is the discovery and characterization of structural variants (SVs), which are ubiquitous in the human population, heterogeneous in their mutational processes, key substrates for evolution and adaptation, and profound drivers of human disease. The recent emergence […]
- Prenatal Care of Parents Who Continued Pregnancies With Down Syndrome, 2003-2022on January 20, 2025
Parents of children with Down syndrome have historically reported poor experiences receiving a prenatal diagnosis. In a 2003 survey, mothers reported that their physicians pitied them, emphasized negative aspects of Down syndrome, and encouraged them to terminate the pregnancy. This study assesses whether parents' perceptions have since improved. Community-based organizations that had distributed the original 2003 survey distributed a similar survey to parents who have had a child with Down...
- Engineering of CRISPR-Cas PAM recognition using deep learning of vast evolutionary dataon January 20, 2025
CRISPR-Cas enzymes must recognize a protospacer-adjacent motif (PAM) to edit a genomic site, significantly limiting the range of targetable sequences in a genome. Machine learning-based protein engineering provides a powerful solution to efficiently generate Cas protein variants tailored to recognize specific PAMs. Here, we present Protein2PAM, an evolution-informed deep learning model trained on a dataset of over 45,000 CRISPR-Cas PAMs. Protein2PAM rapidly and accurately predicts PAM...
- Deleterious coding variation associated with autism is consistent across populations, as exemplified by admixed Latin American populationson January 20, 2025
The past decade has seen remarkable progress in identifying genes that, when impacted by deleterious coding variation, confer high risk for autism spectrum disorder (ASD), intellectual disability, and other developmental disorders. However, most underlying gene discovery efforts have focused on individuals of European ancestry, limiting insights into genetic risks across diverse populations. To help address this, the Genomics of Autism in Latin American Ancestries Consortium (GALA) was […]
- Unsupervised Ensemble Learning for Efficient Integration of Pre-trained Polygenic Risk Scoreson January 20, 2025
The growing availability of pre-trained polygenic risk score (PRS) models has enabled their integration into real-world applications, reducing the need for extensive data labeling, training, and calibration. However, selecting the most suitable PRS model for a specific target population remains challenging, due to issues such as limited transferability, data het-erogeneity, and the scarcity of observed phenotype in real-world settings. Ensemble learning offers a promising avenue to enhance […]
- Prognostic models for depression and post-traumatic stress disorder symptoms following traumatic brain injury: a CENTER-TBI studyon January 17, 2025
CONCLUSION: Preinjury characteristics, such as psychiatric history and unemployment, and injury characteristics, such as violent injury cause, can increase the risk of mental health problems after TBI. The identification of patients at risk should be guided by early screening of mental health.
- Characterizing substructure via mixture modeling in large-scale genetic summary statisticson January 17, 2025
Genetic summary data are broadly accessible and highly useful, including for risk prediction, causal inference, fine mapping, and incorporation of external controls. However, collapsing individual-level data into summary data, such as allele frequencies, masks intra- and inter-sample heterogeneity, leading to confounding, reduced power, and bias. Ultimately, unaccounted-for substructure limits summary data usability, especially for understudied or admixed populations. There is a need for […]
- Enriched phenotypes in rare variant carriers suggest pathogenic mechanisms in rare disease patientson January 17, 2025
CONCLUSIONS: Analyses of large-scale population cohorts such as the UKB can be a critical tool to further our understanding of rare diseases in general. Continued research in this area could lead to more precise diagnostics and personalized treatment strategies for patients with rare and undiagnosed conditions.
- Dissection of type 2 diabetes: a genetic perspectiveon January 16, 2025
Diabetes is a leading cause of global mortality and disability, and its economic burden is substantial. This Review focuses on type 2 diabetes, which makes up 90-95% of all diabetes cases. Type 2 diabetes involves a progressive loss of insulin secretion often alongside insulin resistance and metabolic syndrome. Although obesity and a sedentary lifestyle are considerable contributors, research over the last 25 years has shown that type 2 diabetes develops on a predisposing genetic background,...
- Sex Differences in Natural History and Health Outcomes Among Individuals With Tic Disorderson January 15, 2025
OBJECTIVES: To analyze sex differences in outcomes in Tourette syndrome (TS) and Persistent Motor or Vocal tic disorders (PMVT) in the Tourette Association of America International Consortium for Genetics (TAAICG) dataset.
- Management of epilepsia partialis continua: A systematic reviewon January 15, 2025
CONCLUSION: Despite treatment, EPC typically lasts at least hours, and often days or longer. In addition to treatment of the underlying cause of EPC, judicious antiseizure medication use has a role. However, care should be taken not to cause harm (such as respiratory depression) with antiseizure medications, particularly noting that seizures are likely to be prolonged irrespective of antiseizure medication choice.
- Trans-ancestry genome-wide study of depression identifies 697 associations implicating cell types and pharmacotherapieson January 15, 2025
In a genome-wide association study (GWAS) meta-analysis of 688,808 individuals with major depression (MD) and 4,364,225 controls from 29 countries across diverse and admixed ancestries, we identify 697 associations at 635 loci, 293 of which are novel. Using fine-mapping and functional tools, we find 308 high-confidence gene associations and enrichment of postsynaptic density and receptor clustering. A neural cell-type enrichment analysis utilizing single-cell data implicates excitatory,...
- Genetic Predisposition to Low-Density Lipoprotein Cholesterol and Incident Type 2 Diabeteson January 15, 2025
CONCLUSIONS AND RELEVANCE: In this cohort study, LDL-C and T2D risks were inversely associated across genetic mechanisms for LDL-C variation. Further elucidation of the mechanisms associating low LDL-C risk with increased risk of T2D is warranted.
- Identifying genetic differences between bipolar disorder and major depression through multiple genome-wide association analyseson January 14, 2025
CONCLUSIONS: We find that MDD and BPD, including BPD-D are genetically distinct. Our findings support that controls, MDD and BPD patients primarily lie on a continuum of genetic risk. Future studies with larger and richer samples will likely yield a better understanding of these findings and enable the development of better genetic predictors distinguishing BPD and, importantly, BPD-D from MDD.
- Transcriptome-wide outlier approach identifies individuals with minor spliceopathieson January 13, 2025
RNA-sequencing has improved the diagnostic yield of individuals with rare diseases. Current analyses predominantly focus on identifying outliers in single genes that can be attributed to cis-acting variants within the gene locus. This approach overlooks causal variants with trans-acting effects on splicing transcriptome-wide, such as variants impacting spliceosome function. We present a transcriptomics-first method to diagnose individuals with rare diseases by examining transcriptome-wide...
- An Imperative for Public Sharing of Adverse Events of Gene Therapy Trialson January 13, 2025
No abstract
- Unsupervised deep learning of electrocardiograms enables scalable human disease profilingon January 11, 2025
The 12-lead electrocardiogram (ECG) is inexpensive and widely available. Whether conditions across the human disease landscape can be detected using the ECG is unclear. We developed a deep learning denoising autoencoder and systematically evaluated associations between ECG encodings and ~1,600 Phecode-based diseases in three datasets separate from model development, and meta-analyzed the results. The latent space ECG model identified associations with 645 prevalent and 606 incident Phecodes....
- Design and implementation of an action plan for justice, equity, diversity, and inclusion within the Clinical Genome Resourceon January 10, 2025
How might members of a large, multi-institutional research and resource consortium foster justice, equity, diversity, and inclusion as central to its mission, goals, governance, and culture? These four principles, often referred to as JEDI, can be aspirational-but to be operationalized, they must be supported by concrete actions, investments, and a persistent long-term commitment to the principles themselves, which often requires self-reflection and course correction. We present here the...
- Advancing Monogenic Diabetes Research and Clinical Care by Creating a Data Commons: The Precision Diabetes Consortium (PREDICT)on January 9, 2025
Monogenic diabetes mellitus (MDM) is a group of relatively rare disorders caused by pathogenic variants in key genes that result in hyperglycemia. Lack of identified cases, along with absent data standards, and limited collaboration across institutions have hindered research progress. To address this, the UChicago Monogenic Diabetes Registry (UCMDMR) and UChicago Data for the Common Good (D4CG) created a national consortium of MDM research institutions called the PREcision DIabetes ConsorTium...
- Circadian rhythms, metabolism, and nutrition support in critically ill adult patients: a narrative reviewon January 9, 2025
PURPOSE OF REVIEW: The human circadian system regulates several physiological processes, including metabolism, which becomes significantly disrupted during critical illness. The common use of 24-h continuous nutrition support feeding in the intensive care unit (ICU) may further exacerbate these disruptions; this review evaluates recent evidence comparing continuous and intermittent feeding schedules in critically ill adults.
- Irritability and Social Media Use in US Adultson January 8, 2025
CONCLUSIONS AND RELEVANCE: In this survey study of 42 597 US adults, irritability represented another correlate of social media use that merits further characterization, in light of known associations with depression and suicidality.
- Modifiable Risk Factors Unmask the Heart Failure Phenotype in TTR V142I Carrierson January 8, 2025
No abstract
- Amino acids and KLHL22 do not activate mTORC1 via DEPDC5 degradationon January 8, 2025
No abstract
- Mitochondrial DNA variant detection in over 6,500 rare disease families by the systematic analysis of exome and genome sequencing data resolves undiagnosed caseson January 7, 2025
CONCLUSION: mtDNA variant calling from data generated by exome and genome sequencing for nuclear variant analysis resulted in a genetic diagnosis or detection of a candidate variant for 0.4% of undiagnosed families affected by a broad range of rare diseases.
- Genetics of intracerebral hemorrhageon January 7, 2025
Spontaneous intracerebral hemorrhage(ICH) represents a life-threatening form of stroke, marked by its impact on survival and quality of life. ICH can be categorized from monogenic disorders linked to causal germline variants in ICH-related genes to complex sporadic cases, highlighting the interaction among lifestyle factors, environmental influences, and genetic components in determining risk. Among sporadic ICH, the influence of these factors varies across ICH subtypes, evidenced by...
- GREGoR: Accelerating Genomics for Rare Diseaseson January 7, 2025
Rare diseases are collectively common, affecting approximately one in twenty individuals worldwide. In recent years, rapid progress has been made in rare disease diagnostics due to advances in DNA sequencing, development of new computational and experimental approaches to prioritize genes and genetic variants, and increased global exchange of clinical and genetic data. However, more than half of individuals suspected to have a rare disease lack a genetic diagnosis. The Genomics Research to...
- Evaluating hypothetical prevention strategies for internalizing symptoms in the general population and at-risk childrenon January 6, 2025
CONCLUSIONS: With a causally informed strategy, we demonstrated the potential effects of numerous hypothetical interventions on modifiable factors for depression risk reduction, across multiple preventive settings. (PsycInfo Database Record (c) 2025 APA, all rights reserved).
- Characterizing features affecting local ancestry inference performance in admixed populationson January 3, 2025
In recent years, significant efforts have been made to improve methods for genomic studies of admixed populations using local ancestry inference (LAI). Accurate LAI is crucial to ensure that downstream analyses accurately reflect the genetic ancestry of research participants. Here, we test analytic strategies for LAI to provide guidelines for optimal accuracy, focusing on admixed populations reflective of Latin America's primary continental ancestries-African (AFR), Amerindigenous (AMR), and...
- Genetic insights into global heterogeneity of type 2 diabeteson January 3, 2025
No abstract
- Overcoming Barriers to Genomic Medicine Implementationon January 3, 2025
No abstract
- Researchers Compared Hospital Early Warning Scores for Clinical Deterioration-Here's What They Learnedon January 3, 2025
No abstract
- Rare germline structural variants increase risk for pediatric solid tumorson January 2, 2025
Pediatric solid tumors are a leading cause of childhood disease mortality. In this work, we examined germline structural variants (SVs) as risk factors for pediatric extracranial solid tumors using germline genome sequencing of 1765 affected children, their 943 unaffected parents, and 6665 adult controls. We discovered a sex-biased association between very large (>1 megabase) germline chromosomal abnormalities and increased risk of solid tumors in male children. The overall impact of […]
- Novel Phenotypes and Genotype-Phenotype Correlations in a Large Clinical Cohort of Patients With Kleefstra Syndromeon January 2, 2025
Kleefstra syndrome (KLEFS) is a genetic neurodevelopmental disorder caused by haploinsufficiency of EHMT1. The full spectrum of clinical features and genotype-phenotype correlations is currently not fully understood. We performed a retrospective chart review of patients with KLEFS evaluated at the Boston Children's Hospital Kleefstra Clinic. There were 65 individuals (40 females, 25 males, mean age 9.3 years). 17% had large 9q34 deletions (≥ 1 Mb), 29% had small 9q34 deletions (
- TILTomorrow today: dynamic factors predicting changes in intracranial pressure treatment intensity after traumatic brain injuryon January 2, 2025
Practices for controlling intracranial pressure (ICP) in traumatic brain injury (TBI) patients admitted to the intensive care unit (ICU) vary considerably between centres. To help understand the rational basis for such variance in care, this study aims to identify the patient-level predictors of changes in ICP management. We extracted all heterogeneous data (2008 pre-ICU and ICU variables) collected from a prospective cohort (n = 844, 51 ICUs) of ICP-monitored TBI patients in the […]
- Association between genetically predicted leisure and social activities and cardiovascular disease and other health outcomeson January 2, 2025
Participation in leisure and social activities (LSA) is associated with better health outcomes and lower mortality^(1-3). Previous observational studies demonstrated a relationship between engagement in LSA and both mental and physical health^(4,5). Although several studies⁶ examined the association between LSA and health outcomes, including cardiovascular disease, their possible causal relationship has not been studied. In this study, we investigated the causal relationship between LSA and...
- The impact of common and rare genetic variants on bradyarrhythmia developmenton January 2, 2025
To broaden our understanding of bradyarrhythmias and conduction disease, we performed common variant genome-wide association analyses in up to 1.3 million individuals and rare variant burden testing in 460,000 individuals for sinus node dysfunction (SND), distal conduction disease (DCD) and pacemaker (PM) implantation. We identified 13, 31 and 21 common variant loci for SND, DCD and PM, respectively. Four well-known loci (SCN5A/SCN10A, CCDC141, TBX20 and CAMK2D) were shared for SND and DCD,...
- Implementation of a Digital Disease Management Platform for Heart Failure: AMAZEon January 1, 2025
No abstract
- Editors' Best of 2024on January 1, 2025
There is, in the content of the Journal, an embarrassment of riches, and picking a "best" seems to demand a certain qualification: is the "best" the most interesting, most surprising, most educational, most important, most provocative, most enjoyable? How to choose? We are hardly unbiased and can admit to a special affection for the ones that we and the authors worked hardest on, modifying version after version into shape. Acknowledging these biases, here are the 2024 articles that we think...
- Specialty Care Oases: Utilizing Geographic Information Systems to Evaluate Specialty Care Access for Individuals With Down Syndromeon December 31, 2024
Down syndrome is a chromosomal condition occurring in about 220,000 individuals in the United States. Previous research showed almost 1 in 5 individuals with Down syndrome in the U.S. face significant geographic obstacles to receiving specialty care. The purpose of this study was to extend this work and learn more about socioeconomic barriers to Down syndrome specialty clinics. We quantified the percentage of the general population in each U.S. state living within a 2-hour drive of a Down...
- Evaluating the impact of modeling choices on the performance of integrated genetic and clinical modelson December 29, 2024
CONCLUSION: This work highlights the importance of considering methodological decision points in interpreting the impact of PRS on prediction performance in clinical models.
- Assessment and ascertainment in psychiatric molecular genetics: challenges and opportunities for cross-disorder researchon December 28, 2024
Psychiatric disorders are highly comorbid, heritable, and genetically correlated [1-4]. The primary objective of cross-disorder psychiatric genetics research is to identify and characterize both the shared genetic factors that contribute to convergent disease etiologies and the unique genetic factors that distinguish between disorders [4, 5]. This information can illuminate the biological mechanisms underlying comorbid presentations of psychopathology, improve nosology and prediction of […]
- Family genetic risk communication and reverse cascade testing in the BabySeq projecton December 28, 2024
CONCLUSION: Findings can inform more effective notification and testing practices for families of newborns at risk for hereditary genetic conditions.
- Genome-wide association study of anterior uveitison December 28, 2024
CONCLUSION: We identified six anterior uveitis-associated loci, including three novel loci with genome-wide significance. Our findings deepen our understanding of the genetic basis of anterior uveitis and the genetic connections between anterior uveitis and immune-related disorders, providing a foundation for further research and potential therapeutic interventions.
- Genetic vulnerability and adverse mental health outcomes following mild traumatic brain injury: a meta-analysis of CENTER-TBI and TRACK-TBI cohortson December 25, 2024
BACKGROUND: Post-traumatic stress disorder (PTSD) and depression are common after mild traumatic brain injury (mTBI), but their biological drivers are uncertain. We therefore explored whether polygenic risk scores (PRS) derived for PTSD and major depressive disorder (MDD) are associated with the development of cognate TBI-related phenotypes.
- Association of social vulnerability and depression incidence post intracerebral haemorrhage: a cohort studyon December 25, 2024
CONCLUSIONS: In addition to CAA burden and patient location 1-week post-ICH, social vulnerability was independently associated with depression among ICH survivors. Our findings suggest that social vulnerability influences ICH outcomes. Future studies should investigate how poststroke clinical care interventions can address SDOH effects to reduce incident depression and improve outcomes among ICH survivors.
- Heterozygous UBR5 variants result in a neurodevelopmental syndrome with developmental delay, autism, and intellectual disabilityon December 25, 2024
E3 ubiquitin ligases have been linked to developmental diseases including autism, Angelman syndrome (UBE3A), and Johanson-Blizzard syndrome (JBS) (UBR1). Here, we report variants in the E3 ligase UBR5 in 29 individuals presenting with a neurodevelopmental syndrome that includes developmental delay, autism, intellectual disability, epilepsy, movement disorders, and/or genital anomalies. Their phenotype is distinct from JBS due to the absence of exocrine pancreatic insufficiency and the […]
- The scalable variant call representation: enabling genetic analysis beyond one million genomeson December 24, 2024
MOTIVATION: The Variant Call Format (VCF) is widely used in genome sequencing but scales poorly. For instance, we estimate a 150 000 genome VCF would occupy 900 TiB, making it costly and complicated to produce, analyze, and store. The issue stems from VCF's requirement to densely represent both reference-genotypes and allele-indexed arrays. These requirements lead to unnecessary data duplication and, ultimately, very large files.
PublicationsCGM Admin2023-08-22T11:44:51-04:00