- Coronary Microvascular Function Following Severe Preeclampsiaon March 18, 2024
CONCLUSIONS: In this exploratory study, we observed reduced coronary microvascular function in the early postpartum period following severe preeclampsia, suggesting that systemic microvascular dysfunction in preeclampsia involves the coronary microcirculation. Further research is needed to establish interventions to mitigate risk of preeclampsia-associated cardiovascular disease.
- Assessment of the evidence yield for the calibrated PP3/BP4 computational recommendationson March 18, 2024
CONCLUSION: A small number of variants per proband reached PP3_Strong and PP3_Moderate in 3,424 disease-associated genes, and though not the intended use of the recommendations, also genome-wide. Use of PP3/BP4 evidence as recommended from calibrated computational prediction tools in the clinical diagnostic laboratory is unlikely to inappropriately contribute to the classification of an excessive number of variants as Pathogenic or Likely Pathogenic by ACMG/AMP rules.
- Novel syndromic neurodevelopmental disorder caused by de novo deletion of CHASERR , a long noncoding RNAon March 18, 2024
Genes encoding long non-coding RNAs (lncRNAs) comprise a large fraction of the human genome, yet haploinsufficiency of a lncRNA has not been shown to cause a Mendelian disease. CHASERR is a highly conserved human lncRNA adjacent to CHD2- a coding gene in which de novo loss-of-function variants cause developmental and epileptic encephalopathy. Here we report three unrelated individuals each harboring an ultra-rare heterozygous de novo deletion in the CHASERR locus. We report similarities in...
- Activation of the imprinted Prader-Willi Syndrome locus by CRISPR-based epigenome editingon March 18, 2024
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) is caused by 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 […]
- Neurodevelopmental disorders associated variants in ADAT3 disrupt the activity of the ADAT2/ADAT3 tRNA deaminase complex and impair neuronal migrationon March 18, 2024
The ADAT2/ADAT3 complex catalyzes the adenosine to inosine modification at the wobble position of eukaryotic tRNAs. Mutations in ADAT3 , the catalytically inactive subunit of the ADAT2/ADAT3 complex, have been identified in patients presenting with severe neurodevelopmental disorders (NDDs). Yet, the physiological function of ADAT2/ADAT3 complex during brain development remains totally unknown. Here we showed that maintaining a proper level of ADAT2/ADAT3 catalytic activity is required for...
- Thrombosis Risk in Double Heterozygous Carriers of Factor V Leiden and Prothrombin G20210A in FinnGen and the UK Biobankon March 18, 2024
The Factor V Leiden (FVL, rs6025) and prothrombin G20210A (PTGM, rs1799963) polymorphisms are two of the most well-studied genetic risk factors for venous thromboembolism (VTE). However, double heterozygosity (DH) for FVL and PTGM remains poorly understood, with prior studies in marked disagreement about the thrombosis risk conferred by the DH genotype. Utilizing multi-dimensional data from the UK Biobank (UKB) and the FinnGen biorepositories, we evaluated the clinical impact of DH carrier...
- T cell activation contributes to purifying selection against the MELAS-associated m.3243A>G pathogenic variant in bloodon March 18, 2024
T cells have been shown to maintain a lower percentage (heteroplasmy) of the pathogenic m.3243A>G variant (MT-TL1, associated with maternally inherited diabetes and deafness [MIDD] and mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes [MELAS]). The mechanism(s) underlying this purifying selection, however, remain unknown. Here we report that purified patient memory CD4+ T cells have lower bulk m.3243A>G heteroplasmy compared to naïve CD4+ T cells. In vitro […]
- Rationale and Design of the Statins Use in Intracerebral Hemorrhage Patients (SATURN) Trialon March 17, 2024
CONCLUSION: The results will help to determine the best strategy for statin use in survivors of lobar ICH and may help to identify if there is a subset of patients who would benefit from statins.
- Lipid levels and risk of acute pancreatitis using bidirectional Mendelian randomizationon March 16, 2024
Previous studies found lipid levels, especially triglycerides (TG), are associated with acute pancreatitis, but their causalities and bi-directions were not fully examined. We determined whether abnormal levels of TG, high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) are precursors and/or consequences of acute pancreatitis using bidirectional two-sample Mendelian randomization (MR) with two non-overlapping genome-wide association study (GWAS) […]
- Long-Term Outcomes in Patients With Spontaneous Cerebellar Hemorrhage: An International Cohort Studyon March 15, 2024
CONCLUSIONS: The long-term prognosis of patients who survive a first spontaneous cerebellar ICH is poor and comparable to that of patients who survive a first supratentorial ICH. Further identification of patients at high risk of vascular events following the initial cerebellar ICH is needed. Including patients with cerebellar ICH in randomized controlled trials on secondary prevention of patients with ICH is warranted.
- Treating Hypertension: Important for Heart Health, Fundamental for Brain Healthon March 15, 2024
The Brain Health crisis stands as one of humankind's most pressing threats, with age-related noncommunicable brain diseases, particularly stroke, and dementia, affecting hundreds of millions annually and jeopardizing the economic well-being of populations worldwide. Epidemiological studies indicate that ≈40% of dementia and 60% of stroke cases are attributable to modifiable risk factors. In this Comments and Opinions article, we underscore the pivotal role of blood pressure (BP) control in...
- Feasibility and tolerability of portable, low-field brain MRI for patients with multiple sclerosison March 15, 2024
Low-field, portable MRI (LF-MRI) promises to expand neuroimaging access for patients with multiple sclerosis (MS). We aimed to measure the feasibility and tolerability of LF-MRI for clinical use in 50 people with MS (mean age 46.5 ± 15.3 years; 72 % female; median disease duration 5.9 years), 38 % of whom reported barriers to undergoing MRI, and 34 % of whom were low-income or unemployed. Experience ratings of LF-MRI were strongly positive (mean rating of 9.2 on a ten-point scale). Seventy...
- Admix-kit: an integrated toolkit and pipeline for genetic analyses of admixed populationson March 15, 2024
SUMMARY: Admixed populations, with their unique and diverse genetic backgrounds, are often underrepresented in genetic studies. This oversight not only limits our understanding but also exacerbates existing health disparities. One major barrier has been the lack of efficient tools tailored for the special challenges of genetic study of admixed populations. Here, we present admix-kit, an integrated toolkit and pipeline for genetic analyses of admixed populations. Admix-kit implements a suite […]
- DNM1L variant presenting as adolescent-onset sensory neuronopathy, spasticity, dystonia, and ataxiaon March 14, 2024
DMN1L encodes for dynamin-like protein 1 (DLP1) which plays a key role in perixosomal and mitochondrial fission. Individuals with heterozygous variants in DNM1L present with a wide range of neurologic symptoms, including encephalopathy, epilepsy, and motor deficits. Here we report on a woman presenting with adolescence onset of sensory neuronopathy, spasticity, dystonia, and ataxia. Trio genome sequencing identified a heterozygous variant in DNM1L (NM_012062.3 c.121G>A/p.Val41Met) which […]
- Plasma Metabolites and Life's Simple 7 in REGARDSon March 14, 2024
CONCLUSIONS: We identified guanosine, cotinine, and acetylneuraminic acid that were associated with LS7, incident ischemic stroke, and mediated the relationship between LS7 and ischemic stroke.
- Clinical decision support for bipolar depression using large language modelson March 14, 2024
Management of depressive episodes in bipolar disorder remains challenging for clinicians despite the availability of treatment guidelines. In other contexts, large language models have yielded promising results for supporting clinical decisionmaking. We developed 50 sets of clinical vignettes reflecting bipolar depression and presented them to experts in bipolar disorder, who were asked to identify 5 optimal next-step pharmacotherapies and 5 poor or contraindicated choices. The same vignettes...
- Patterns of Undertreatment and Overtreatment in Adjuvant Radiotherapy for Early-Stage Endometrial Cancer Based on Molecular Classificationon March 14, 2024
No abstract
- De novo variants in FRYL are associated with developmental delay, intellectual disability, and dysmorphic featureson March 13, 2024
FRY-like transcription coactivator (FRYL) belongs to a Furry protein family that is evolutionarily conserved from yeast to humans. The functions of FRYL in mammals are largely unknown, and variants in FRYL have not previously been associated with a Mendelian disease. Here, we report fourteen individuals with heterozygous variants in FRYL who present with developmental delay, intellectual disability, dysmorphic features, and other congenital anomalies in multiple systems. The variants are...
- Preclinical evaluation of the third-generation, bi-steric mechanistic target of rapamycin complex 1-selective inhibitor RMC-6272 in NF2-deficient modelson March 13, 2024
CONCLUSIONS: Our study in preclinical models of NF2 supports possible future clinical evaluation of third-generation, investigational mTORC1 inhibitors, such as RMC-5552, as a potential treatment strategy for NF2.
- Cardiovascular Significance and Genetics of Epicardial and Pericardial Adiposityon March 13, 2024
CONCLUSIONS AND RELEVANCE: Results of this cohort study suggest that epicardial and pericardial adiposity was associated with incident cardiovascular diseases, but this may largely reflect a metabolically unhealthy adiposity phenotype similar to abdominal visceral adiposity.
- Evidence for the additivity of rare and common variant burden throughout the spectrum of intellectual disabilityon March 12, 2024
Intellectual disability (ID) is a common disorder, yet there is a wide spectrum of impairment from mild to profoundly affected individuals. Mild ID is seen as the low extreme of the general distribution of intelligence, while severe ID is often seen as a monogenic disorder caused by rare, pathogenic, highly penetrant variants. To investigate the genetic factors influencing mild and severe ID, we evaluated rare and common variation in the Northern Finland Intellectual Disability cohort (n = […]
- Polygenic Risk for Type 2 Diabetes in African Americanson March 12, 2024
African Americans (AAs) have been underrepresented in polygenic risk score (PRS) studies. Herein, we integrated genome-wide data from multiple observational studies on type 2 diabetes (T2D), encompassing a total of 101,987 AAs, to train and optimize an AA focused T2D PRS (PRSAA), using a Bayesian polygenic modeling method (PRS-CS). We further tested the score in three independent studies with a total of 7,275 AAs. We then compared the PRSAA to other published scores. Results show that a 1...
- Validation of an ICD-code-based case definition for psychotic illness across three health systemson March 11, 2024
CONCLUSIONS: We found that the first documented psychosis diagnostic code accurately captured true episodes of psychosis but was a poor index of FEP. These data have important implications for the development of risk prediction models designed to predict or detect undiagnosed psychosis.
- Continuous-Time and Dynamic Suicide Attempt Risk Prediction with Neural Ordinary Differential Equationson March 11, 2024
Suicide is one of the leading causes of death in the US, and the number of attributable deaths continues to increase. Risk of suicide-related behaviors (SRBs) is dynamic, and SRBs can occur across a continuum of time and locations. However, current SRB risk assessment methods, whether conducted by clinicians or through machine learning models, treat SRB risk as static and are confined to specific times and locations, such as following a hospital visit. Such a paradigm is unrealistic as SRB […]
- Tissue- and cell-type-specific molecular and functional signatures of 16p11.2 reciprocal genomic disorder across mouse brain and human neuronal modelson March 8, 2024
No abstract
- Publisher Correction: Impact of polygenic score for BMI on weight loss effectiveness and genome-wide association analysison March 8, 2024
No abstract
- Genome-wide association studies highlight novel risk loci for septal defects and left-sided congenital heart defectson March 8, 2024
CONCLUSIONS: Our results of general CHD and different CHD subcategories identified a complex risk locus on chromosome 17 near BAHCC1 and LRRC37A2, interacting with the genes WNT9B, WNT3 and MYL4, may constitute potential novel CHD risk associated loci, warranting future experimental tests to determine their role.
- Early vs Late Fixation of Extremity Fractures Among Adults With Traumatic Brain Injuryon March 8, 2024
CONCLUSIONS AND RELEVANCE: The outcomes of extremity fracture fixation performed within 24 hours after TBI appear not to be worse than those of procedures performed 24 hours or later. This finding suggests that early fixation after TBI could be considered in patients with mild head injuries.
- Heterozygous MAP3K20 variants cause ectodermal dysplasia, craniosynostosis, sensorineural hearing loss, and limb anomalieson March 7, 2024
Biallelic pathogenic variants in MAP3K20, which encodes a mitogen-activated protein kinase, are a rare cause of split-hand foot malformation (SHFM), hearing loss, and nail abnormalities or congenital myopathy. However, heterozygous variants in this gene have not been definitively associated with a phenotype. Here, we describe the phenotypic spectrum associated with heterozygous de novo variants in the linker region between the kinase domain and leucine zipper domain of MAP3K20. We report five...
- Modification of Huntington's disease by short tandem repeatson March 7, 2024
Expansions of glutamine-coding CAG trinucleotide repeats cause a number of neurodegenerative diseases, including Huntington's disease and several of spinocerebellar ataxias. In general, age-at-onset of the polyglutamine diseases is inversely correlated with the size of the respective inherited expanded CAG repeat. Expanded CAG repeats are also somatically unstable in certain tissues, and age-at-onset of Huntington's disease corrected for individual HTT CAG repeat length (i.e. residual...
- Circulating N-lactoyl-amino acids and N-formyl-methionine reflect mitochondrial dysfunction and predict mortality in septic shockon March 6, 2024
CONCLUSION: Future studies which validate the measurement of lac-AAs and f-Met in conjunction with lactate could define a sepsis subtype characterized by mitochondrial dysfunction.
- Multi-ancestry polygenic mechanisms of type 2 diabeteson March 5, 2024
Type 2 diabetes (T2D) is a multifactorial disease with substantial genetic risk, for which the underlying biological mechanisms are not fully understood. In this study, we identified multi-ancestry T2D genetic clusters by analyzing genetic data from diverse populations in 37 published T2D genome-wide association studies representing more than 1.4 million individuals. We implemented soft clustering with 650 T2D-associated genetic variants and 110 T2D-related traits, capturing known and novel […]
- Genetic sex validation for sample tracking in next-generation sequencing clinical testingon March 3, 2024
OBJECTIVE: Data from DNA genotyping via a 96-SNP panel in a study of 25,015 clinical samples were utilized for quality control and tracking of sample identity in a clinical sequencing network. The study aimed to demonstrate the value of both the precise SNP tracking and the utility of the panel for predicting the sex-by-genotype of the participants, to identify possible sample mix-ups.
- Fibrinolytic Agents in Thromboembolic Diseases: Historical Perspectives and Approved Indicationson March 1, 2024
Fibrinolytic agents catalyze the conversion of the inactive proenzyme plasminogen into the active protease plasmin, degrading fibrin within the thrombus and recanalizing occluded vessels. The history of these medications dates to the discovery of the first fibrinolytic compound, streptokinase, from bacterial cultures in 1933. Over time, researchers identified two other plasminogen activators in human samples, namely urokinase and tissue plasminogen activator (tPA). Subsequently, tPA was […]
- Digenic inheritance involving a muscle-specific protein kinase and the giant titin protein causes a skeletal muscle myopathyon March 1, 2024
In digenic inheritance, pathogenic variants in two genes must be inherited together to cause disease. Only very few examples of digenic inheritance have been described in the neuromuscular disease field. Here we show that predicted deleterious variants in SRPK3, encoding the X-linked serine/argenine protein kinase 3, lead to a progressive early onset skeletal muscle myopathy only when in combination with heterozygous variants in the TTN gene. The co-occurrence of predicted deleterious […]
- Comprehensive Inherited Risk Estimation for Risk-Based Breast Cancer Screening in Womenon February 29, 2024
CONCLUSION: Using real-life screening data, this study demonstrates the effectiveness of a breast cancer PRS for risk stratification, alone and combined with FH and PVs. Further research is required to evaluate their impact in a prospective risk-stratified screening program, including cost-effectiveness.
- The evolutionary impact of childhood cancer on the human gene poolon February 29, 2024
Germline pathogenic variants associated with increased childhood mortality must be subject to natural selection. Here, we analyze publicly available germline genetic metadata from 4,574 children with cancer [11 studies; 1,083 whole exome sequences (WES), 1,950 whole genome sequences (WGS), and 1,541 gene panel] and 141,456 adults [125,748 WES and 15,708 WGS]. We find that pediatric cancer predisposition syndrome (pCPS) genes [n = 85] are highly constrained, harboring only a quarter of the...
- Novel Polygenic Risk Score and Established Clinical Risk Factors for Risk Estimation of Aortic Stenosison February 28, 2024
CONCLUSIONS: This study developed and validated 1 of the first aortic stenosis PRSs. While aortic stenosis genetic risk was independent from clinical risk factors and performed comparably to all other risk factors besides age, genetic risk resulted in only a small improvement in overall aortic stenosis risk discrimination beyond age and clinical risk factors. This work sets the stage for further development of an aortic stenosis PRS.
- Applying a genetic risk score model to enhance prediction of future multiple sclerosis diagnosis at first presentation with optic neuritison February 28, 2024
Optic neuritis (ON) is associated with numerous immune-mediated inflammatory diseases, but 50% patients are ultimately diagnosed with multiple sclerosis (MS). Differentiating MS-ON from non-MS-ON acutely is challenging but important; non-MS ON often requires urgent immunosuppression to preserve vision. Using data from the United Kingdom Biobank we showed that combining an MS-genetic risk score (GRS) with demographic risk factors (age, sex) significantly improved MS prediction in […]
- PMF-seq: a highly scalable screening strategy for linking genetics to mitochondrial bioenergeticson February 27, 2024
Our current understanding of mitochondrial organelle physiology has benefited from two broad approaches: classically, cuvette-based measurements with suspensions of isolated mitochondria, in which bioenergetic parameters are monitored acutely in response to respiratory chain substrates and inhibitors^(1-4), and more recently, highly scalable genetic screens for fitness phenotypes associated with coarse-grained properties of the mitochondrial state^(5-10). Here we introduce permeabilized-cell...
- Identifying genetic differences between bipolar disorder and major depression through multiple GWASon February 27, 2024
CONCLUSIONS: We find that MDD and BD, including BD with a depressive onset, are genetically distinct. Further, our findings support the hypothesis that Controls - MDD - BD 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 BD and, importantly, BD with depressive onset from MDD.
- Nightmares share genetic risk factors with sleep and psychiatric traitson February 27, 2024
Nightmares are vivid, extended, and emotionally negative or negative dreams that awaken the dreamer. While sporadic nightmares and bad dreams are common and generally harmless, frequent nightmares often reflect underlying pathologies of emotional regulation. Indeed, insomnia, depression, anxiety, or alcohol use have been associated with nightmares in epidemiological and clinical studies. However, the connection between nightmares and their comorbidities are poorly understood. Our goal was to...
- Fine-mapping genomic loci refines bipolar disorder risk geneson February 26, 2024
Bipolar disorder (BD) is a heritable mental illness with complex etiology. While the largest published genome-wide association study identified 64 BD risk loci, the causal SNPs and genes within these loci remain unknown. We applied a suite of statistical and functional fine-mapping methods to these loci, and prioritized 22 likely causal SNPs for BD. We mapped these SNPs to genes, and investigated their likely functional consequences by integrating variant annotations, brain cell-type […]
- 50,000 years of Evolutionary History of India: Insights from ~2,700 Whole Genome Sequenceson February 26, 2024
India has been underrepresented in whole genome sequencing studies. We generated 2,762 high coverage genomes from India-including individuals from most geographic regions, speakers of all major languages, and tribal and caste groups-providing a comprehensive survey of genetic variation in India. With these data, we reconstruct the evolutionary history of India through space and time at fine scales. We show that most Indians derive ancestry from three ancestral groups related to ancient […]
- Detecting missed diagnoses of spinal muscular atrophy in genome, exome, and panel sequencing datasetson February 26, 2024
Spinal muscular atrophy (SMA) is a genetic disorder that causes progressive degeneration of lower motor neurons and the subsequent loss of muscle function throughout the body. It is the second most common recessive disorder in individuals of European descent and is present in all populations. Accurate tools exist for diagnosing SMA from short read and long read genome sequencing data. However, there are no publicly available tools for GRCh38-aligned data from panel or exome sequencing assays...
- Use of Tobacco Products and Suicide Attempts Among Elementary School-Aged Childrenon February 26, 2024
CONCLUSIONS AND RELEVANCE: This study of US children suggests that the increased risk of SAs, consistently reported for adolescents and adults who smoke cigarettes, extends to a range of emerging tobacco products and manifests among elementary school-aged children. Further investigations are imperative to clarify the underlying mechanisms and to implement effective preventive policies for children.
- Body mass index stratified meta-analysis of genome-wide association studies of polycystic ovary syndrome in women of European ancestryon February 26, 2024
CONCLUSIONS: Genetic variation at the XBP1, LINC02905 and ERBB4 loci were associated with PCOS within unique BMI strata, while DENND1A demonstrated associations across multiple strata, providing evidence of both distinct and shared genetic features between lean and overweight/obese PCOS-affected women. This study demonstrated that PCOS-affected women with contrasting body weight are not only phenotypically distinct but also show variation in genetic architecture; lean PCOS women typically...
- Whole-exome sequencing in UK Biobank reveals rare genetic architecture for depressionon February 26, 2024
Nearly two hundred common-variant depression risk loci have been identified by genome-wide association studies (GWAS). However, the impact of rare coding variants on depression remains poorly understood. Here, we present whole-exome sequencing analyses of depression with seven different definitions based on survey, questionnaire, and electronic health records in 320,356 UK Biobank participants. We showed that the burden of rare damaging coding variants in loss-of-function intolerant genes is...
- Clinical utility of polygenic risk scores for embryo selection: A points to consider statement of the American College of Medical Genetics and Genomics (ACMG)on February 23, 2024
No abstract
- CAGI, the Critical Assessment of Genome Interpretation, establishes progress and prospects for computational genetic variant interpretation methodson February 23, 2024
CONCLUSIONS: Results show that while current methods are imperfect, they have major utility for research and clinical applications. Emerging methods and increasingly large, robust datasets for training and assessment promise further progress ahead.
- Normative modelling of brain morphometry across the lifespan with CentileBrain: algorithm benchmarking and model optimisationon February 23, 2024
The value of normative models in research and clinical practice relies on their robustness and a systematic comparison of different modelling algorithms and parameters; however, this has not been done to date. We aimed to identify the optimal approach for normative modelling of brain morphometric data through systematic empirical benchmarking, by quantifying the accuracy of different algorithms and identifying parameters that optimised model performance. We developed this framework with […]
- Lithium response in bipolar disorder is associated with focal adhesion and PI3K-Akt networks: a multi-omics replication studyon February 23, 2024
Lithium is the gold standard treatment for bipolar disorder (BD). However, its mechanism of action is incompletely understood, and prediction of treatment outcomes is limited. In our previous multi-omics study of the Pharmacogenomics of Bipolar Disorder (PGBD) sample combining transcriptomic and genomic data, we found that focal adhesion, the extracellular matrix (ECM), and PI3K-Akt signaling networks were associated with response to lithium. In this study, we replicated the results of our...
- Somatic CAG Repeat Stability in a Transgenic Sheep Model of Huntington's Diseaseon February 23, 2024
Somatic instability of the huntingtin (HTT) CAG repeat mutation modifies age-at-onset of Huntington's disease (HD). Understanding the mechanism and pathogenic consequences of instability may reveal therapeutic targets. Using small-pool PCR we analyzed CAG instability in the OVT73 sheep model which expresses a full-length human cDNA HTT transgene. Analyses of five- and ten-year old sheep revealed the transgene (CAG)69 repeat was remarkably stable in liver, striatum, and other brain tissues. As...
- De novo variants in DENND5B cause a neurodevelopmental disorderon February 22, 2024
The Rab family of guanosine triphosphatases (GTPases) includes key regulators of intracellular transport and membrane trafficking targeting specific steps in exocytic, endocytic, and recycling pathways. DENND5B (Rab6-interacting Protein 1B-like protein, R6IP1B) is the longest isoform of DENND5, an evolutionarily conserved DENN domain-containing guanine nucleotide exchange factor (GEF) that is highly expressed in the brain. Through exome sequencing and international matchmaking platforms, we...
- Continuous glucose monitoring and advanced glycation endproducts for prediction of clinical outcomes and development of cystic fibrosis-related diabetes in adults with CFon February 21, 2024
CONCLUSIONS: Several key CGM measures of hyperglycemia and glycemic variability were predictive of future decline in weight and BMI over one year in this population of adults with CF with and without CFRD. None of the baseline glycemic variables predicted progression to CFRD over 2 years. To our knowledge, this is the first report correlating AGE levels with key clinical and glycemic measures in CF. Limitations of these analyses include the small number of participants who developed CFRD […]
- Novel ancestry-specific primary open-angle glaucoma loci and shared biology with vascular mechanisms and cell proliferationon February 21, 2024
Primary open-angle glaucoma (POAG), a leading cause of irreversible blindness globally, shows disparity in prevalence and manifestations across ancestries. We perform meta-analysis across 15 biobanks (of the Global Biobank Meta-analysis Initiative) (n = 1,487,441: cases = 26,848) and merge with previous multi-ancestry studies, with the combined dataset representing the largest and most diverse POAG study to date (n = 1,478,037: cases = 46,325) and identify 17 novel significant loci, 5 of […]
- Selection, optimization and validation of ten chronic disease polygenic risk scores for clinical implementation in diverse US populationson February 20, 2024
Polygenic risk scores (PRSs) have improved in predictive performance, but several challenges remain to be addressed before PRSs can be implemented in the clinic, including reduced predictive performance of PRSs in diverse populations, and the interpretation and communication of genetic results to both providers and patients. To address these challenges, the National Human Genome Research Institute-funded Electronic Medical Records and Genomics (eMERGE) Network has developed a framework and...
- The frequency of pathogenic variation in the All of Us cohort reveals ancestry-driven disparitieson February 20, 2024
Disparities in data underlying clinical genomic interpretation is an acknowledged problem, but there is a paucity of data demonstrating it. The All of Us Research Program is collecting data including whole-genome sequences, health records, and surveys for at least a million participants with diverse ancestry and access to healthcare, representing one of the largest biomedical research repositories of its kind. Here, we examine pathogenic and likely pathogenic variants that were identified in […]
- Early systemic insults following traumatic brain injury: association with biomarker profiles, therapy for intracranial hypertension, and neurological outcomes-an analysis of CENTER-TBI dataon February 20, 2024
CONCLUSION: Though less frequent than previously described, SIs in TBI patients are associated with higher release of neuronal than glial injury biomarkers and with increased requirements for ICU therapies aimed at reducing intracranial hypertension. Hypotension or combined SIs are significantly associated with adverse 6-month outcomes. Current criteria for hypotension may lead to higher biomarker levels and more negative outcomes than those for hypoxemia suggesting a need to revisit pressure...
- The spectrum of neurological presentation in individuals affected by TBL1XR1 gene defectson February 20, 2024
CONCLUSION: TBL1XR1-related disorder encompasses a spectrum of clinical presentations, marked by early developmental delay ranging in severity, with a subset of patients experiencing developmental regression in later childhood.
- SARS-CoV-2 infection elucidates unique features of pregnancy-specific immunityon February 19, 2024
Pregnancy is a risk factor for increased severity of SARS-CoV-2 and other respiratory infections. The mechanisms underlying this risk have not been well-established, partly due to a limited understanding of how pregnancy shapes immune responses. To gain insight into the role of pregnancy in modulating immune responses at steady state and upon perturbation, we collected peripheral blood mononuclear cells (PBMC), plasma, and stool from 226 women, including 152 pregnant individuals (n = 96 with...
- Considerations for reporting variants in novel candidate genes identified during clinical genomic testingon February 19, 2024
Since the first novel gene discovery for a Mendelian condition was made via exome sequencing (ES), the rapid increase in the number of genes known to underlie Mendelian conditions coupled with the adoption of exome (and more recently, genome) sequencing by diagnostic testing labs has changed the landscape of genomic testing for rare disease. Specifically, many individuals suspected to have a Mendelian condition are now routinely offered clinical ES. This commonly results in a precise genetic...
- Sex Differences in the Association of Multiethnic Genome-Wide Blood Pressure Polygenic Risk Score With Population-Level Systolic Blood Pressure Trajectorieson February 19, 2024
No abstract
- Genomic data in the All of Us Research Programon February 19, 2024
Comprehensively mapping the genetic basis of human disease across diverse individuals is a long-standing goal for the field of human genetics^(1-4). The All of Us Research Program is a longitudinal cohort study aiming to enrol a diverse group of at least one million individuals across the USA to accelerate biomedical research and improve human health^(5,6). Here we describe the programme's genomics data release of 245,388 clinical-grade genome sequences. This resource is unique in its […]
- Genetic drivers of heterogeneity in type 2 diabetes pathophysiologyon February 19, 2024
Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes^(1,2) and molecular mechanisms that are often specific to cell type^(3,4). Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P
- Associations of a multidimensional polygenic sleep health score and a sleep lifestyle index on health outcomes and their interaction in a clinical biobankon February 19, 2024
Sleep is a complex behavior regulated by genetic and environmental factors, and is known to influence health outcomes. However, the effect of multidimensional sleep encompassing several sleep dimensions on diseases has yet to be fully elucidated. Using the Mass General Brigham Biobank, we aimed to examine the association of multidimensional sleep with health outcomes and investigate whether sleep behaviors modulate genetic predisposition to unfavorable sleep on mental health outcomes. First, […]
- RNA Interference With Zilebesiran for Mild to Moderate Hypertension: The KARDIA-1 Randomized Clinical Trialon February 16, 2024
CONCLUSIONS AND RELEVANCE: In adults with mild to moderate hypertension, treatment with zilebesiran across a range of doses at 3-month or 6-month intervals significantly reduced 24-hour mean ambulatory SBP at month 3.
- Clonal Hematopoiesis of Indeterminate Potential With Loss of Tet2 Enhances Risk for Atrial Fibrillation Through Nlrp3 Inflammasome Activationon February 15, 2024
CONCLUSIONS: We identified a modest association between CHIP, particularly TET2 CHIP, and incident AF in the UK Biobank population. In a mouse model of AF resulting from hematopoietic-specific inactivation of Tet2, we propose altered calcium handling as an arrhythmogenic mechanism, dependent on Nlrp3 inflammasome activation. Our data are in keeping with previous studies of CHIP in cardiovascular disease, and further studies into the therapeutic potential of NLRP3 inhibition for individuals […]
- Genome-wide association analysis of composite sleep health scores in 413,904 individualson February 14, 2024
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, and together may provide a more complete picture of sleep health, while also 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...
- Personalized allele-specific CRISPR-Cas9 strategies for myofibrillar myopathy 6on February 14, 2024
Myofibrillar myopathy 6 (MFM6) is a rare childhood-onset myopathy characterized by myofibrillar disintegration, muscle weakness, and cardiomyopathy. The genetic cause of MFM6 is p.Pro209Leu mutation (rs121918312-T) in the BAG3 gene, which generates the disease outcomes in a dominant fashion. Since the consequences of the BAG3 mutation are strong and rapidly progressing, most MFM6 patients are due to de novo mutation. There are no effective treatments for MFM6 despite its well-known genetic...
- Assessing the genetic contribution of cumulative behavioral factors associated with longitudinal type 2 diabetes risk highlights adiposity and the brain-metabolic axison February 14, 2024
While genetic factors, behavior, and environmental exposures form a complex web of interrelated associations in type 2 diabetes (T2D), their interaction is poorly understood. Here, using data from ~500K participants of the UK Biobank, we identify the genetic determinants of a "polyexposure risk score" (PXS) a new risk factor that consists of an accumulation of 25 associated individual-level behaviors and environmental risk factors that predict longitudinal T2D incidence. PXS-T2D had a […]
- Predicting post-stroke cognitive impairment using electronic health record dataon February 14, 2024
CONCLUSIONS AND RELEVANCE: Five-year risk of PSCI can be accurately predicted using routinely collected data. Model output can be used to risk stratify and identify individuals at increased risk for PSCI for preventive efforts.
- Cognitive Symptoms of Post-COVID-19 Condition and Daily Functioningon February 14, 2024
CONCLUSIONS AND RELEVANCE: The findings of this survey study of US adults suggest that cognitive symptoms are common among individuals with post-COVID-19 condition and associated with greater self-reported functional impairment, lesser likelihood of full-time employment, and greater depressive symptom severity. Screening for and addressing cognitive symptoms is an important component of the public health response to post-COVID-19 condition.
- Lipoprotein(a), C-Reactive Protein, and Cardiovascular Risk in Primary and Secondary Prevention Populationson February 14, 2024
CONCLUSIONS AND RELEVANCE: In this study, higher levels of Lp(a) were associated with MACE, MI, and PAD in both primary and secondary prevention populations regardless of baseline hs-CRP value.
- Impact of the COVID-19 Pandemic on People Living With Rare Diseases and Their Families: Results of a National Surveyon February 14, 2024
CONCLUSIONS: Self-reported COVID-19 was more frequent than expected and was associated with increased prevalence and severity of RD symptoms and greater use of medications. The pandemic negatively affected access to care and caused mood changes in the respondents and family members. Continued surveillance is necessary.
- Differences in Circulating Progenitor Cells and Risk of Atherosclerotic Cardiovascular Disease in South Asian Individualson February 14, 2024
No abstract
- Offspring cardiometabolic outcomes and postnatal growth trajectories after exposure to maternal SARS-CoV-2 infectionon February 14, 2024
CONCLUSIONS: Exposure to maternal SARS-CoV-2 infection was associated with an increased risk of receiving a cardiometabolic diagnosis by 18 months preceded by greater BMI-for-age at 6 months.
- Distinguishing different psychiatric disorders using DDx-PRSon February 14, 2024
Despite great progress on methods for case-control polygenic prediction (e.g. schizophrenia vs. control), there remains an unmet need for a method that genetically distinguishes clinically related disorders (e.g. schizophrenia (SCZ) vs. bipolar disorder (BIP) vs. depression (MDD) vs. control); such a method could have important clinical value, especially at disorder onset when differential diagnosis can be challenging. Here, we introduce a method, Differential Diagnosis-Polygenic Risk Score...
- Risk and protection of different rare protein-coding variants of complement component C4A in age-related macular degenerationon February 13, 2024
Introduction: Age-related macular degeneration (AMD) is the leading cause of central vision loss in the elderly. One-third of the genetic contribution to this disease remains unexplained. Methods: We analyzed targeted sequencing data from two independent cohorts (4,245 cases, 1,668 controls) which included genomic regions of known AMD loci in 49 genes. Results: At a false discovery rate of
- EFEMP1 haploinsufficiency causes a Marfan-like hereditary connective tissue disorderon February 13, 2024
Phenotypic features of a hereditary connective tissue disorder, including craniofacial characteristics, hyperextensible skin, joint laxity, kyphoscoliosis, arachnodactyly, inguinal hernia, and diverticulosis associated with biallelic pathogenic variants in EFEMP1 have been previously described in four patients. Genome sequencing on a proband and her mother with comparable phenotypic features revealed that both patients were heterozygous for a stop-gain variant c.1084C>T (p.Arg362*)....
- Host DNA depletion on frozen human respiratory samples enables successful metagenomic sequencing for microbiome studieson February 12, 2024
CONCLUSIONS: Metagenomics sequencing without host depletion will underestimate microbial diversity of most respiratory samples due to shallow effective sequencing depth and is not recommended. Optimal host depletion methods vary by sample type.
- Relationship of fat mass ratio - a biomarker for lipodystrophy - with cardiometabolic traitson February 12, 2024
Familial partial lipodystrophy (FPLD) is a heterogenous group of syndromes associated with a high prevalence of cardiometabolic diseases. Prior work has proposed DEXA-derived fat mass ratio (FMR) - defined as trunk fat percentage (trunk fat %) divided by leg fat percentage (leg fat %) - as a biomarker of FPLD, but this metric has not previously been characterized in large cohort studies. We set out to (1) understand the cardiometabolic burden of individuals with high FMR in up to 40,796...
- Unique Capabilities of Genome Sequencing for Rare Disease Diagnosison February 8, 2024
CONCLUSION: We describe the diagnostic yield of GS in a large and diverse cohort, illustrating several types of pathogenic variation eluding ES or other techniques. Our results reveal a higher diagnostic yield of GS, supporting the utility of a genome-first approach, with consideration of GS as a secondary or tertiary test when higher-resolution structural variant analysis is needed or there is a strong clinical suspicion for a condition and prior targeted genetic testing has been negative.
- Genetic Analysis of Obstructive Sleep Apnea and Its Relationship with Severe COVID-19on February 8, 2024
CONCLUSIONS: Our analysis identified novel genetic risk factors for OSA and showed that OSA is a causal risk factor for severe COVID-19. The effect is predominantly explained by higher BMI and suggests BMI-dependent effects at the level of individual variants and at the level of comorbid causality.
- Convergence of coronary artery disease genes onto endothelial cell programson February 7, 2024
Linking variants from genome-wide association studies (GWAS) to underlying mechanisms of disease remains a challenge^(1-3). For some diseases, a successful strategy has been to look for cases in which multiple GWAS loci contain genes that act in the same biological pathway^(1-6). However, our knowledge of which genes act in which pathways is incomplete, particularly for cell-type-specific pathways or understudied genes. Here we introduce a method to connect GWAS variants to functions. This...
- Recurring homozygous ACTN2 variant (p.Arg506Gly) causes a recessive myopathyon February 4, 2024
OBJECTIVE: ACTN2, encoding alpha-actinin-2, is essential for cardiac and skeletal muscle sarcomeric function. ACTN2 variants are a known cause of cardiomyopathy without skeletal muscle involvement. Recently, specific dominant monoallelic variants were reported as a rare cause of core myopathy of variable clinical onset, although the pathomechanism remains to be elucidated. The possibility of a recessively inherited ACTN2-myopathy has also been proposed in a single series.
- Polygenic risk for suicide attempt is associated with lifetime suicide attempt in US soldiers independent of parental riskon February 3, 2024
CONCLUSIONS: PRS for SA conveys information about likelihood of lifetime SA (but not NSSI, demonstrating specificity), independent of self-reported parental history of MDD and parental history of SA.
- SRCAP mutations drive clonal hematopoiesis through epigenetic and DNA repair dysregulationon February 2, 2024
No abstract
- Performance of a Maternal Risk Stratification System for Predicting Low Apgar Scoreson February 1, 2024
CONCLUSION: A maternal morbidity risk stratification system does not perform well in most patients giving birth, at low risk for neonatal complications. The findings suggest that the association between EOCS and 5-minute Apgar
- Heterozygous loss-of-function SMC3 variants are associated with variable growth and developmental featureson February 1, 2024
Heterozygous missense variants and in-frame indels in SMC3 are a cause of Cornelia de Lange syndrome (CdLS), marked by intellectual disability, growth deficiency, and dysmorphism, via an apparent dominant-negative mechanism. However, the spectrum of manifestations associated with SMC3 loss-of-function variants has not been reported, leading to hypotheses of alternative phenotypes or even developmental lethality. We used matchmaking servers, patient registries, and other resources to identify...
- Rare ACTN2 Frameshift Variants Resulting in Protein Extension Cause Distal Myopathy and Hypertrophic Cardiomyopathy through Protein Aggregationon January 31, 2024
Distal myopathies are a group of rare, inherited muscular disorders characterized by progressive loss of muscle fibers that begins in the distal parts of arms and legs. Recently, variants in a new disease gene, ACTN2 , have been shown to cause distal myopathy. ACTN2 , a gene previously only associated with cardiomyopathies, encodes alpha-actinin-2, a protein expressed in both cardiac and skeletal sarcomeres. The primary function of alpha-actinin-2 is to link actin and titin to the sarcomere...
- Familial Hypercholesterolemia Variant and Cardiovascular Risk in Individuals With Elevated Cholesterolon January 31, 2024
CONCLUSIONS AND RELEVANCE: In this pooled cohort study, the presence of FH variants was associated with a 2-fold higher CHD risk, even when LDL-C was only moderately elevated. The increased CHD risk appeared to be largely explained by the higher cumulative LDL-C exposure in individuals with an FH variant compared to those without. Further research is needed to assess the value of adding genetic testing to traditional phenotypic FH screening.
- Potential causal association between gut microbiome and posttraumatic stress disorderon January 31, 2024
CONCLUSION: Our study provides the potential causal impact of gut microbiomes on the development of PTSD, shedding new light on the understanding of the dysfunctional gut-brain axis in this disorder. Our findings present novel evidence and call for investigations to confirm the association between their links, as well as to illuminate the underlying mechanisms.
- Substance Use, Suicidal Thoughts, and Psychiatric Comorbidities Among High School Studentson January 29, 2024
No abstract
- Polygenic Variation Underlying Educational Attainment and Attention-Deficit/Hyperactivity Disorder Indexes Behavior Ratings of Executive Functions in Child Psychiatry Outpatientson January 28, 2024
CONCLUSION: Genetic data extend evidence that the BRIEF measures a construct relevant to educational success that differs from what is indexed by cognitive testing.
- Genetic architecture and biology of youth-onset type 2 diabeteson January 26, 2024
The prevalence of youth-onset type 2 diabetes (T2D) and childhood obesity has been rising steadily¹, producing a growing public health concern¹ that disproportionately affects minority groups². The genetic basis of youth-onset T2D and its relationship to other forms of diabetes are unclear³. Here we report a detailed genetic characterization of youth-onset T2D by analysing exome sequences and common variant associations for 3,005 individuals with youth-onset T2D and 9,777 adult control...
- LUSTR: a new customizable tool for calling genome-wide germline and somatic short tandem repeat variantson January 26, 2024
CONCLUSIONS: LUSTR offers a powerful and user-friendly approach that allows for the identification of STR variants and can facilitate more comprehensive studies evaluating the role of pathogenic STR variants across human diseases.
- Clonal Hematopoiesis and Incident Heart Failure With Preserved Ejection Fractionon January 25, 2024
CONCLUSIONS AND RELEVANCE: In this cohort study, TET2 CHIP was an independent risk factor associated with incident HFpEF. This finding may have implications for the prevention and management of HFpEF, including development of targeted therapies.
- Development and multi-site external validation of a generalizable risk prediction model for bipolar disorderon January 25, 2024
Bipolar disorder is a leading contributor to disability, premature mortality, and suicide. Early identification of risk for bipolar disorder using generalizable predictive models trained on diverse cohorts around the United States could improve targeted assessment of high risk individuals, reduce misdiagnosis, and improve the allocation of limited mental health resources. This observational case-control study intended to develop and validate generalizable predictive models of bipolar disorder […]
- Impact of polygenic score for BMI on weight loss effectiveness and genome-wide association analysison January 24, 2024
CONCLUSION: Our findings are expected to help in developing personalized weight loss approaches based on genetics.
PublicationsCGM Admin2023-08-22T11:44:51-04:00