Publications

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Type 1 diabetes (T1D) and other autoimmune diseases (AIDs) often co-occur in families. Leveraging data from 58,284 family trios in Finnish nationwide registers (FinRegistry), we identified that, of 50 parental AIDs examined, 15 were associated with an increased T1D risk in offspring. These identified epidemiological associations were further assessed in 470,000 genotyped Finns from the FinnGen study through comprehensive genetic analyses, partitioned into human leukocyte antigen (HLA) and...

CONCLUSIONS: This study identifies novel PTSD-associated CpGs in individual immune cell types and supports the role of immune dysregulation and inflammation in PTSD.

CONCLUSION: The GWAS detected two novel genetic associations with OTSCC. Further research is needed to identify the genes at these loci that contribute to the molecular pathogenesis of OTSCC.

Frontotemporal lobar degeneration with neuronal inclusions of the TAR DNA-binding protein 43 (FTLD-TDP) is a fatal neurodegenerative disorder with only a limited number of risk loci identified. We report our comprehensive genome-wide association study as part of the International FTLD-TDP Whole-Genome Sequencing Consortium, including 985 patients and 3,153 controls compiled from 26 institutions/brain banks in North America, Europe and Australia, and meta-analysis with the Dementia-seq cohort. […]

In the last two decades, significant progress has been made toward understanding the genetic basis of type 2 diabetes. An important supporter of this research has been the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), most recently through the Accelerating Medicines Partnership Program for Type 2 Diabetes (AMP T2D) and Accelerating Medicines Partnership Program for Common Metabolic Diseases (AMP CMD). These public-private partnerships of the National Institutes of...

The current-day epidemic of type 2 diabetes, largely driven by increased adiposity and reduced physical activity in the setting of genetic susceptibility, is a major public health challenge. The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) presciently proposed the Diabetes Prevention Program (DPP), a multicenter randomized clinical trial, designed by investigators in conjunction with NIDDK staff and initiated in 1996. The primary goal of DPP was to determine […]

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The circadian system maintains optimal biological functions at the appropriate time of day, and the disruption of this organization can contribute to the pathogenesis of cardiometabolic disorders. The timing of eating is a prominent external time cue that influences the circadian system. "Chrononutrition" is an emerging dimension of nutrition and active area of research that examines how timing-related aspects of eating and nutrition impact circadian rhythms, biological processes, and disease...

CONCLUSIONS: Alcohol responsiveness of LD symptoms is a robust feature related to the genes regulating the GABAergic synapses. This finding provides support for the evaluation of novel oral medications with mechanisms of action similar to alcohol for the treatment of patients with alcohol-responsive dystonia.

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CONCLUSIONS: The majority of participants in this study did not receive NCCN-compliant care. Germline genetic testing for hereditary ovarian cancer screening is underutilized and access to this testing is currently inequitable.

Engineering and characterizing proteins can be time-consuming and cumbersome, motivating the development of generalist CRISPR-Cas enzymes^(1-4) to enable diverse genome editing applications. However, such enzymes have caveats such as an increased risk of off-target editing^(3,5,6). To enable scalable reprogramming of Cas9 enzymes, here we combined high-throughput protein engineering with machine learning (ML) to derive bespoke editors more uniquely suited to specific targets. Via...

The modeling of psychiatric disorders poses significant challenges due to the complex nature of these conditions, which encompass a range of neuropsychiatric diseases such as autism spectrum disorder (ASD), schizophrenia (SCZ), bipolar disorder (BD), post-traumatic stress disorder (PTSD), anxiety disorder (AD) and depression. The rising global prevalence of mental disorders and the urgency for more effective treatments have propelled the development of innovative in vitro models. This review...

Canavan disease (CD) is a rare autosomal recessive leukodystrophy caused by biallelic pathogenic variants in the ASPA gene. CD is characterized by developmental delay, macrocephaly, and abnormal muscle tone. The biochemical diagnosis is confirmed by increased N-acetylaspartic acid levels. The phenotypic presentation varies, with 85-90% of individuals exhibiting the severe, typical form, while 10-15% present with a milder, atypical form. Here we report on five patients with a clinical and...

CONCLUSIONS: Here, we identify 5 novel loci associated with IA. Integration of summary statistics with cerebrovascular single-nuclear RNA sequencing reveals an association of cell types involved in matrix production. We validated a polygenic risk score that predicts IA, controlling for demographic variables including smoking status and blood pressure. Our findings suggest that a deficit in matrix production may drive IA pathogenesis independent of hypertension and smoking.

Single-cell CRISPR screens such as Perturb-seq enable transcriptomic profiling of genetic perturbations at scale. However, the data produced by these screens are noisy, and many effects may go undetected. Here we introduce transcriptome-wide analysis of differential expression (TRADE)-a statistical model for the distribution of true differential expression effects that accounts for estimation error appropriately. TRADE estimates the 'transcriptome-wide impact', which quantifies the total […]

PURPOSE OF REVIEW: Studies examining the effects of social factors on the epigenome have proliferated over the last two decades. Social epigenetics research to date has broadly demonstrated that social factors spanning childhood adversity, to neighborhood disadvantage, educational attainment, and economic instability are associated with alterations to DNA methylation that may have a functional impact on health. These relationships are particularly relevant to brain-based health outcomes such […]

CONCLUSIONS: In this cohort study in older adults, we identified modestly increased risk of VTE in individuals with CHIP, mainly driven by TET2 mutation. Future research should explore the mechanisms driving these associations and assess potential therapeutic and preventive strategies.

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Obesity is a major public health challenge. Glucagon-like peptide-1 receptor agonists (GLP1-RA) and bariatric surgery (BS) are effective weight loss interventions; however, the genetic factors influencing treatment response remain largely unexplored. Moreover, most previous studies have focused on race and ethnicity rather than genetic ancestry. Here we analyzed 10,960 individuals from 9 multiancestry biobank studies across 6 countries to assess the impact of known genetic factors on weight...

Variants in the mitochondrial genome (mtDNA) cause a diverse collection of mitochondrial diseases and have extensive phenotypic overlap with Mendelian diseases encoded on the nuclear genome. The mtDNA is not always specifically evaluated in patients with suspected Mendelian disease, resulting in overlooked diagnostic variants. Here, we analyzed a cohort of 6,660 rare disease families (5,625 genetically undiagnosed, 84%) from the Genomics Research to Elucidate the Genetics of Rare diseases...

Introduction: Whether stroke survivors can meet risk factor recommendations set by guidelines is unknown. We investigated the proportion of stroke survivors that met the secondary prevention guideline recommendations, analyzed the trends over time, and assessed the impact on mortality. Methods: Using cross-sectional data on stroke survivors from the National Health and Nutrition Examination Survey (NHANES) from 1999-2018, we determined the proportion of stroke survivors who met guideline...

Focal segmental glomerulosclerosis (FSGS) is a leading cause of nephrotic syndrome, with an annual incidence of 24 cases per million among African-Americans and 5 per million among European-Americans in the United States. It ranks as the second most common glomerular disease in Europe and Latin America and the fifth in Asia. We conducted a case-control study involving 726 FSGS cases and 13,994 controls from diverse ethnic backgrounds, using panel sequencing of ∼2,500 podocyte-expressed […]

Pragmatic clinical trials (PCTs) evaluate interventions in real-world settings, often using electronic health records (EHRs) for efficient data collection. We report on the challenges in performing EHR analysis of healthcare provider orders in a PCT within the eMERGE consortium, which investigates the impact of reporting genome-informed risk assessments (GIRA) to over 25,000 patients across 10 academic medical centers. Clinical informaticians conducted a landscape analysis to identify […]

Admixed individuals have largely been understudied in medical research due to their complex genetic ancestries. However, the consideration of admixture can help identify ancestry-enriched genetic associations, delineating some of the genetic underpinnings of cross-population phenotypic variation. To this end, we performed local ancestry inference within the All of Us Research Program to identify individuals with recent admixture between African (AFR) and European (EUR) populations (N=48,921). […]

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 heterogeneity, and the scarcity of observed phenotype in real-world settings. Ensemble learning offers a promising avenue to enhance the...

BACKGROUND: Epilepsy is one of the most common neurological disorders, affecting over 50 million people worldwide. One-third of people with epilepsy do not respond to currently available anti-seizure medications, constituting one of the most important problems in epilepsy. Little is known about the molecular pathology of drug resistance in epilepsy, in particular, possible underlying genetic factors are largely unknown.

CONCLUSION: Genetic risks for sleep and diurnal preference vary between non-affective psychosis, affective psychosis, and the general population. The findings in this study emphasize the heterogeneity in genetic etiology of the objective features of disease severity and the more subjective measures related to well-being and self-reported measures of sleep.

Chronic kidney disease (CKD) afflicts over 10% of US adults, with its prevalence increasing sharply with age. Clonal hematopoiesis of indeterminate potential (CHIP) is a common, genetically heterogeneous blood cell disorder characterized by the age-related clonal expansion of hematopoietic cells driven by leukemogenic somatic mutations yet without hematologic malignancy or dysplasia. While CHIP is a strong risk factor for future hematologic malignancy (estimated at ∼0.5% per year, compared […]

Diabetes mellitus is a heterogeneous condition with substantial clinical variability across global populations. The standard classification of type 1 and type 2 diabetes is primarily based on phenotypic characteristics in European-ancestry populations. However, diabetes exhibits diverse phenotypes in other populations, including a varied relationship between diabetes risk and body mass index. These differences may be partly attributable to genetic variation among populations. Understanding […]

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BACKGROUND AND OBJECTIVES: Previous studies have shown that increased body fat is associated with stroke risk, with evidence suggesting that body fat distribution, rather than total body fat, exerts a more prominent role in cerebrovascular risk prediction. In this study, we explore causal associations between body mass index (BMI)-independent adipose tissue distribution profiles and cerebrovascular disease (CVD) risk, aiming to refine the association between body fat distribution and stroke.

CONCLUSION: Higher POAG PRS and NTG PRS were associated with paracentral VF loss, while higher HTG GRS was linked to total VF loss but not paracentral defects. Genetic risk for glaucoma subtypes is associated with specific VF defects, which may affect disease diagnosis and prognostication.

CONCLUSIONS: Favorable sleep behaviors and genetic predisposition to healthy sleep may independently protect against disease, underscoring the impact of multidimensional sleep on population health and the need for prevention strategies focused on healthy sleep habits.

Here, we present a multi-omics study of type 2 diabetes and quantitative blood lipid and lipoprotein traits conducted to date in Hispanic/Latino populations (n(max) = 63,184). We conduct a meta-analysis of 16 type 2 diabetes and 19 lipid trait GWAS, identifying 20 genome-wide significant loci for type 2 diabetes, including one novel locus and novel signals at two known loci, based on fine-mapping. We also identify sixty-one genome-wide significant loci across the lipid/lipoprotein traits,...

CONCLUSIONS AND RELEVANCE: Clinicians stratify patients for suicide risk at levels significantly above chance. However, the predictive accuracy improves significantly by statistically incorporating information about recent suicidal thoughts and behaviors and other factors routinely assessed during clinical suicide risk assessment.

CONCLUSIONS: Non-DNMT3A CHIP was associated with CKD progression among individuals with CKD. Further, Tet2-CHIP mouse models support a causal role in kidney injury.

CONCLUSIONS: Lower genetic risk and higher first-trimester CVH were independently and additively associated with lower risk of developing HDPs in nulliparous individuals. Favorable CVH in early pregnancy may mitigate high genetic risk for HDP.

Osteoarthritis is the third most rapidly growing health condition associated with disability, after dementia and diabetes¹. By 2050, the total number of patients with osteoarthritis is estimated to reach 1 billion worldwide². As no disease-modifying treatments exist for osteoarthritis, a better understanding of disease aetiopathology is urgently needed. Here we perform a genome-wide association study meta-analyses across up to 489,975 cases and 1,472,094 controls, establishing 962 […]

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CONCLUSIONS: In patients with CKD, non-DNMT3A CHIP was associated with cardiovascular disease with an effect size similar to that reported in the general population.

Psychiatric disorders exhibit substantial genetic overlap, raising questions about the utility of transdiagnostic genetic risk models. Using data from the All of Us Research Program (N=102,091), we evaluated common psychiatric genetic (CPG) factor-based polygenic risk scores (PRSs) compared to standard disorder-specific PRSs. The CPG PRS consistently outperformed disorder-specific scores in predicting individual disorder risk, explaining 1.07 to 24.6 times more phenotypic variance across 11...

CONCLUSIONS: This study provides novel evidence linking polygenic risk to PSU in early adolescence and highlights PSU as a more severe manifestation of substance use liability driven by heightened genetic vulnerability and adverse environmental exposures.

CONCLUSION: Whereas, in recent years, the population size of people with DS is decreasing in Australia, New Zealand, and Europe, the number of people with DS is still growing in the United States and Canada. In Canada, however, the growth rate is increasingly slowing down, probably foreshadowing a population contraction in the coming years.

AIM: To describe seizure prevalence in childhood cerebral adrenoleukodystrophy (CCALD) and the relationship to disease severity/progression.

The Yale-Brown Obsessive-Compulsive Scale, Second Edition (Y-BOCS-II) is an evidence-based clinician-rated measure for assessing the presence and severity of obsessive-compulsive symptoms. The Spanish version of the Y-BOCS-II has not yet been validated. The present study examines the psychometric properties of the Spanish Y-BOCS-II (Spanish-Y-BOCS-II) in adults with obsessive-compulsive disorder (OCD) who are of Hispanic/Latino ancestry. The Spanish-Y-BOCS-II was administered to 1805 adults […]

CONCLUSION: A foundational LLM performed poorly but consistently across subgroups in imputing PHQ-9 scores from notes when actual PHQ-9 reporting was ablated. This result suggests the extent to which inclusion of PROMs may impoverish documentation of psychiatric symptoms.

Genome-wide association studies (GWASs) have identified thousands of genetic loci associated with cardiometabolic disorders. However, the functional interpretation of these loci remains a daunting challenge. This is particularly true for adipose tissue, a critical organ in systemic metabolism and the pathogenesis of various cardiometabolic diseases. We discuss how variant-to-function (V2F) approaches are used to elucidate the mechanisms by which GWAS loci increase the risk of cardiometabolic...

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Insomnia symptoms double the risk of cardiovascular disease (CVD), yet shared genetic pathways remain unclear. Genome-wide association studies (GWAS) identified a genetic locus (near ATP5G1, UBE2Z, SNF8, IGF2BP1, and GIP) linked to insomnia and CVD. We used Drosophila models to perform tissue-specific RNAi knockdowns of four conserved orthologues (ATPSynC, Lsn, Bruce, and Imp) in neurons and the heart. Neuronal-specific knockdown of ATPSynC, Imp, and Lsn impaired sleep quantity and quality. […]

CONCLUSIONS: This study identified overlapping modifiable risk factors and calculated the relative impact of these factors on the risk of a composite outcome of stroke, dementia and LLD. These findings could guide preventative strategies and serve as an empirical foundation for future development of tools that can empower people to reduce their risk of these diseases.

Youth depression is a global emergency. Redressing this emergency requires a sophisticated understanding of the multisystemic risks and biopsychosocial, economic, and environmental resources associated with young people's experiences of no/limited versus severe depression. Too often, however, personal risks and a focus on individual-level protective resources dominate accounts of young people's trajectories towards depression. Further, studies of depression in high-income countries (i.e.,...

Psychiatric disorders are highly heritable and polygenic, influenced by environmental factors and often comorbid. Large-scale genome-wide association studies (GWASs) through consortium efforts have identified genetic risk loci and revealed the underlying biology of psychiatric disorders and traits. However, over 85% of psychiatric GWAS participants are of European ancestry, limiting the applicability of these findings to non-European populations. Latin America and the Caribbean, regions […]

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Polygenic scores (PGS) are widely used for estimating genetic predisposition to complex traits by aggregating the effects of common variants into a single measure. They hold promise in identifying individuals at increased risk for diseases, allowing earlier screening and interventions. Genotyping arrays, commonly used for PGS computation, are affordable and computationally efficient, while whole-genome sequencing (WGS) offers a comprehensive view of genetic variation. Using the same set of...

CONCLUSIONS: Our findings link TRPML-1 dysfunction to the development of kidney disease in MLIV.

The present study examines the safety profile of intravenous onasemnogene abeparvovec gene therapy in a real-world setting, both alone or in combination with intrathecal antisense oligonucleotide nusinersen therapy in two cohorts of patients with spinal muscular atrophy (SMA). The first cohort included eight presymptomatic infants treated solely with onasemnogene abeparvovec, while the second cohort comprised six symptomatic infants receiving onasemnogene abeparvovec and nusinersen […]

CONCLUSION: T1D polygenic scores already have clinical utility to aid in the accurate diagnosis of pediatric diabetes. Efforts are now needed to advance their use in clinical practice.

Mental health disorders affect over 1 billion people worldwide, profoundly impacting individuals, families, and the global economy. Risk for psychopathology begins early in life, with the perinatal period representing a critical window of vulnerability. The Brain health Begins Before Birth (B4) Study at Massachusetts General Hospital (MGH) is a prospective birth cohort designed to identify modifiable risk and resilience factors influencing early brain development and child- and adult-onset...

CONCLUSIONS: This study nominates three strong novel candidate oCCDD genes (SEMA3F, OLIG2, and FRMD4B) and supports the functionality and putative pathogenicity of transcription factor candidate variants PHOX2A p.(Trp137Cys), MAFB p.(Glu223Lys), and OLIG2 p.(Arg156Leu). Our findings support that G0 loss-of-function screening in zebrafish can be coupled with human sequence analysis and protein binding microarrays to aid in prioritizing oCCDD candidate genes/variants.

Genetic sequencing technologies are powerful tools for identifying rare variants and genes associated with Mendelian and complex traits; indeed, whole-exome and whole-genome sequencing are increasingly popular methods for population-scale genetic studies. However, careful quality control steps should be taken to ensure study accuracy and reproducibility, and sequencing data require extensive quality filtering to delineate true variants from technical artifacts. Although processing standards […]

Metabolites are small molecules that are useful for estimating disease risk and elucidating disease biology. Here, we perform two-sample Mendelian randomization to systematically infer the potential causal effects of 1099 plasma metabolites measured in 6136 Finnish men from the METSIM study on risk of 2099 binary disease endpoints measured in 309,154 Finnish individuals from FinnGen. We find evidence for 282 putative causal effects of 70 metabolites on 183 disease endpoints. We also identify […]

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Approximately 8% of the human genome consists of repetitive elements called tandem repeats (TRs): short tandem repeats (STRs) of 1-6 bp motifs and variable number tandem repeats (VNTRs) of 7 + bp motifs. TR variants contribute to several dozen monogenic diseases but remain understudied and enigmatic. It remains comparatively challenging to interpret the clinical significance of TR variants, particularly relative to single nucleotide variants. We present STRchive ( http://strchive.org/ ), a...

BACKGROUND AND OBJECTIVES: Uncontrolled hypertension is a risk factor of heart attack, stroke, dementia, and other conditions. In outpatients with hypertension, blood pressure (BP) may be controlled at only 30%-50% of visits depending on the population studied. Hospital admission is ideal for achieving guideline-directed BP targets, given the resource-intensive environment. We evaluated the relationship between BP control performance during neurocritical care and hospital admission and rates […]

INTRODUCTION: Myopathy and dysphagia are common manifestations of nephropathic cystinosis, a rare autosomal recessive lysosomal storage disorder. We previously demonstrated that both the oral and pharyngeal phases of swallowing are affected and impact function and quality of life in patients. To better understand and characterize swallowing impairment, we evaluated patients with nephropathic cystinosis experiencing dysphagia and myopathy.

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Individuals with neurofibromatosis type 1 (NF1) are prone to the evolution of neurodevelopmental symptomatology including motor delays, learning disabilities, autism, and attention deficits. Caused by heterozygous germline mutations in the NF1 gene, this monogenic condition offers unique opportunities to study the genetic etiologies for neurodevelopmental disorders and the mechanisms that underlie their formation. Although numerous small animal models have been generated to elucidate the […]

CONCLUSIONS: Carriers of an experimentally confirmed damaging CCR2 variant are at a lower lifetime risk of myocardial infarction and coronary artery disease without carrying a higher risk of infections. Our findings provide genetic support for the translational potential of CCR2-targeting as an atheroprotective approach.

The ADAT2/ADAT3 (ADAT) 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. Yet, the physiological function of ADAT2/ADAT3 complex during brain development remains totally unknown. Here, we investigated the role of the ADAT2/ADAT3 complex in cortical development. First, we […]

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CONCLUSIONS: In conclusion, the reliability and validity of self-reported risk factors for stroke and dementia differ between risk factors. Although self-reported measures vary in their reliability, they perform equally as well as objective metrics for evaluating the risk of stroke- and dementia-related mortality.

DYT1 dystonia is a neurological movement disorder characterized by a dominant 3-base pair deletion (ΔGAG) in the TOR1A gene. This study demonstrates a gene-editing approach that selectively targets the ΔGAG mutation in the TOR1A DYT1 allele while safeguarding the wild-type (WT) TOR1A allele. We optimized an adeno-associated virus (AAV) vector-compatible variant of the Staphylococcus aureus Cas9 nuclease ortholog (SaCas9-KKH) in DYT1 patient-derived human neuronal progenitor cells (hNPCs)....

CONCLUSIONS: HE significantly impacts severe outcomes only when the final ICH volume exceeds a critical target threshold, and this threshold is lower in deep versus lobar ICH. These findings might inform clinical practice and future trials.

Accentuated Lines (ALs) in tooth enamel can reflect metabolic disruptions from physiological or psychological stresses during development. They can therefore serve as a retrospective biomarker of generalized stress exposure in archaeological and clinical research. However, little consensus exists on when ALs are identified and inter-rater reliability is poorly quantified across studies. Here, we sought to address this gap by examining the reliability of accentuated (AL) markings across […]

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De novo variants (DNs) are sporadically occurring variants that most commonly arise in the germline and are present in offspring but absent in both parents. As they are not under selective pressure, they may be enriched for disease-causing alleles and have been implicated in multiple rare genetic disorders. Cleft palate (CP) is a common craniofacial congenital anomaly occurring in ~1 in 1700 live births. Genome-wide association studies for CP have found fewer than a dozen loci, while exome […]

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Elevated fasting insulin levels (FI), indicative of altered insulin secretion and sensitivity, may precede type 2 diabetes (T2D) and cardiovascular disease onset. In this study, we group FI-associated genetic variants based on their genetic and phenotypic similarities and identify seven clusters with distinct mechanisms contributing to elevated FI levels. Clusters fall into two types: "non-diabetogenic hyperinsulinemia," where clusters are not associated with increased T2D risk, and...

Diabetes is a rapidly growing global health concern projected to affect one in eight adults by 2045, which translates to roughly 783 million people. The profound metabolic alterations often present in dysglycaemia significantly increase the risk of cardiovascular complications. While genetic susceptibility plays a crucial role in diabetes and its vascular complications, identifying genes and molecular mechanisms that influence both diseases simultaneously has proven challenging. A key reason […]

Current clinician-based and automated risk assessment methods treat the risk of suicide-related behaviors (SRBs) as static, while in actual clinical practice, SRB risk fluctuates over time. Here, we develop two closely related model classes, Event-GRU-ODE and Event-GRU-Discretized, that can predict the dynamic risk of events as a continuous trajectory across future time points, even without new observations, while updating these estimates as new data become available. Models were trained and...

CONCLUSION: At calibrated thresholds, three new computational predictors provided evidence for variant pathogenicity at similar strength to the four previously recommended predictors (and comparable with functional assays for some variants). This calibration broadens the scope of computational tools for application in clinical variant classification. Their new approaches offer promise for future advancement of the field.

Brain arteriovenous malformations (AVMs), cerebral cavernous malformations (CCMs), and intracranial aneurysms are major causes of hemorrhagic stroke, yet noninvasive therapies to prevent growth or rupture are lacking. Understanding the genetic basis of these malformations is critical for uncovering underlying mechanisms, developing targeted prevention strategies, and identifying novel therapeutic targets. This review highlights the causal genes and signaling pathways in AVMs, CCMs, and...

Orchestrated changes in cell arrangements and cell-to-cell contacts are susceptible to cellular stressors during central nervous system development. Effects of mitochondrial complex I inhibition on cell-to-cell contacts have been studied in vascular and intestinal structures; however, its effects on developing neuronal cells are largely unknown. We investigated the effects of the classical mitochondrial stressor and complex I inhibitor, rotenone, on the architecture of neural […]

CONCLUSIONS: The WMH risk score demonstrated accurate performance and reproducibility across cohorts, supporting its potential as a screening tool for identifying patients at risk of significant WMH burden. Appropriately targeted pMRI screening in high-risk individuals could allow providers and patients to proactively manage vascular risk factors and improve neurological outcomes.

Despite insufficient evidence to support direct-to-consumer genetic testing in routine clinical care, cardiovascular clinicians increasingly face questions about its utility and interpretation because individuals can purchase these tests directly from laboratories. A burgeoning marketplace offers an expanding array of testing options. In many cases, direct-to-consumer genetic testing advertises information that could inform one's risk of heritable disease, including insight into having a […]

CONCLUSION: Higher pre-pandemic resilience may have protected women against poor sleep outcomes during the pandemic. Findings could have long-term health implications, particularly if they generalize to other stressors.

Family-based genome-wide association studies (FGWASs) use random, within-family genetic variation to remove confounding from estimates of direct genetic effects (DGEs). Here we introduce a 'unified estimator' that includes individuals without genotyped relatives, unifying standard and FGWAS while increasing power for DGE estimation. We also introduce a 'robust estimator' that is not biased in structured and/or admixed populations. In an analysis of 19 phenotypes in the UK Biobank, the unified...

Colonic mucus forms a first line of defense against bacterial invasion while providing nutrition to support coinhabiting microbes in the gut. Mucus is composed of polymeric networks of mucin proteins, which are heavily modified post-translationally. The full compendium of enzymes responsible for these modifications and their roles in health and disease remain incompletely understood. Herein, we determine the biochemical function of NXPE1, a gene implicated in ulcerative colitis (UC), and...

Obesity is a highly heterogeneous disease that cannot be captured by one single adiposity trait. Here, we performed a multi-trait analysis to study obesity in the context of its common cardiometabolic comorbidities, acknowledging that not all individuals with obesity suffer from cardiometabolic comorbidities and that not all those with normal weight clinically present without them. We leveraged individual-level genotype-phenotype data of 452,768 individuals from the UK Biobank and designed...

CONCLUSION AND RELEVANCE: These findings demonstrate the potential of a triangulation approach to uncover scalable and clinically relevant biomarkers for PTSD.

Background: Multiple acyl-CoA dehydrogenase deficiency (MADD) is an inherited metabolic disorder (IMD) that affects the electron transfer chain and fatty acid oxidation. The late-onset form of MADD has a heterogenous clinical presentation that typically results in episodic lethargy, hypoglycemia, acidosis, and rhabdomyolysis during metabolic decompensations. Purpose: In this case report series we describe three cases of late-onset MADD presenting with hyperammonemia and encephalopathy, a less...

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Differences in the patterning of genetic sharing between groups of individuals may arise from biological pathways, social mechanisms, phenotyping and ascertainment. We expand genomic structural equation modeling to allow for testing genomic structural invariance (GSI), that is, the formal comparison of multivariate genetic architecture across groups. We apply GSI to compare the autosomal multivariate genetic architecture of eight psychiatric disorders spanning three factors (psychotic,...

Targeted metabolomics was conducted on plasma samples from a nested case-cohort study within the biracial REasons for Geographic and Racial Differences in Stroke (REGARDS) cohort. This longitudinal study investigates health outcomes with a focus on stroke disparities across the United States, particularly in the Southeastern "Stroke Belt," where stroke risk and mortality are 2-4 times higher in the Black population. The REGARDS study recruited 30,239 Black and White participants aged 45 years […]

Atrial fibrillation (AF) is the most common heart rhythm abnormality and is a leading cause of heart failure and stroke. This large-scale meta-analysis of genome-wide association studies increased the power to detect single-nucleotide variant associations and found more than 350 AF-associated genetic loci. We identified candidate genes related to muscle contractility, cardiac muscle development and cell-cell communication at 139 loci. Furthermore, we assayed chromatin accessibility using […]

Atrial fibrillation (AF) is a prevalent and morbid abnormality of the heart rhythm with a strong genetic component. Here, we meta-analyzed genome and exome sequencing data from 36 studies that included 52,416 AF cases and 277,762 controls. In burden tests of rare coding variation, we identified novel associations between AF and the genes MYBPC3, LMNA, PKP2, FAM189A2 and KDM5B. We further identified associations between AF and rare structural variants owing to deletions in CTNNA3 and […]