Publications

MOTIVATION: Functional Annotation of genomic Variants Online Resources (FAVOR) offers multi-faceted, whole genome variant functional annotations, which is essential for Whole Genome and Exome Sequencing (WGS/WES) analysis and the functional prioritization of disease-associated variants. A versatile chatbot designed to facilitate informative interpretation and interactive, user-centric summary of the whole genome variant functional annotation data in the FAVOR database is needed.

CONCLUSION: Patients with DS and severe persistent OSA who undergo HGNS implantation may continue to experience improvement in PSG parameters at long-term follow-up. Future studies are needed to assess additional long-term outcomes in this patient population, including neurocognition and quality of life.

CONCLUSIONS AND RELEVANCE: In this case-control study among ethnically diverse African participants, psychological distress was associated with traumatic stress, substance use, and physical symptoms. These findings were observed to be consistent with previous research that emphasizes the importance of traumatic events as a factor associated with risk for psychopathology and notes the frequent co-occurrence of conditions such as physical symptoms, depression, and anxiety.

CONCLUSIONS: Hematologic cancer developed in a subgroup of patients who were treated with eli-cel; the cases are associated with clonal vector insertions within oncogenes and clonal evolution with acquisition of somatic genetic defects. (Funded by Bluebird Bio; ALD-102, ALD-104, and LTF-304 ClinicalTrials.gov numbers, NCT01896102, NCT03852498, and NCT02698579, respectively.).

CONCLUSIONS: At a median follow-up of 6 years after lentiviral gene therapy, most patients with early cerebral adrenoleukodystrophy and MRI abnormalities had no major functional disabilities. However, insertional oncogenesis is an ongoing risk associated with the integration of viral vectors. (Funded by Bluebird Bio; ALD-102 and LTF-304 ClinicalTrials.gov numbers NCT01896102 and NCT02698579, respectively.).

CONCLUSIONS: Deep phenotyping is an important next step to improve understanding of the genetic etiology of AUBs, in addition to increasing sample size. Further effort is required to uncover the genetic heterogeneity underlying AUBs using methods that account for their complex, multidimensional nature.

CONCLUSIONS: Lifelong exposure to decreased PZ levels confers a significantly increased risk of NCEIS, consistent with the role of PZ as an anticoagulant factor.

CONCLUSIONS: Recipients of DCD demonstrated similar renal outcomes compared with recipients of DBD, supporting the ongoing use of DCD transplantation. Early AKI was associated with persistent renal dysfunction for recipients of both DCD and DBD.

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Type 2 diabetes (T2D) genome-wide association studies (GWASs) often overlook rare variants as a result of previous imputation panels' limitations and scarce whole-genome sequencing (WGS) data. We used TOPMed imputation and WGS to conduct the largest T2D GWAS meta-analysis involving 51,256 cases of T2D and 370,487 controls, targeting variants with a minor allele frequency as low as 5 × 10^(-5). We identified 12 new variants, including a rare African/African American-enriched enhancer variant […]

Migraine is a highly prevalent neurovascular disorder for which genome-wide association studies (GWAS) have identified over one hundred risk loci, yet the causal variants and genes remain mostly unknown. Here, we meta-analyzed three migraine GWAS including 98,374 cases and 869,160 controls and identified 122 independent risk loci of which 35 were new. Fine-mapping of a meta-analysis is challenging because some variants may be missing from some participating studies and accurate linkage...

Rare coding alleles play crucial roles in the molecular diagnosis of genetic diseases. However, the systemic identification of these alleles has been challenging due to their scarcity in the general population. Here, we discovered and characterized rare coding alleles contributing to genetic dyslipidemia, a principal risk for coronary artery disease, among over a million individuals combining three large contemporary genetic datasets (the Million Veteran Program, n = 634,535, UK Biobank, n =...

Subcortical brain structures are involved in developmental, psychiatric and neurological disorders. We performed GWAS meta-analyses of intracranial and nine subcortical brain volumes (brainstem, caudate nucleus, putamen, hippocampus, globus pallidus, thalamus, nucleus accumbens, amygdala and, for the first time, the ventral diencephalon) in 74,898 participants of European ancestry. We identified 254 independent loci associated with these brain volumes, explaining up to 35% of phenotypic...

The fields of coping and emotion regulation have mostly evolved separately over decades, although considerable overlap exists. Despite increasing efforts to unite them from a conceptual standpoint, it remains unclear whether conceptual similarities translate into their measurement. The main objective of this review was to summarize and compare self-reported measures of coping and emotion regulation strategies. The secondary objective was to examine whether other psychological measures (e.g.,...

Overall adiposity and body fat distribution are heritable traits associated with altered risk of cardiometabolic disease and mortality. Performing rare variant (minor allele frequency

Although X-linked adrenoleukodystrophy (ALD) has historically been considered a childhood disease managed by pediatric neurologists, it is one of the most common leukodystrophies diagnosed in adulthood. An increase in both male and female adults reaching diagnosis due to familial cases identified by state newborn screening panels and more widespread use of genetic testing results in a large cohort of presymptomatic or early symptomatic adults. This population is in urgent need of standardized...

Major depressive disorder (MDD) is highly prevalent in youth and generally characterized by psychiatric comorbidities. Secular trends in co-occurring diagnoses remain unclear, especially in healthcare settings. Using large-scale electronic health records data from a major U.S. healthcare system, we examined the prevalence of MDD diagnoses and co-occurring psychiatric conditions during adolescence (12-18 years; N = 133,753) across four generations (birth years spanning 1985 to 2002) and by […]

CONCLUSIONS: Individuals with a history of PCC were more likely to use a variety of health services and report barriers to medical care. Health systems should consider developing accessible, multidisciplinary care pathways for this population.

Genomic data from millions of individuals have been generated worldwide to drive discovery and clinical impact in precision medicine. Lowering the barriers to using these data collectively is needed to equitably realize the benefits of the diversity and scale of population data. We examine the current landscape of global genomic data sharing, including the evolution of data sharing models from data aggregation through to data visiting, and for certain use cases, cross-cohort analysis using...

Cold-induced lipolysis is widely studied as a potential therapeutic strategy to combat metabolic disease, but its effect on lipid homeostasis in humans remains largely unclear. Blood plasma comprises an enormous repertoire in lipids allowing insights into whole body lipid homeostasis. So far, reported results originate from studies carried out with small numbers of male participants. Here, the blood plasma's lipidome of 78 male and 93 female volunteers, who were exposed to cold below the...

Structural birth defects affect 3-4% of all live births and, depending on the type, tend to manifest in a sex-biased manner. Orofacial clefts (OFCs) are the most common craniofacial structural birth defects and are often divided into cleft lip with or without cleft palate (CL/P) and cleft palate only (CP). Previous studies have found sex-specific risks for CL/P, but these risks have yet to be evaluated in CP. CL/P is more common in males and CP is more frequently observed in females, so we...

Research on brain expression quantitative trait loci (eQTLs) has illuminated the genetic underpinnings of schizophrenia (SCZ). Yet most of these studies have been centered on European populations, leading to a constrained understanding of population diversities and disease risks. To address this gap, we examined genotype and RNA-seq data from African Americans (AA, n = 158), Europeans (EUR, n = 408), and East Asians (EAS, n = 217). When comparing eQTLs between EUR and non-EUR populations, we...

Human genetic variants are associated with many traits through largely unknown mechanisms. Here, combining approximately 260,000 Japanese study participants, a Japanese-specific genotype reference panel and statistical fine-mapping, we identified 4,423 significant loci across 63 quantitative traits, among which 601 were new, and 9,406 putatively causal variants. New associations included Japanese-specific coding, splicing and noncoding variants, exemplified by a damaging missense variant...

Identifying genetic risk factors for highly heterogeneous disorders such as epilepsy remains challenging. Here we present, to our knowledge, the largest whole-exome sequencing study of epilepsy to date, with more than 54,000 human exomes, comprising 20,979 deeply phenotyped patients from multiple genetic ancestry groups with diverse epilepsy subtypes and 33,444 controls, to investigate rare variants that confer disease risk. These analyses implicate seven individual genes, three gene sets and...

Post-COVID-19 cognitive deficits are common, persistent, and disabling. Evidence on effective treatments is limited. The goal of this study was to investigate the efficacy of a digital intervention to reduce cognitive and functional deficits in adults with persistent post-COVID-19 cognitive dysfunction. We used the remotely-delivered intervention in a randomized clinical trial conducted from July 13, 2021 to April 26, 2023. We hypothesized that participants in the intervention group would...

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CONCLUSIONS AND RELEVANCE: This study suggests that nonprobability survey data can be used to estimate the temporal evolution of test-confirmed infections during an emerging disease outbreak. Self-reporting tools may enable government and health care officials to implement accessible and affordable at-home testing for efficient infection monitoring in the future.

Metabolic syndrome (MetS) is a complex hereditary condition comprising various metabolic traits as risk factors. Although the genetics of individual MetS components have been investigated actively through large-scale genome-wide association studies, the conjoint genetic architecture has not been fully elucidated. Here, we performed the largest multivariate genome-wide association study of MetS in Europe (n(observed) = 4,947,860) by leveraging genetic correlation between MetS components. We...

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.

INTRODUCTION: Stroke and vascular cognitive impairment (VCI) are major global public health pandemics. The increased incidence of stroke and VCI is in part due to modifiable risk factors (MRFs), with hypertension (HTN) being the strongest single MRF. Even though the underlying causes of HTN are multifactorial, lifestyle choices (eg, poor diet, physical inactivity, alcohol consumption) are chief contributors. Lifestyle medicine (LSM) is a medical and evidence-based discipline that is a […]

Genetic diagnosis plays a crucial role in rare diseases, particularly with the increasing availability of emerging and accessible treatments. The International Rare Diseases Research Consortium (IRDiRC) has set its primary goal as: "Ensuring that all patients who present with a suspected rare disease receive a diagnosis within one year if their disorder is documented in the medical literature". Despite significant advances in genomic sequencing technologies, more than half of the patients […]

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CONCLUSIONS: AGS is a heterogeneous disease with multi-organ system dysfunction that compounds throughout the clinical course, resulting in profound neurological and extra-neurological disease impact. Systemic symptoms precede neurologic disease features in most cases. Disease onset before the age of one year, microcephaly, feeding tube placement, and seizures were associated with worse neurological outcomes. This work will inform evidence-based clinical monitoring guidelines and clinical […]

Unsolved Mendelian cases often lack obvious pathogenic coding variants, suggesting potential non-coding etiologies. Here, we present a single cell multi-omic framework integrating embryonic mouse chromatin accessibility, histone modification, and gene expression assays to discover cranial motor neuron (cMN) cis-regulatory elements and subsequently nominate candidate non-coding variants in the congenital cranial dysinnervation disorders (CCDDs), a set of Mendelian disorders altering cMN...

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In this study, we present an approach to neuropharmacological research by integrating few-shot meta-learning algorithms with brain activity mapping (BAMing) to enhance the discovery of central nervous system (CNS) therapeutics. By utilizing patterns from previously validated CNS drugs, our approach facilitates the rapid identification and prediction of potential drug candidates from limited datasets, thereby accelerating the drug discovery process. The application of few-shot meta-learning...

CONCLUSIONS AND RELEVANCE: These results demonstrated that a model based on administrative variables available at the time of leaving active Army service can predict suicides with meaningful accuracy over the subsequent decade. However, final determination of cost-effectiveness would require information beyond the scope of this report about intervention content, costs, and effects over relevant horizons in relation to the monetary value placed on preventing suicides.

X-linked adrenoleukodystrophy (ALD) is a peroxisomal disorder caused by mutations in the ABCD1 gene and characterized by impaired very long-chain fatty acid beta-oxidation. Clinically, male patients develop adrenal failure and progressive myelopathy in adulthood, although the age of onset and rate of progression are highly variable. In addition, 40% of male patients develop a leukodystrophy (cerebral ALD) before the age of 18 years. Women with ALD also develop myelopathy, but generally at a...

Obesity is a significant public health concern. GLP-1 receptor agonists (GLP1-RA), predominantly in use as a type 2 diabetes treatment, are a promising pharmacological approach for weight loss, while bariatric surgery (BS) remains a durable, but invasive, intervention. Despite observed heterogeneity in weight loss effects, the genetic effects on weight loss from GLP1-RA and BS have not been extensively explored in large sample sizes, and most studies have focused on differences in race and...

CONCLUSIONS: Overall, we demonstrate our antidepressant response algorithm can be deployed across multiple EHR systems to increase sample size of genetic and epidemiologic studies of antidepressant response.

Evening chronotypes (a.k.a. "night-owls") are held to be at greater risk for psychiatric disorders. This is postulated to be due to delayed circadian timing increasing the likelihood of circadian misalignment in an early-oriented society. Circadian misalignment is known to heighten sleep inertia, the difficulty transitioning from sleep to wake characterized by low arousal and cognitive impairment, and evening chronotypes experience greater sleep inertia. Therefore, difficulty awakening may...

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.

BACKGROUND: While the NIMH Research Domain Criteria framework stresses understanding how neuropsychiatric phenotypes vary across populations, little is known outside of small clinical cohorts about conspiratorial thoughts as an aspect of cognition.

CONCLUSIONS: Our findings emphasize the value of leveraging diverse populations to enhance biological insights from proteomics GWAS, and we have made this resource readily available as an interactive web portal.

CONCLUSIONS AND RELEVANCE: In this cohort study of adults with Down syndrome who were enrolled in Medicaid and Medicare, Alzheimer dementia occurred at high rates. Consistency with clinical studies of dementia in Down syndrome supports the use of administrative data in Down syndrome-Alzheimer dementia research.

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Autosomal recessive coding variants are well-known causes of rare disorders. We quantified the contribution of these variants to developmental disorders in a large, ancestrally diverse cohort comprising 29,745 trios, of whom 20.4% had genetically inferred non-European ancestries. The estimated fraction of patients attributable to exome-wide autosomal recessive coding variants ranged from ~2-19% across genetically inferred ancestry groups and was significantly correlated with average...

In 2020, we wrote to you about our dedication and vision for JAACAP "to be antiracist at every level."¹ Over the last 4 years we have pursued initiatives "to reshape the Journal to pursue this vision."^(2-4) In this article, we provide an update on these goals and initiatives (Figure 1). These initiatives include both scientific journals in the JAACAP family, JAACAP and JAACAP Open. Through this work we aspire to be a leader among mental health journals in our intentional pursuit of […]

CONCLUSIONS: LLM may be able to assist with the efficient collection of stroke audit data. Such approaches may be pursued in other specialties. Future studies should seek to examine the most effective way to deploy such approaches in conjunction with human auditors and researchers.

Objective: Research establishing the validity of neuropsychological assessment using telehealth (teleNP) is much needed in pediatric populations. Method: Current analyses compared performances on twelve common neuropsychological measures completed at home via teleNP or in-person during the COVID-19 pandemic in 476 youth (ages 6 to 17, M(age) 11.4 ± 3.0). Results: No differences were found on nine measures. In-person performances on three verbal tests were ∼1 scaled score point lower (all...

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CONCLUSIONS: Our findings reveal behavioral state-dependent patterns of cortical dysconnectivity in schizophrenia. Furthermore, these findings are largely unrelated to previous sleep-related EEG markers of schizophrenia such as decreased sleep spindles. Therefore, these findings are driven by previously undescribed sleep-related pathology in schizophrenia.

CONCLUSIONS: These findings support the concept of CCx as a multi-organ syndrome with diverse metabolic alterations, providing insights into the pathophysiology and organ cross-talk of human CCx. This study pioneers spatial metabolomics for CCx, demonstrating the feasibility of distinguishing cachexia status at the organ level using serum.

CONCLUSION: Our results suggest that genetic variants in CDHR3 and GSDMB modulate susceptibility to bronchiolitis, especially when caused by viruses other than RSV. Severe bronchiolitis in infancy may trigger the development of asthma in genetically susceptible individuals, or it could be a marker of genetic predisposition to asthma.

Multiple facets of sleep neurophysiology, including electroencephalography (EEG) metrics such as non-rapid eye movement (NREM) spindles and slow oscillations, are altered in individuals with schizophrenia (SCZ). However, beyond group-level analyses, the extent to which NREM deficits vary among patients is unclear, as are their relationships to other sources of heterogeneity including clinical factors, ageing, cognitive profiles and medication regimens. Using newly collected high-density sleep...

Although large-scale genome-wide association studies (GWASs) have revealed the genetic architecture of schizophrenia, these studies have mainly focused on populations of European ancestry. This study aimed to identify common genetic variants associated with schizophrenia in the Korean population and evaluate the performance of polygenic risk scores (PRSs) derived from large-scale GWASs across ancestries. In the Korean psychiatric GWAS project (KPGP), seven academic institutes and their...

CONCLUSIONS: Recalibration and personalized treatment thresholds derived within a health system may improve prevention treatment allocation efficiency.

CONCLUSIONS: Our results provided novel glycemic trait associations and highlighted pathways implicated in glycemic regulation. Exome-array summary statistic results are being made available to the scientific community to enable further discoveries.

We deployed the Blended Genome Exome (BGE), a DNA library blending approach that generates low pass whole genome (1-4× mean depth) and deep whole exome (30-40× mean depth) data in a single sequencing run. This technology is cost-effective, empowers most genomic discoveries possible with deep whole genome sequencing, and provides an unbiased method to capture the diversity of common SNP variation across the globe. To evaluate this new technology at scale, we applied BGE to sequence […]

CONCLUSIONS: Estimates of lifetime MDD heritability in this Nepalese sample were similar to previous European ancestry samples, but PGS trained on European data did not predict MDD in this sample. This may be due to differences in ancestry-linked causal variants, differences in depression phenotyping between the training and target data, or setting-specific environmental factors that modulate genetic effects. Additional research among under-represented global populations will ensure equitable...

Preeclampsia (PE) is a major cause of maternal and neonatal morbidity and mortality worldwide, with the placenta playing a central role in disease pathophysiology. This review synthesizes recent advancements in understanding the molecular mechanisms underlying PE, focusing on placental genes, proteins, and genetic variants identified through multi-omic approaches. Transcriptomic studies in bulk placental tissue have identified many dysregulated genes in the PE placenta, including the PE...

Leukodystrophies are progressive single gene disorders affecting the white matter of the brain. Several gene therapy trials are in progress to address the urgent unmet need for this patient population. We performed a comprehensive literature review of all gene therapy clinical trials listed in www.clinicaltrials.gov through August 2024, and the relevant preclinical studies that enabled clinical translation. Of the approximately 50 leukodystrophies described to date, only eight have existing […]

Insulin resistance causes multiple epidemic metabolic diseases, including type 2 diabetes, cardiovascular disease, and fatty liver, but is not routinely measured in epidemiological studies. To discover novel insulin resistance genes in the general population, we conducted genome-wide association studies in 382,129 individuals for triglyceride to HDL-cholesterol ratio (TG/HDL), a surrogate marker of insulin resistance calculable from commonly measured serum lipid profiles. We identified 251...

OBJECTIVE: The All of Us Evenings with Genetics (EwG) Research Program at Baylor College of Medicine (BCM), funded to engage research scholars to work with the All of Us data, developed a training curriculum for the Researcher Workbench, the platform to access and analyze All of Us data. All of Us EwG developed the curriculum so that it could teach scholars regardless of their skills and background in programming languages and cloud computing. All of Us EwG delivered this curriculum at the […]

Large-scale, multi-ethnic whole-genome sequencing (WGS) studies, such as the National Human Genome Research Institute Genome Sequencing Program's Centers for Common Disease Genomics (CCDG), play an important role in increasing diversity for genetic research. Before performing association analyses, assessing Hardy-Weinberg equilibrium (HWE) is a crucial step in quality control procedures to remove low quality variants and ensure valid downstream analyses. Diverse WGS studies contain […]

CONCLUSIONS: Although use of hospitalized control subjects excludes individuals with less severe disease, leading to selection bias, the study results suggest that caution should be exercised when prescribing high doses of amphetamines, with regular screening for symptoms of psychosis or mania.

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CONCLUSIONS: Clozapine-induced ileus and pneumonia were notably more frequent than has previously been reported and were associated with increased mortality. Two CYP genes influenced pneumonia risk. Pneumonia and ileus call for improved utilization of available preventive measures.

Traumatic brain injury (TBI), a global leading cause of mortality and disability, lacks effective treatments to enhance recovery. Synaptic remodeling has been postulated as one mechanism that influences outcomes after TBI. We sought to investigate whether common mechanisms affecting synapse maintenance are shared between TBI and other neuropsychiatric conditions using pathway enrichment tools and genome-wide genotype data, with the goal of highlighting novel treatment targets. We leveraged an...

Modern sequencing technology enables the systematic detection of complex structural variation (SV) across genomes. However, extensive DNA rearrangements arising through a series of mutations, a phenomenon we refer to as serial SV (sSV), remain underexplored, posing a challenge for SV discovery. Here, we present NAHRwhals ( https://github.com/WHops/NAHRwhals ), a method to infer repeat-mediated series of SVs in long-read genomic assemblies. Applying NAHRwhals to haplotype-resolved human […]

OBJECTIVE: Educational offerings to fill the bioinformatics knowledge gap are a key component to enhancing access and use of health data from the All of Us Research Program. We developed a Train the Trainer-based, innovative training series including project-based learning, modular on-demand demonstrations, and unstructured tutorial time as a model for educational engagement in the All of Us community.

While respiratory diseases such as COPD and asthma share many risk factors, most studies investigate them in insolation and in predominantly European ancestry populations. Here, we conducted the most powerful multi-trait and -ancestry genetic analysis of respiratory diseases and auxiliary traits to date. Our approach improves the power of genetic discovery across traits and ancestries, identifying 44 novel loci associated with lung function in individuals of East Asian ancestry. Using these...

Amino acid substitutions may substantially alter protein stability and function, but the contribution of substitutions arising from alternate translation (deviations from the genetic code) is unknown. To explore it, we analyzed deep proteomic and transcriptomic data from over 1,000 human samples, including 6 cancer types and 26 healthy human tissues. This global analysis identified 60,024 high confidence substitutions corresponding to 8,801 unique sites in proteins derived from 1,990 genes. […]

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 downstream analyses reflect the genetic ancestry of research participants accurately. 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...

Clonal hematopoiesis of indeterminate potential (CHIP) is linked to diverse aging-related diseases, including hematologic malignancy and atherosclerotic cardiovascular disease (ASCVD). While CHIP is common among older adults, the underlying factors driving its development are largely unknown. To address this, we performed whole-exome sequencing on 8,374 blood DNA samples collected from 4,187 Atherosclerosis Risk in Communities Study (ARIC) participants over a median follow-up of 21 years. […]

CONCLUSIONS: Self- or parent-report-based assessments tend to overestimate prevalences of psychiatric disorders in the ABCD Study, particularly when longitudinal data are summed to create lifetime prevalences. Such assessments should be accompanied by more in-depth assessments or clinician-administered structured interviews if using data where accurate disorder classifications are paramount.

CONCLUSION: These results document considerable preference similarities among cardiologist and PCP prescribers of LDL-C lowering therapies for ASCVD. Broad availability of several therapies with varying administration frequencies and product profiles are likely of great value to prescribing physicians aiming to achieve target LDL-C concentrations. Considering all aspects of treatment, most participants preferred a PCSK9 siRNA-like drug.

CONCLUSIONS: Anxiety/depression accelerate the development of CVDRFs. This association appears to be most notable among younger women and may be mediated by stress-related neuro-immune pathways. Evaluations of tailored preventive measures for individuals with anxiety/depression are needed to reduce CVD risk.

A core task when establishing the strength of evidence for a gene's role in a monogenic disorder is determining the appropriate disease entity to curate. Establishing this concept determines which evidence can be applied and quantified toward the final gene-disease validity, variant pathogenicity, or actionability classification. Genes with implications in more than one phenotype can necessitate a process of lumping and splitting, disease reorganization, and updates to disease nomenclature....

We systematically reviewed observational and Mendelian randomization (MR) articles that evaluated the association between obesity and 17 gastrointestinal (GI) diseases to integrate causal and observational evidence. A total of 594 observational studies from 26 systematic reviews and meta-analyses and nine MR articles were included. For every 5 kg/m² increase in body mass index (BMI), there was an increased risk of GI diseases ranging from 2% for rectal cancer (relative risk [RR]: 1.02, 95%...

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, including 41 probands and some family members, […]

CONCLUSION: PTSD-CV comorbidities exhibit shared risk loci, and genes involved in tissue-specific regulatory mechanisms.

Clonal hematopoiesis (CH) is defined by the expansion of a lineage of genetically identical cells in blood. Genetic lesions that confer a fitness advantage, such as point mutations or mosaic chromosomal alterations (mCAs) in genes associated with hematologic malignancy, are frequent mediators of CH. However, recent analyses of both single cell-derived colonies of hematopoietic cells and population sequencing cohorts have revealed CH frequently occurs in the absence of known driver genetic...

Metformin, an oral antihyperglycemic drug that has been in use for over 60 years, remains a first-line therapy for type 2 diabetes (T2D). Numerous studies have suggested that metformin promotes health benefits beyond T2D management, including weight loss, cancer prevention and treatment, and anti-aging, through several proposed mechanistic targets. Here we discuss the established effects of metformin and the progress made in identifying its direct targets. Additionally, we emphasize the...

BACKGROUND: Genetic variants in COL4A1 and COL4A2 (encoding collagen IV alpha chain 1/2) occur in genetic and sporadic forms of cerebral small vessel disease (CSVD), a leading cause of stroke, dementia and intracerebral haemorrhage (ICH). However, the molecular mechanisms of CSVD with ICH and COL4A1/COL4A2 variants remain obscure.

Polygenic risk scores (PRS) continue to improve with novel methods and expanding genome-wide association studies. Healthcare and third-party laboratories are increasingly deploying PRS reports to patients. Although new PRS show improving strengths of association with traits, it is unknown how the classification of high polygenic risk changes across individual PRS for the same trait. Here, we determined classification of high genetic risk from all cataloged PRS for three complex traits. While...

CONCLUSIONS: These results highlight the potential value of colchicine to mitigate the higher cardiovascular risk of carriers of somatic TET2 mutations in blood cells. These observations set the basis for the development of clinical trials that evaluate the efficacy of precision medicine approaches tailored to the effects of specific mutations linked to CH.

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Glycine is an obligatory co-agonist at excitatory NMDA receptors in the brain, especially in the dentate gyrus, which has been postulated to be crucial for the development of psychotic associations and memories with psychotic content. Drugs modulating glycine levels are in clinical development for improving cognition in schizophrenia. However, the functional relevance of the regulation of glycine metabolism by endogenous enzymes is unclear. Using a chromosome-engineered allelic series in […]

CONCLUSIONS AND RELEVANCE: The results of this analysis of 14 328 ICI-treated patients followed up from ICI initiation determined the incidence, risk factors and clinical spectrum of ICI-induced diabetes. Widespread implementation of this approach across organ-specific irAEs may enhance diagnosis and management of these conditions, and this becomes especially pertinent as ICI treatment rapidly expands to treat a wide spectrum of cancers and is used at earlier stages of treatment.

INTRODUCTION: Evidence suggests that higher C-reactive protein (CRP) is associated with lower risk of Alzheimer's disease (AD) and lobar intracerebral hemorrhage (ICH). Whether interleukin (IL)-6 signaling, an active pharmacological target upstream of CRP, is associated with these amyloid-related pathologies remains unknown.

Large-scale sequencing has enabled unparalleled opportunities to investigate the role of rare coding variation in human phenotypic variability. Here, we present a pan-ancestry analysis of sequencing data from three large biobanks, including the All of Us research program. Using mixed-effects models, we performed gene-based rare variant testing for 601 diseases across 748,879 individuals, including 155,236 with ancestry dissimilar to European. We identified 363 significant associations, which...

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Myocardial infarction is a leading cause of death globally but is notoriously difficult to predict. We aimed to identify biomarkers of an imminent first myocardial infarction and design relevant prediction models. Here, we constructed a new case-cohort consortium of 2,018 persons without prior cardiovascular disease from six European cohorts, among whom 420 developed a first myocardial infarction within 6 months after the baseline blood draw. We analyzed 817 proteins and 1,025 metabolites in...

Genetic variants in HTRA1 are associated with stroke risk. However, the mechanisms mediating this remain largely unknown, as does the full spectrum of phenotypes associated with genetic variation in HTRA1. Here we show that rare HTRA1 variants are linked to ischemic stroke in the UK Biobank and BioBank Japan. Integrating data from biochemical experiments, we next show that variants causing loss of protease function associated with ischemic stroke, coronary artery disease and skeletal traits […]

Clonal hematopoiesis (CH) is an age-related process whereby hematopoietic stem and progenitor cells (HSPCs) acquire mutations that lead to a proliferative advantage and clonal expansion. The most commonly mutated genes are epigenetic regulators, DNA damage response genes, and splicing factors, which are essential to maintain functional HSPCs and are frequently involved in the development of hematologic malignancies. Established risk factors for CH, including age, prior cytotoxic therapy, and...

BACKGROUND: Traumatic brain injury is conventionally categorised as mild, moderate, or severe on the Glasgow Coma Scale (GCS). Recently developed biomarkers can provide more objective and nuanced measures of the extent of brain injury.

CONCLUSIONS: Our study, combining deep learning with genomics, presents a new framework to uncover the splenic axis of CAD. Notably, our study provides evidence for the underlying genetic connection between the spleen as a candidate causal tissue-type and CAD with insight into the mechanisms of 9p21, whose mechanism is still elusive despite its initial discovery in 2007. More broadly, our study provides a unique application of deep learning radiomics to non-invasively find associations […]

Genome-wide association studies (GWAS) of human complex traits or diseases often implicate genetic loci that span hundreds or thousands of genetic variants, many of which have similar statistical significance. While statistical fine-mapping in individuals of European ancestry has made important discoveries, cross-population fine-mapping has the potential to improve power and resolution by capitalizing on the genomic diversity across ancestries. Here we present SuSiEx, an accurate and...