Publications

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CONCLUSIONS: The T2D polygenic score serves as an independent predictor of incident diabetes, particularly among individuals with lower distribution of traditional risk factors.

CONCLUSIONS AND RELEVANCE: The 2024 LC research index for adults builds on the 2023 index with additional data and symptoms to help researchers classify symptomatic LC and its symptom subtypes. Continued future refinement of the index will be needed as the understanding of LC evolves.

Preeclampsia is a common multifactorial disease of pregnancy. Dysregulation of complement activation is among emerging candidates responsible for disease pathogenesis. In a targeted exomic sequencing study of 609 women with preeclampsia and 2092 non-preeclamptic controls, we identified 14 variants within nine genes coding for components of the membrane attack complex (MAC, C5b-9) that are associated with preeclampsia. We found two rare missense variants in the C5 gene that predispose to...

Genetic mutations that yield defective cystic fibrosis transmembrane regulator ( CFTR ) protein cause cystic fibrosis, a life-limiting autosomal recessive Mendelian disorder. A protective role of CFTR loss-of-function mutations in inflammatory bowel disease (IBD) has been suggested, but its evidence has been inconclusive and contradictory. Here, leveraging the largest IBD exome sequencing dataset to date, comprising 38,558 cases and 66,945 controls in the discovery stage, and 35,797 cases and...

Ultraviolet (UV) radiation is known to be the most important environmental carcinogen for cutaneous melanoma. While genomic analyses of melanoma tumors implicate a high rate of UV damage, the experimental induction and recovery of bona fide UV-signature changes have not been directly observed. To replicate recurrent UV mutations from TCGA_SKCM specimens, we UV-irradiated cultured immortalized human melanocytes and subjected them to in vivo tumorigenesis assays. Exome sequencing of the...

CONCLUSION: The ARID1B spectrum is broad, and as patients age, there is a significant shift in the medical aspects requiring attention. To address the changing medical needs with increasing age, we have formulated recommendations to promote timely intervention in an attempt to mitigate disease progression.

CONCLUSION: Our extensive evaluation of SMA Finder on exome, genome and panel sequencing samples found it to have nearly 100% accuracy and demonstrated its ability to reduce diagnostic delays, particularly in individuals with milder subtypes of SMA. Given this accuracy, the common misdiagnoses identified here, the widespread availability of clinical confirmatory testing for SMA, as well as the existence of treatment options, we propose that it is time to add SMN1 to the ACMG list of genes […]

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The complete blood count (CBC) is an important screening tool for healthy adults and a common test at periodic exams. However, results are usually interpreted relative to one-size-fits-all reference intervals^(1,2), undermining the precision medicine goal to tailor care for patients on the basis of their unique characteristics^(3,4). Here we study thousands of diverse patients at an academic medical centre and show that routine CBC indices fluctuate around stable values or setpoints⁵, and...

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Familial dysautonomia (FD) is a fatal inherited congenital neuropathy characterized by both progressive neurological symptoms and systemic abnormalities, and patients have a reduced life expectancy. FD is caused by a T-to-C mutation in intron 20 of the Elongator acetyltransferase complex subunit 1 ( ELP1 ) gene, which affects the ELP1 splicing process by causing tissue-specific skipping of exon 20. Here, we developed a CRISPR base editor (BE) approach capable of precisely correct this […]

CONCLUSIONS: Our findings reveal pleiotropic genetic factors influencing chronotype and ease of getting-up, emphasizing GPR61 's rs12044778 and nearby genes like AMIGO1 and ATXN7L2 . These insights advance understanding of circadian preferences and suggest potential therapeutic interventions.

CONCLUSIONS: Our EWAS on early DKD progression identified a podocyte-specific CDKN1C locus. EWAS on late progression proposed novel CpGs for ESKD risk and confirmed previously known sites for kidney function. Since DNA methylation signals could improve disease course prediction, a combination of blood-derived methylation sites could serve as a potential prognostic biomarker.

CONCLUSION: Elevated Lp(a) is associated with an increased risk of MACE independent of hs-CRP levels in both primary and secondary prevention populations.

KIF21A encodes a kinesin motor protein associated with isolated congenital fibrosis of the extraocular muscles (CFEOM), which occurs when the autoinhibitory interaction between its motor and third coiled-coil domains is disrupted. In this study, we describe a female child who is heterozygous for a novel de novo missense variant in KIF21A p.Leu664Pro, located in the second coiled-coil domain that was absent in her unaffected parents and in healthy population cohorts. She presented with...

Iron homoeostasis is tightly regulated, with hepcidin and soluble transferrin receptor (sTfR) playing significant roles. However, the genetic determinants of these traits and the biomedical consequences of iron homoeostasis variation are unclear. In a meta-analysis of 12 cohorts involving 91,675 participants, we found 43 genomic loci associated with either hepcidin or sTfR concentration, of which 15 previously unreported. Mapping to putative genes indicated involvement in iron-trait […]

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The human genome is packaged within a three-dimensional (3D) nucleus and organized into structural units known as compartments, topologically associating domains (TADs), and loops. TAD boundaries, separating adjacent TADs, have been found to be well conserved across mammalian species and more evolutionarily constrained than TADs themselves. Recent studies show that structural variants (SVs) can modify 3D genomes through the disruption of TADs, which play an essential role in insulating genes...

Alzheimer's disease (AD) is associated with memory and cognitive impairment caused by progressive degeneration of neurons. The events leading to neuronal death are associated with the accumulation of aggregating proteins in neurons and glia of the affected brain regions, in particular extracellular deposition of amyloid plaques and intracellular formation of tau neurofibrillary tangles. Moreover, the accumulation of pathological tau proteoforms in the brain concurring with disease progression […]

Canavan disease (CD) is an ultra-rare autosomal recessive leukodystrophy caused by loss-of-function mutations in ASPA, which encodes aspartoacylase (ASPA), leading to accumulation of N-acetylaspartate (NAA). Patients with CD typically present with profound psychomotor deficits within the first 6 months of life and meet few motor milestones. Within CD a subset of patients exhibits a milder phenotype with more milestone acquisition, possibly related to greater residual ASPA activity. An ongoing […]

Patients with undiagnosed and/or rare disorders frequently manifest dysmorphic and neurological features. There is a lack of information on the effectiveness of telehealth in the evaluation of these disorders. We thus compared an unassisted virtual physical examination (PE) with an in-person PE in undiagnosed individuals and also assessed participant telehealth satisfaction. Twenty-six individuals enrolled in the Undiagnosed Diseases Network study underwent an in-home synchronous virtual PE, […]

CONCLUSIONS: Our findings link TRPML-1 dysfunction to the development of kidney disease in MLIV, providing new insights into its pathogenesis and potential therapeutic targets.

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Portable, low-field magnetic resonance imaging (LF-MRI) of the brain may facilitate point-of-care assessment of patients with Alzheimer's disease (AD) in settings where conventional MRI cannot. However, image quality is limited by a lower signal-to-noise ratio. Here, we optimize LF-MRI acquisition and develop a freely available machine learning pipeline to quantify brain morphometry and white matter hyperintensities (WMH). We validate the pipeline and apply it to outpatients presenting with […]

Multidimensional host and viral factors determine the clinical course of COVID-19. While the virology of the disease is well studied, investigating host-related factors, including genome, transcriptome, metabolome, and exposome, can provide valuable insights into the underlying pathophysiology. We conducted integrative omics analyses to explore their intricate interplay in COVID-19. We used data from the UK Biobank (UKB), and employed single-omics, pairwise-omics, and multi-omics models to...

CONCLUSIONS: When compared with other clinical risk factors, PGS was the strongest predictor of event recurrence among patients with an early-onset MI. Though the discriminative power of recurrent event prediction in this cohort was modest, the addition of PGS significantly improved discrimination.

Most respiratory microbiome studies use amplicon sequencing due to high host DNA. Metagenomics sequencing offers finer taxonomic resolution, phage assessment, and functional characterization. We evaluated five host DNA depletion methods on frozen nasal swabs from healthy adults, sputum from people with cystic fibrosis (pwCF), and bronchoalveolar lavage (BAL) from critically ill patients. Median sequencing depth was 76.4 million reads per sample. Untreated nasal, sputum, and BAL had 94.1%, […]

Genetic vascular disorders are prevalent diseases that have diverse etiologies and few treatment options. Pathogenic missense mutations in the alpha actin isotype 2 gene (ACTA2) primarily affect smooth muscle cell (SMC) function and cause multisystemic smooth muscle dysfunction syndrome (MSMDS), a genetic vasculopathy that is associated with stroke, aortic dissection, and death in childhood. Here, we explored genome editing to correct the most common MSMDS-causative mutation ACTA2 R179H. In a...

Age-related macular degeneration (AMD) is a prevalent cause of vision loss in the elderly with limited therapeutic options. A single chromosomal region around the complement factor H gene (CFH) is reported to explain nearly 25% of genetic AMD risk. Here, we used association testing, statistical finemapping and conditional analyses in 12,495 AMD cases and 461,686 controls to deconvolute four major CFH haplotypes that convey protection from AMD. We show that beyond CFH, two of these are […]

CONCLUSION: Given that forthcoming professional guidance in variant classification will advise the use of VUS subclasses, the experience of our laboratories in using VUS subclasses can inform future practices.

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CONCLUSION: The SD-GCEP addresses a critical gap in gene curation efforts, enabling inclusion of genes for syndromic disorders in clinical testing and contributing to keeping pace with the rapid discovery of new genetic syndromes.

Using quality improvement methods, we aimed to implement a protocol to assess for dementia among adults with Down syndrome (DS). To track implementation, interval retrospective chart review of patients with DS with visits to the Massachusetts General Hospital DS Program (MGH DSP) was conducted quarterly. The impact of a newly implemented protocol created and informed by clinical experts in the MGH DSP including laboratory tests, imaging, referrals, and screening tools for dementia and mental...

CONCLUSION AND RELEVANCE: Tenecteplase and alteplase had comparable DTN times for treatment of AIS and similar safety endpoints. Further studies are warranted to identify opportunities to streamline DTN times with tenecteplase.

[This corrects the article DOI: 10.3389/fpsyt.2024.1373797.].

PURPOSE OF REVIEW: This review highlights contributions of the Global Lipids Genetics Consortium (GLGC) in advancing the understanding of the genetic etiology of blood lipid traits, including total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides, and non-HDL cholesterol. We emphasize the consortium's collaborative efforts, discoveries related to lipid and lipoprotein biology, methodological advancements, and utilization in areas extending beyond lipid research.

Brentuximab vedotin is a combination monoclonal antibody to anti-CD30 conjugated to the anti-tubulin agent monomethyl auristatin E. It is approved for the treatment of mycosis fungoides, Hodgkin's lymphoma, and systemic anaplastic large cell lymphoma. Brentuximab has been associated with a number of potential adverse reactions; however, reports of renal complications are rare. A 73-year-old male with mycosis fungoides was admitted to hospital with acute kidney injury following his third cycle […]

DNA methylation (DNAm) is the most commonly measured epigenetic mechanism in human populations, with most studies using Illumina arrays to assess DNAm levels. In 2023, Illumina updated their DNAm arrays to the EPIC version 2 (EPICv2), building on prior iterations, namely the EPIC version 1 (EPICv1) and 450K arrays. Whether DNAm measurements are stable across these three generations of arrays has yet not been investigated, limiting the ability of researchers-especially those with longitudinal...

CONCLUSIONS: Metabolically stable HPN adult consumers have 24-h glucose measures comparable to healthy adults yet are notable for more time spent below range. The glucose profiles are influenced by HPN parameters such as tapering and dextrose and behaviors including smoking, depressive symptoms, and insomnia.

Huntington's disease (HD) arises from a CAG expansion in the huntingtin (HTT) gene beyond a critical threshold. A major thrust of current HD therapeutic development is lowering levels of mutant HTT mRNA (mHTT) and protein (mHTT) with the aim of reducing the toxicity of these product(s). Human genetic data also support a key role for somatic instability (SI) in HTT's CAG repeat - whereby it lengthens with age in specific somatic cell types - as a key driver of age of motor dysfunction onset....

Obstructive sleep apnea (OSA) is a multifactorial sleep disorder characterized by a strong genetic basis. Excessive daytime sleepiness (EDS) is a symptom that is reported by a subset of OSA patients, persisting even after treatment with continuous positive airway pressure (CPAP). It is recognized as a clinical subtype underlying OSA carrying alarming heightened cardiovascular risk. Thus, conceptualizing EDS as an exposure variable, we sought to investigate EDS's influence on genetic variation...

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BACKGROUND: No treatment is available to prevent brain oedema, which can occur after a large hemispheric infarction. Glibenclamide has previously been shown to improve functional outcome and reduce neurological or oedema-related death in patients younger than 70 years who were at risk of brain oedema after an acute ischaemic stroke. We aimed to assess whether intravenous glibenclamide could improve functional outcome at 90 days in patients with large hemispheric infarction.

Early identification of high-risk individuals through the analysis of their unique disease trajectories has a strong potential to support efficient prevention and clinical management across a range of chronic conditions. In this paper we present a novel approach for dynamic modeling of the evolution of chronic disease risks over time, incorporating individual genetic predispositions. Our approach uses a hierarchical Bayesian topic model including Gaussian Processes to capture age effects. It...

Cardiac diseases represent common highly morbid conditions for which molecular mechanisms remain incompletely understood. Here we report the analysis of 1,459 protein measurements in 44,313 UK Biobank participants to characterize the circulating proteome associated with incident coronary artery disease, heart failure, atrial fibrillation and aortic stenosis. Multivariable-adjusted Cox regression identified 820 protein-disease associations-including 441 proteins-at Bonferroni-adjusted P

Dilated cardiomyopathy (DCM) is a heart muscle disease that represents an important cause of morbidity and mortality, yet causal mechanisms remain largely elusive. Here, we perform a large-scale genome-wide association study and multitrait analysis for DCM using 9,365 cases and 946,368 controls. We identify 70 genome-wide significant loci, which show broad replication in independent samples and map to 63 prioritized genes. Tissue, cell type and pathway enrichment analyses highlight the […]

Glioblastoma (GB), the most aggressive tumor of the central nervous system (CNS), has poor patient outcomes with limited effective treatments available. MicroRNA-21 (miR-21(a)) is a known oncogene, abundantly expressed in many cancer types. miR-21(a) promotes GB progression, and lack of miR-21(a) reduces the tumorigenic potential. Here, we propose a single adeno-associated virus (AAV) vector strategy targeting mmu-miR-21a using the Staphylococcus aureus Cas9 ortholog (SaCas9) guided by a...

Schizophrenia (SCZ) is a severe mental disorder affecting around 1% of individuals worldwide. The variability in response to antipsychotic drugs (APDs) among SCZ patients presents a significant challenge for clinicians in determining the most effective medication. In this study, we investigated the biological markers and established a predictive model for APD response based on a large-scale genome-wide association study using 3269 Chinese schizophrenia patients. Each participant underwent an...

Female infertility is a common and complex health problem affecting millions of women worldwide. While multiple factors can contribute to this condition, the underlying cause remains elusive in up to 15%-30% of affected individuals. In our large genome-wide association study (GWAS) of 22,849 women with infertility and 198,989 control individuals from the Finnish population cohort FinnGen, we unveil a landscape of genetic factors associated with the disorder. Our recessive analysis identified […]

Although rare neurodevelopmental conditions have a large Mendelian component¹, common genetic variants also contribute to risk^(2,3). However, little is known about how this polygenic risk is distributed among patients with these conditions and their parents nor its interplay with rare variants. It is also unclear whether polygenic background affects risk directly through alleles transmitted from parents to children, or whether indirect genetic effects mediated through the family […]

[This corrects the article DOI: 10.3389/fneur.2023.1291020.].

By improving disease risk prediction, polygenic risk scores (PRSs) could have a significant impact on health promotion and disease prevention. Due to the historical oversampling of populations with European ancestry for genome-wide association studies, PRSs perform less well in other, understudied populations, leading to concerns that clinical use in their current forms could widen health care disparities. The PRIMED Consortium was established to develop methods to improve the performance of...

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Plasma proteomic profiles associated with subclinical somatic mutations in blood cells may offer novel insights into downstream clinical consequences. Here, we explore such patterns in clonal hematopoiesis of indeterminate potential (CHIP), which is linked to several cancer and non-cancer outcomes, including coronary artery disease (CAD). Among 61,833 ancestrally diverse participants (3,881 with CHIP) from NHLBI TOPMed and UK Biobank with blood-based DNA sequencing and proteomic measurements...

The integration of Large Language Models (LLMs) into mental healthcare and research heralds a potentially transformative shift, one offering enhanced access to care, efficient data collection, and innovative therapeutic tools. This paper reviews the development, function, and burgeoning use of LLMs in psychiatry, highlighting their potential to enhance mental healthcare through improved diagnostic accuracy, personalized care, and streamlined administrative processes. It is also acknowledged […]

Malnutrition is a well-studied and significant prognostic risk factor for morbidity and mortality in critically ill perioperative patients. Common nutrition myths in the critically ill may prevent early, consistent, and adequate delivery of enteral nutrition. We outlined 9 common intensive care unit (ICU) nutrition misconceptions and our recommendations to optimize enteral nutrition in critically ill patients based on the review of available literature. Our approach is to treat every patient...

CONCLUSIONS: The incidence of RIMMS remains low in our primarily proton-treated pediatric cohort with a cumulative incidence of 2.4% over 8 years and is similar to photon-treated cohorts. Development of RIMMS was associated with higher doses to the COW and OC.

Myasthenia gravis (MG) is a rare autoantibody-mediated disease affecting the neuromuscular junction. We performed a genome-wide association study of 5708 MG cases and 432,028 controls of European ancestry and a replication study in 3989 cases and 226,643 controls provided by 23andMe Inc. We identified 12 independent genome-wide significant hits (P

Rigid spine syndrome is a rare childhood-onset myopathy characterised by slowly progressive or non-progressive scoliosis, neck and spine contractures, hypotonia, and respiratory insufficiency. Biallelic variants in SELENON account for most cases of rigid spine syndrome, however, the underlying genetic cause in some patients remains unexplained. We used exome and genome sequencing to investigate the genetic basis of rigid spine syndrome in patients without a genetic diagnosis. In five patients...

CONCLUSIONS: Substantial disparities between India and Europe exist along the neurotrauma care chain, with both systems being likely to face unique features and challenges in the future.

Adrenomyeloneuropathy is a progressive neurodegenerative disease caused by pathogenic variants in the ABCD1 gene, resulting in very-long-chain fatty acid (VLCFA) accumulation that leads to dying-back axonopathy. Our candidate gene therapy, SBT101 (AAV9-human ABCD1 [hABCD1]), aims to ameliorate pathology by delivering functional copies of hABCD1 to the spinal cord. Transduced cells produce functional ABCD1 protein, thereby repairing the underlying biochemical defect. In vitro and in vivo mouse...

Delineation of structural variants (SVs) at sequence resolution in highly repetitive genomic regions has long been intractable. The sequence properties, origins, and functional effects of classes of genomic rearrangements such as ring chromosomes and Robertsonian translocations thus remain unknown. To resolve these complex structures, we leveraged several recent milestones in the field, including (1) the emergence of long-read sequencing, (2) the gapless telomere-to-telomere (T2T) assembly, […]

CONCLUSIONS: In sum, we identified 1%-6.6% of atypical diabetes cases in a pediatric diabetes population with high racial and ethnic diversity using systematic review of the EMR. Better identification of these cases using unbiased approaches may advance precision diabetes.

Given that lumbar disc herniation (LDH) is a prevalent spinal condition that causes significant individual suffering and societal costs, the genetic basis of LDH has received relatively little research. Our aim is to increase understanding of the genetic factors influencing LDH. We perform a genome-wide association analysis (GWAS) of LDH in the FinnGen project and in Estonian and UK biobanks, followed by a genome-wide meta-analysis to combine the results. In the meta-analysis, we identify 41...

BACKGROUND: The Populations Underrepresented in Mental illness Association Studies (PUMAS) project is attempting to remediate the historical underrepresentation of African and Latin American populations in psychiatric genetics through large-scale genetic association studies of individuals diagnosed with a serious mental illness [SMI, including schizophrenia (SCZ), schizoaffective disorder (SZA) bipolar disorder (BP), and severe major depressive disorder (MDD)] and matched controls. Given […]

Mitochondrial biogenesis relies on both the nuclear and mitochondrial genomes, and imbalance in their expression can lead to inborn errors of metabolism, inflammation, and aging. Here, we investigate N6AMT1, a nucleo-cytosolic methyltransferase that exhibits genetic codependency with mitochondria. We determine transcriptional and translational profiles of N6AMT1 and report that it is required for the cytosolic translation of TRMT10C (MRPP1) and PRORP (MRPP3), two subunits of the mitochondrial...

CONCLUSIONS AND RELEVANCE: This GWAS adjusted for CAD found a distinct genetic risk profile for AS at the single-marker and polygenic level. These findings provide new targets for future AS research.

Pregnancy is a risk factor for increased severity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and other respiratory infections, but the mechanisms underlying this risk are poorly understood. To gain insight into the role of pregnancy in modulating immune responses at baseline and upon SARS-CoV-2 infection, we collected peripheral blood mononuclear cells and plasma from 226 women, including 152 pregnant individuals and 74 non-pregnant women. We find that SARS-CoV-2 […]

BACKGROUND AND OBJECTIVES: The 21-point Brain Care Score (BCS) is an index that ranks behaviors and clinical measurements with the aim of encouraging lifestyle adjustments to lower the incidence of age-related brain disease, including stroke, late-life depression (LLD), and dementia. A higher BCS at baseline is associated with a lower risk of these outcomes. We aimed to investigate whether the associations between BCS and stroke, LLD, and dementia risks are independent of genetic […]

The All of Us Research Program (AoU) is an initiative designed to gather a comprehensive and diverse dataset from at least one million individuals across the USA. This longitudinal cohort study aims to advance research by providing a rich resource of genetic and phenotypic information, enabling powerful studies on the epidemiology and genetics of human diseases. One critical challenge to maximizing its use is the development of accurate algorithms that can efficiently and accurately identify...

OBJECTIVE: The limited existing evidence on sex differences in the clinical characteristics of patients with spontaneous, non-traumatic intracerebral hemorrhage (ICH) comes from small, single-center studies. Here, we performed an individual patient data meta-analysis of 3 randomized clinical trials and 1 multi-ethnic observational study of ICH to investigate the impact of sex on ICH severity and outcome.

Thanks to methodological advances, large-scale data collections, and longitudinal designs, psychiatric neuroimaging is better equipped than ever to identify the neurobiological underpinnings of youth mental health problems. However, the complexity of such endeavors has become increasingly evident, as the field has been confronted by limited clinical relevance, inconsistent results, and small effect sizes. Some of these challenges parallel those historically encountered by psychiatric […]

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In Finland, the frequency of isolated cleft palate (CP) is higher than that of isolated cleft lip with or without cleft palate (CL/P). This trend contrasts to that in other European countries but its genetic underpinnings are unknown. We conducted a genome-wide association study in the Finnish population and identified rs570516915, a single nucleotide polymorphism highly enriched in Finns, as strongly associated with CP (P = 5.25 × 10^(-34), OR = 8.65, 95% CI 6.11-12.25), but not with CL/P (P […]

Biomolecular condensates are membraneless compartments that organize biochemical processes in cells. In contrast to well-understood mechanisms describing how condensates form and dissolve, the principles underlying condensate patterning - including their size, number and spacing in the cell - remain largely unknown. We hypothesized that RNA, a key regulator of condensate formation and dissolution, influences condensate patterning. Using nucleolar fibrillar centers (FCs) as a model condensate, […]

CONCLUSIONS: In this small initial cohort, HGNS appears to be a safe, well-tolerated and efficacious treatment option for adults with DS with moderate-severe obstructive sleep apnea and positive airway pressure therapy intolerance.

CONCLUSIONS: PostMVP should not only be considered an isolated degenerative pathology but as a specific heritable phenotypic trait with genetic and functional pathophysiological origins. The identification of loss-of-function variants in ARHGAP24 further reinforces the pivotal role of mechano-transduction pathways in the pathogenesis of MVP.

Atherosclerotic cardiovascular disease, the leading cause of global mortality, is driven by lipid accumulation and plaque formation within arterial walls. Carotid plaques, detectable via ultrasound, are a well-established marker of subclinical atherosclerosis. In this study, we trained a deep learning model to detect plaques in 177,757 carotid ultrasound images from 19,499 UK Biobank (UKB) participants (aged 47-83 years) to assess the prevalence, risk factors, prognostic significance, and...

Sleep is integral to cardiovascular health^(1,2). Yet, the circuits that connect cardiovascular pathology and sleep are incompletely understood. It remains unclear whether cardiac injury influences sleep and whether sleep-mediated neural outputs contribute to heart healing and inflammation. Here we report that in humans and mice, monocytes are actively recruited to the brain after myocardial infarction (MI) to augment sleep, which suppresses sympathetic outflow to the heart, limiting...

CONCLUSIONS: In a well-characterized community sample, we isolated reward sensitivity as a robust mediator of the prospective association between early-life threat and adolescent internalizing psychopathology. Interventions aimed at bolstering reward sensitivity may mitigate the impact of early-life threat experiences on internalizing problems.

OBJECTIVE: To develop a prediction model for adverse neonatal outcomes using electronic fetal monitoring (EFM) interpretation data and other relevant clinical information known at the start of the second stage of labor.

CONCLUSION: The addition of three-month follow-up data causes a notable increase in model performance. The reduced model - containing Glasgow Outcome Scale Extended, pre-injury job class, pre-injury employment status, length of stay and age - matched the predictive performance of the full models. Accurate predictions on post-TBI vocational outcomes contribute to realistic prognosis and goal setting, targeting the right interventions to the right patients.

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CONCLUSIONS AND RELEVANCE: Sexual trauma and mental health polygenic scores, while correlated with one another, were independent and joint risk factors for severe mental illness in a large, diverse hospital biobank population. Furthermore, associations of schizophrenia and bipolar disorder polygenic scores with respective diagnoses were greater in those without disclosures, suggesting that genetic predisposition to mental illness as measured by polygenic scores may be less impactful in the...

CONCLUSIONS AND RELEVANCE: Neural associations with harsh parenting were widespread across the brain in early childhood but localized in late childhood. Neural associations with warm parenting were localized in middle childhood and, in turn, were associated with mental health during future stress. These developmentally contingent associations can inform the type and timing of interventions.

OBJECTIVE: X-linked adrenoleukodystrophy (ALD) is caused by mutations in ABCD1, a peroxisomal gene. More than half of males with an ABCD1 mutation develop inflammatory cerebral demyelination (cALD), but underlying mechanisms remain unknown and therapies are limited. We sought to develop and characterize a mouse model of cALD to facilitate study of disease mechanisms and therapy development.

The protein glycome of individual cell types in the brain is unexplored, despite the critical function of these modifications in development and disease. In aggregate, the most abundant asparagine (N-) linked glycans in the adult brain are high mannose structures, and specifically Man(5)GlcNAc(2) (Man-5), which normally exits the ER for further processing in the Golgi. Mannose structures are uncommon in other organs and often overlooked or excluded in most studies. To understand cell-specific...

CONCLUSIONS: We have identified a panel of kidney-specific transcripts correlated with severity and progression of kidney disease, and from this have identified a possible role for FRMD3 in tubule cell structure and health.

CONCLUSION: The balance between net benefit and harm on aspirin in the primary prevention setting shifts favourably in individuals with an elevated genetic predisposition.

Low drug adherence is a major obstacle to the benefits of pharmacotherapies and it is therefore important to identify factors associated with discontinuing or being poorly adherent to a prescribed treatment regimen. Using high-quality nationwide health registry data and genome-wide genotyping, we evaluate the impact of socio-demographic and genetic risk factors on adherence and persistence for 5 common medication classes that require long-term, regular therapy (N = 1,814,591 individuals from...

CHASERR encodes a human long noncoding RNA (lncRNA) adjacent to CHD2, a coding gene in which de novo loss-of-function variants cause developmental and epileptic encephalopathy. Here, we report our findings in three unrelated children with a syndromic, early-onset neurodevelopmental disorder, each of whom had a de novo deletion in the CHASERR locus. The children had severe encephalopathy, shared facial dysmorphisms, cortical atrophy, and cerebral hypomyelination - a phenotype that is distinct...

CONCLUSIONS: In this study, incorporating genomic information into clinical prediction models for suicide attempt did not improve patient risk stratification. Larger studies that include more diverse participants are required to validate whether the inclusion of psychiatric PRSs in clinical prediction models can enhance the stratification of patients at risk of suicide attempts.

Loss-of-function mutations in CLN3 cause juvenile Batten disease, featuring neurodegeneration and early-stage neuroinflammation. How loss of CLN3 function leads to early neuroinflammation is not yet understood. Here, we have comprehensively studied microglia from Cln3^(∆ex7/8) mice, a genetically accurate disease model. Loss of CLN3 function in microglia leads to lysosomal storage material accumulation and abnormal morphology of subcellular organelles. Moreover, pathological proteomic […]

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Subcortical brain structures are involved in developmental, psychiatric and neurological disorders. Here we performed genome-wide association studies meta-analyses of intracranial and nine subcortical brain volumes (brainstem, caudate nucleus, putamen, hippocampus, globus pallidus, thalamus, nucleus accumbens, amygdala and 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...

CONCLUSIONS: These findings support the feedback diet-regulatory mechanism of FGF21 in humans, but highlights the need for mechanistic characterization of the complex FGF21 genetic region.

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Genome wide studies are yielding a growing catalogue of common and rare variants that confer risk for psychopathology. Yet, despite representing unprecedented progress, emerging data also indicate that the full promise of psychiatric genetics - including understanding pathophysiology and improving personalized care - will not be fully realized by targeting traditional, dichotomous diagnostic categories. The current article provides reflections on themes emerging from a 2021 NIMH sponsored...