Admixed gene expression models expand molecular and neurological insights into 6 major psychiatric disorders.

Our understanding of the influence of ancestral background on genetically determined expression remains limited, especially when gene expression models are applied to studies from different or multiple populations. We performed transcriptome wide association studies (TWAS) in 6 different psychiatric conditions, leveraging gene expression models trained in cohorts with different proportions of African, European, and Indigenous American genetic ancestries. For comparison we repeated each TWAS using a model trained in individuals of predominantly European ancestry.

Dynamic responses to rejection in the transplanted human heart revealed through spatial transcriptomics.

Allograft rejection following solid-organ transplantation is a major cause of graft dysfunction and mortality. Current approaches to diagnosis rely on histology, which exhibits wide diagnostic variability and lacks access to molecular phenotypes that may stratify therapeutic response. Here, we leverage image-based spatial transcriptomics at sub-cellular resolution in longitudinal human cardiac biopsies to characterize transcriptional heterogeneity in 62 adult and pediatric heart transplant (HT) recipients during and following histologically-diagnosed rejection.

Cardiomyocyte-derived circulating extracellular vesicles allow a non-invasive liquid biopsy of myocardium in health and disease.

The ability to track disease without tissue biopsy in patients is a major goal in biology and medicine. Here, we identify and characterize cardiomyocyte-derived extracellular vesicles in circulation (EVs; "cardiovesicles") through comprehensive studies of induced pluripotent stem cell-derived cardiomyocytes, genetic mouse models, and state-of-the-art mass spectrometry and low-input transcriptomics. These studies identified two markers (, ) enriched on cardiovesicles for biotinylated antibody-based immunocapture.

Multiplexed Assays of Variant Effect and Automated Patch Clamping Improve -LQTS Variant Classification and Cardiac Event Risk Stratification.

Background: Long QT syndrome is a lethal arrhythmia syndrome, frequently caused by rare loss-of-function variants in the potassium channel encoded by . Variant classification is difficult, often because of lack of functional data. Moreover, variant-based risk stratification is also complicated by heterogenous clinical data and incomplete penetrance.

Integration of estimated regional gene expression with neuroimaging and clinical phenotypes at biobank scale.

An understanding of human brain individuality requires the integration of data on brain organization across people and brain regions, molecular and systems scales, as well as healthy and clinical states. Here, we help advance this understanding by leveraging methods from computational genomics to integrate large-scale genomic, transcriptomic, neuroimaging, and electronic-health record data sets. We estimated genetically regulated gene expression (gr-expression) of 18,647 genes, across 10 cortical and subcortical regions of 45,549 people from the UK Biobank.

A transcriptomic atlas of the human brain reveals genetically determined aspects of neuropsychiatric health.

Regulation of gene expression is a vital component of neurological homeostasis. Cataloging the consequences of endogenous gene expression on the physical structure and connectivity of the brain offers a means of unifying trait-associated genetic variation with trait-associated neurological features. We perform tissue-specific transcriptome-wide association studies (TWASs) on over 3,400 neuroimaging phenotypes in the UK Biobank (N = 33,224) using our joint-tissue imputation (JTI)-TWAS method.

Multiplexed Assays of Variant Effect and Automated Patch-clamping Improve -LQTS Variant Classification and Cardiac Event Risk Stratification.

Background: Long QT syndrome (LQTS) is a lethal arrhythmia syndrome, frequently caused by rare loss-of-function variants in the potassium channel encoded by . Variant classification is difficult, often owing to lack of functional data. Moreover, variant-based risk stratification is also complicated by heterogenous clinical data and incomplete penetrance.

A Transcriptomic Atlas of the Human Brain Reveals Genetically Determined Aspects of Neuropsychiatric Health.

Imaging features associated with neuropsychiatric traits can provide valuable insights into underlying pathophysiology. Using data from the UK biobank, we perform tissue-specific TWAS on over 3,500 neuroimaging phenotypes to generate a publicly accessible resource detailing the neurophysiologic consequences of gene expression. As a comprehensive catalog of neuroendophenotypes, this resource represents a powerful neurologic gene prioritization schema that can improve our understanding of brain function, development, and disease.

Whole Exome Sequencing in Individuals with Idiopathic Clubfoot Reveals a Recurrent Filamin B (FLNB) Deletion.

Background: Clubfoot, a congenital deformity that presents as a rigid, inward turning of the foot, affects approximately 1 in 1000 infants and occurs as an isolated birth defect in 80% of patients. Despite its high level of heritability, few causative genes have been identified, and mutations in known genes are only responsible for a small portion of clubfoot heritability.

Questions/purposes: (1) Are any rare gene variants enriched (that is, shared) in unrelated patients with isolated clubfoot? (2) Are there other rare variants in the identified gene (Filamin B) in these patients with clubfoot?

Methods: Whole-exome sequence data were generated from a discovery cohort of 183 unrelated probands with clubfoot and 2492 controls.

Distal chromosome 16p11.2 duplications containing in patients with scoliosis.

Introduction: Adolescent idiopathic scoliosis (AIS) is a common musculoskeletal disorder with strong evidence for a genetic contribution. CNVs play an important role in congenital scoliosis, but their role in idiopathic scoliosis has been largely unexplored.

Methods: Exome sequence data from 1197 AIS cases and 1664 in-house controls was analysed using coverage data to identify rare CNVs.

Lack of joint hypermobility increases the risk of surgery in adolescent idiopathic scoliosis.

Generalized joint hypermobility (GJH) is a risk factor for developing adolescent idiopathic scoliosis (AIS); however, it is not known whether joint hypermobility influences the risk of progression to surgery. Beighton joint hypermobility scores were assessed in 570 female AIS patients. Multivariate analysis was carried out to determine whether Beighton hypermobility scores were predictors of surgical intervention.