Aberrant recursive splicing in a human disease locus.

Recursive splice sites are rare motifs postulated to facilitate splicing across massive introns and shape isoform diversity, especially for long, brain-expressed genes. The necessity of this unique mechanism remains unsubstantiated, as does the role of recursive splicing (RS) in human disease. From analyses of rare copy number variants (CNVs) from almost one million individuals, we previously identified large, heterozygous deletions eliminating an RS site (RS1) in the first intron of that conferred substantial risk for attention deficit hyperactivity disorder (ADHD) and other neurobehavioral traits.

Genome-Wide Association Studies of Delay Discounting and Impulsive Personality Traits in Children From the Adolescent Behavior and Cognitive Development Study.

Impulsivity, often operationalized as delay discounting (DD) and as impulsive personality traits via the UPPS-P scales, is a key transdiagnostic construct across psychiatric disorders. Recent genome-wide association studies (GWAS) have studied the genetic basis of impulsivity in adults, but it remains unclear how similar the genetic architecture of DD is in children. The present study conducted GWAS of DD and impulsivity traits in 5548 children (ages 9-10 years old) of genetically inferred European ancestry from the Adolescent Brain Cognitive Development (ABCD) Study.

Long Read Genome Sequencing Elucidates Diverse Functional Consequences of Structural and Repeat Variation in Autism.

Long-read whole genome sequencing (LR-WGS) technologies enhance the discovery of structural variants (SVs) and tandem repeats (TRs). Application of LR-WGS has potential to identify novel risk factors that contribute to autism spectrum disorder (ASD). We performed LR-WGS on 243 individuals from 63 ASD families and generated an integrated call set combining long- and short-read data.

Genome-wide association study of cocaine self-administration behavior in Heterogeneous Stock rats.

Background: Cocaine use disorder (CUD) is a major public health crisis with detrimental individual and societal effects. The specific genes mediating CUD remain largely unknown.

Methods: We conducted a genome-wide association study (GWAS) using outbred N/NIH Heterogeneous Stock (HS; n = 836, female = 415, male = 421) rats.

Genomic structural equation study reveals links between anorexia nervosa and delay discounting and lack of perseverance but not other facets of impulsivity.

Anorexia nervosa (AN) is a heritable condition, characterized by a fear of weight gain and a distorted body image, for which treatments are only limited. AN is characterized by excessive control over feeding behaviors, which has been hypothesized to indicate that low impulsivity, including low emotional impulsivity (urgency), may place certain individuals at risk for AN; however, this has not been fully genetically evaluated. We used genomic structural equation modeling and genome-wide association studies (GWASs) based on individuals of European ancestry (n = 72,517-903,147) to examine the latent genetic architecture between AN and several measures of impulsivity.

Sex-specific transcriptional signatures of oxycodone persist during withdrawal and abstinence in the suprachiasmatic nucleus of heterogeneous stock rats.

Unlabelled: Opioid use disorder (OUD) is a major public health issue. Sleep and circadian disruptions are recognized as hallmarks of opioid addiction, often emerging during withdrawal and lasting into abstinence. However, little is known about the impact of opioids on the brain's primary circadian pacemaker, the suprachiasmatic nucleus (SCN).

Prescription Opioid Medication Survey: A Tool to Collect Deep Phenotypic Data on the Multifactorial Pathways to Opioid Use Disorder in Clinical and Population-Based Cohorts.

Introduction: We are in the midst of an opioid epidemic. In the USA, more than a third of the country knows someone who has died from an opioid overdose. Prescription opioids (e.

Perinatal fentanyl exposure drives enduring addiction risk and central amygdala gene dysregulation.

The use of fentanyl and other opioids during pregnancy is a pressing public health issue due to its association with Neonatal Opioid Withdrawal Syndrome (NOWS) and long-term neurobehavioral deficits. Human epidemiologic studies are confounded by both genetic and environmental factors that differ between exposed and unexposed children. We developed a novel rat model of perinatal fentanyl exposure in heterogeneous stock (HS) rats characterized by high genetic diversity, to investigate NOWS symptoms and its long-term effects on adult fentanyl self-administration, drug-seeking behavior, and central amygdala (CeA) transcriptomic changes, addressing a critical gap in understanding synthetic opioid impacts.

Genomic structural equation modeling of impulsivity and risk-taking traits reveals three latent factors distinctly associated with brain structure and development.

Background: Impulsivity is a multifaceted transdiagnostic trait that emerges in childhood. Research has identified genetic loci and brain systems associated with different facets of impulsivity and risk-taking. However, how these genetic underpinnings overlap across different facets, and how they are associated with brain development during childhood remain unknown.

Perinatal Fentanyl Exposure Drives Enduring Addiction Risk and Central Amygdala Gene Dysregulation.

The use of fentanyl and other opioids during pregnancy is a pressing public health issue due to its association with Neonatal Opioid Withdrawal Syndrome (NOWS) and long-term neurobehavioral deficits. Human epidemiologic studies are confounded by both genetic and environmental factors that differ between exposed and unexposed children. We developed a novel rat model of perinatal fentanyl exposure to characterize NOWS symptoms and investigate enduring behavioral and molecular outcomes.

Pharmacological and genetic manipulation of glyoxalase-1 (GLO1) does not alter locomotor responses or conditioned place preference induced by cocaine or oxycodone.

Methylglyoxal (MG) is an endogenously produced non-enzymatic side product of glycolysis that acts as a partial agonist at GABA receptors. MG is metabolized by the enzyme glyoxalase-1 (GLO1). Inhibition of GLO1 increases methylglyoxal levels, and has been shown to modulate various behaviors, including decreasing seeking of cocaine-paired cues and ethanol consumption.

Genome-Wide Association Study of Age-Related Hearing Loss in CFW Mice Identifies Multiple Genes and Loci, Including Prkag2.

Purpose: Age-related hearing loss (ARHL) is one of the most prevalent conditions affecting the elderly. ARHL is influenced by a combination of environmental and genetic factors; the identification of the genes that confer risk will aid in the prevention and treatment of ARHL. The mouse and human inner ears are functionally and genetically homologous.

Associations Between a Genetic Liability Toward Externalizing and Behavioral Outcomes Spanning Toddlerhood Through Early Adulthood in Five Developmental Cohorts.

Objective: Understanding how genetic risk unfolds across development will be important for using genetics to inform prevention and early intervention. The current study leverages information from 5 large datasets to characterize behavioral manifestations of a genetic liability toward externalizing from ages 6 months to 26 years.

Method: We used polygenic scores (PGS) derived from a multivariate genome-wide association study (GWAS) of externalizing that identified hundreds of significantly associated genetic variants (EXT) to estimate associations of genetic liability with relevant phenotypes within and across developmental periods, ranging from toddlerhood to early adulthood.

Sex-Specific Concordance of Striatal Transcriptional Signatures of Opioid Addiction in Human and Rodent Brains.

Background: Opioid use disorder (OUD) has emerged as a severe, ongoing public health emergency. Current treatments for OUD are unsuccessful in leading to lasting abstinence in most users. This underscores the lasting effects of chronic opioid use and emphasizes the need to understand the molecular mechanisms of drug seeking and taking and how those alterations persist through acute and protracted withdrawal.

Psychiatric genetics in the diverse landscape of Latin American populations.

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.

Subjective Response to Opioids Predicts Risk for Opioid Use Disorder.

Exposure to prescription opioids can lead to opioid use disorder (OUD) in some individuals, but we lack scalable tools to predict who is at risk. We collected retrospective data on the initial subjective effects of prescription opioids from 117,508 research participants, 5.3% of whom self-reported OUD.

Novel insights into the genetic architecture and mechanisms of host/microbiome interactions from a multi-cohort analysis of outbred laboratory rats.

The intestinal microbiome influences health and disease. Its composition is affected by host genetics and environmental exposures. Understanding host genetic effects is critical but challenging in humans, due to the difficulty of detecting, mapping and interpreting them.

RatXcan: A framework for cross-species integration of genome-wide association and gene expression data.

Genome-wide association studies (GWAS) have implicated specific alleles and genes as risk factors for numerous complex traits. However, translating GWAS results into biologically and therapeutically meaningful discoveries remains extremely challenging. Most GWAS results identify noncoding regions of the genome, suggesting that differences in gene regulation are the major driver of trait variability.

Genetic Propensity for Delay Discounting and Educational Attainment in Adults Are Associated With Delay Discounting in Preadolescents: Findings From the Adolescent Brain Cognitive Development Study.

Higher delay discounting (DD) (i.e., propensity to devalue larger, delayed rewards over immediate, smaller rewards) is a transdiagnostic marker underpinning multiple health behaviors.

Do polygenic indices capture "direct" effects on child externalizing behavior problems? Within-family analyses in two longitudinal birth cohorts.

Failures of self-control can manifest as externalizing behaviors (e.g., aggression, rule-breaking) that have far-reaching negative consequences.

Bioenergetic-related gene expression in the hippocampus predicts internalizing vs. externalizing behavior in an animal model of temperament.

Externalizing and internalizing behavioral tendencies underlie many psychiatric and substance use disorders. These tendencies are associated with differences in temperament that emerge early in development via the interplay of genetic and environmental factors. To better understand the neurobiology of temperament, we have selectively bred rats for generations to produce two lines with highly divergent behavior: bred Low Responders (bLRs) are highly inhibited and anxious in novel environments, whereas bred High Responders (bHRs) are highly exploratory, sensation-seeking, and prone to drug-seeking behavior.

The Farm Animal Genotype-Tissue Expression (FarmGTEx) Project.

Genetic mutation and drift, coupled with natural and human-mediated selection and migration, have produced a wide variety of genotypes and phenotypes in farmed animals. We here introduce the Farm Animal Genotype-Tissue Expression (FarmGTEx) Project, which aims to elucidate the genetic determinants of gene expression across 16 terrestrial and aquatic domestic species under diverse biological and environmental contexts. For each species, we aim to collect multiomics data, particularly genomics and transcriptomics, from 50 tissues of 1,000 healthy adults and 200 additional animals representing a specific context.

Genetic Loci Influencing Cue-Reactivity in Heterogeneous Stock Rats.

Addiction vulnerability is associated with the tendency to attribute incentive salience to reward predictive cues. Both addiction and the attribution of incentive salience are influenced by environmental and genetic factors. To characterize the genetic contributions to incentive salience attribution, we performed a genome-wide association study (GWAS) in a cohort of 1596 heterogeneous stock (HS) rats.

Genome-wide association study reveals multiple loci for nociception and opioid consumption behaviors associated with heroin vulnerability in outbred rats.

The increased prevalence of opioid use disorder (OUD) makes it imperative to disentangle the biological mechanisms contributing to individual differences in OUD vulnerability. OUD shows strong heritability, however genetic variants contributing to vulnerability remain poorly defined. We performed a genome-wide association study using over 850 male and female heterogeneous stock (HS) rats to identify genes underlying behaviors associated with OUD such as nociception, as well as heroin-taking, extinction and seeking behaviors.