Investigating the Role of Glyoxalase 1 as a Therapeutic Target for Cocaine and Oxycodone Use Disorder.

Methylglyoxal (MG) is an endogenously produced non-enzymatic side product of glycolysis that acts as a partial agonist at GABA receptors. MG that 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.

Genomic structural equation modeling of reward-related traits: exploring the genetic factor structure and its relationship with psychopathology.

Reward sensitivity has a partial genetic background, and extreme levels may increase vulnerability to psychopathology. This study explores the genetic factor structure underlying reward-related traits and examines how genetic variance links to psychopathology. We modeled GWAS data from ten reward-related traits: risk tolerance (N = 975,353), extraversion (N = 122,886), sensation seeking (N = 132,395), (lack of) premeditation (N = 132,667), (lack of) perseverance (N = 133,517), positive urgency (N = 132,132), negative urgency (N = 132,559), attentional impulsivity (N = 124,739), motor impulsivity (N = 124,104), and nonplanning impulsivity (N = 123,509) to derive their genetic factor structure.

A Cost-effective, High-throughput, Highly Accurate Genotyping Method for Outbred Populations.

Affordable sequencing and genotyping methods are essential for large scale genome-wide association studies. While genotyping microarrays and reference panels for imputation are available for human subjects, non-human model systems often lack such options. Our lab previously demonstrated an efficient and cost-effective method to genotype heterogeneous stock rats using double-digest genotyping-by-sequencing.

Multi-omic network analysis identifies dysregulated neurobiological pathways in opioid addiction.

Background: Opioid addiction is a worldwide public health crisis. In the United States, for example, opioids cause more drug overdose deaths than any other substance. Yet, opioid addiction treatments have limited efficacy, meaning that additional treatments are needed.

An emerging multi-omic understanding of the genetics of opioid addiction.

Opioid misuse, addiction, and associated overdose deaths remain global public health crises. Despite the tremendous need for pharmacological treatments, current options are limited in number, use, and effectiveness. Fundamental leaps forward in our understanding of the biology driving opioid addiction are needed to guide development of more effective medication-assisted therapies.

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

Opioid use disorder (OUD) has emerged as a severe, ongoing public health emergency. Current, frontline addiction treatment strategies fail to produce lasting abstinence in most users. This underscores the lasting effects of chronic opioid exposure and emphasizes the need to understand the molecular mechanisms of drug seeking and taking, but also how those alterations persist through acute and protracted withdrawal.

Executive Function and Impulsivity Predict Distinct Genetic Variance in Internalizing Problems, Externalizing Problems, Thought Disorders, and Compulsive Disorders: A Genomic Structural Equation Modeling Study.

Individual differences in self-control predict many health and life outcomes. Building on twin literature, we used genomic structural equation modeling to test the hypothesis that genetic influences on executive function and impulsivity predict independent variance in mental health and other outcomes. The impulsivity factor (comprising urgency, lack of premeditation, and other facets) was only modestly genetically correlated with low executive function ( =.

Y and mitochondrial chromosomes in the heterogeneous stock rat population.

Genome-wide association studies typically evaluate the autosomes and sometimes the X Chromosome, but seldom consider the Y or mitochondrial (MT) Chromosomes. We genotyped the Y and MT Chromosomes in heterogeneous stock (HS) rats (Rattus norvegicus), an outbred population created from 8 inbred strains. We identified 8 distinct Y and 4 distinct MT Chromosomes among the 8 founders.

A multi-symptomatic model of heroin use disorder in rats reveals distinct behavioral profiles and neuronal correlates of heroin vulnerability versus resiliency.

Objective: The behavioral and diagnostic heterogeneity within human opioid use disorder (OUD) diagnosis is not readily captured in current animal models, limiting translational relevance of the mechanistic research that is conducted in experimental animals. We hypothesize that a non-linear clustering of OUD-like behavioral traits will capture population heterogeneity and yield subpopulations of OUD vulnerable rats with distinct behavioral and neurocircuit profiles.

Methods: Over 900 male and female heterogeneous stock rats, a line capturing genetic and behavioral heterogeneity present in humans, were assessed for several measures of heroin use and rewarded and non-rewarded seeking behaviors.

A Cost-effective, High-throughput, Highly Accurate Genotyping Method for Outbred Populations.

Affordable sequencing and genotyping methods are essential for large scale genome-wide association studies. While genotyping microarrays and reference panels for imputation are available for human subjects, non-human model systems often lack such options. Our lab previously demonstrated an efficient and cost-effective method to genotype heterogeneous stock rats using double-digest genotyping-by-sequencing.

Rare and common variants associated with alcohol consumption identify a conserved molecular network.

Background: Genome-wide association studies (GWAS) have identified hundreds of common variants associated with alcohol consumption. In contrast, genetic studies of alcohol consumption that use rare variants are still in their early stages. No prior studies of alcohol consumption have examined whether common and rare variants implicate the same genes and molecular networks, leaving open the possibility that the two approaches might identify distinct biology.

Genome-wide association studies of coffee intake in UK/US participants of European ancestry uncover cohort-specific genetic associations.

Coffee is one of the most widely consumed beverages. We performed a genome-wide association study (GWAS) of coffee intake in US-based 23andMe participants (N = 130,153) and identified 7 significant loci, with many replicating in three multi-ancestral cohorts. We examined genetic correlations and performed a phenome-wide association study across hundreds of biomarkers, health, and lifestyle traits, then compared our results to the largest available GWAS of coffee intake from the UK Biobank (UKB; N = 334,659).

Multimodal analysis of RNA sequencing data powers discovery of complex trait genetics.

Transcriptome data is commonly used to understand genome function via quantitative trait loci (QTL) mapping and to identify the molecular mechanisms driving genome wide association study (GWAS) signals through colocalization analysis and transcriptome-wide association studies (TWAS). While RNA sequencing (RNA-seq) has the potential to reveal many modalities of transcriptional regulation, such as various splicing phenotypes, such studies are often limited to gene expression due to the complexity of extracting and analyzing multiple RNA phenotypes. Here, we present Pantry (Pan-transcriptomic phenotyping), a framework to efficiently generate diverse RNA phenotypes from RNA-seq data and perform downstream integrative analyses with genetic data.

Multi-ancestry meta-analysis of tobacco use disorder identifies 461 potential risk genes and reveals associations with multiple health outcomes.

Tobacco use disorder (TUD) is the most prevalent substance use disorder in the world. Genetic factors influence smoking behaviours and although strides have been made using genome-wide association studies to identify risk variants, most variants identified have been for nicotine consumption, rather than TUD. Here we leveraged four US biobanks to perform a multi-ancestral meta-analysis of TUD (derived via electronic health records) in 653,790 individuals (495,005 European, 114,420 African American and 44,365 Latin American) and data from UK Biobank (n = 898,680).

A phenome-wide association and Mendelian randomisation study of alcohol use variants in a diverse cohort comprising over 3 million individuals.

Background: Alcohol consumption is associated with numerous negative social and health outcomes. These associations may be direct consequences of drinking, or they may reflect common genetic factors that influence both alcohol consumption and other outcomes.

Methods: We performed exploratory phenome-wide association studies (PheWAS) of three of the best studied protective single nucleotide polymorphisms (SNPs) in genes encoding ethanol metabolising enzymes (ADH1B: rs1229984-T, rs2066702-A; ADH1C: rs698-T) using up to 1109 health outcomes across 28 phenotypic categories (e.