Variants in the apolipoprotein E (APOE) gene strongly influence Alzheimer’s disease (AD) risk, neuropathology, and longevity. The APOE ε4 allele confers the greatest genetic risk for AD in Europeans and Japanese populations and is associated with reduced lifespan, whereas the protective ε2 allele is enriched among centenarians. Notably, APOE ε4 risk is attenuated in individuals of African ancestry, who also show reduced neuropathologic burden. We hypothesize that ancestry-specific regulatory variation at the APOE locus alters risk allele dosage and contributes to these differences. Single-nucleus RNA-seq studies show reduced APOE ε4 expression in astrocytes of African carriers, but the underlying regulatory variants remain unknown. This proposal aims to define the APOE transcript repertoire in human brain (Aim 1) and functionally evaluate ancestry-enriched APOE variants for effects on transcription, splicing, and RNA processing (Aim 2) using targeted long-read RNA sequencing and multiplex reporter assays. This work will generate a regulatory map of APOE and identify variants that lower APOE expression and protect against AD.
Geographic Area: University of Washington
Regulatory variation that affects splicing of the Alzheimer’s disease risk gene TREM2
Alzheimer’s disease (AD) risk is strongly influenced by genetic variation, much of which lies in noncoding regions that regulate gene expression and RNA splicing. Protein-coding variants explain only ~30% of AD heritability, highlighting the need to functionally characterize regulatory variants. TREM2 is a microglia-specific immune receptor in which heterozygous missense variants increase late-onset AD risk, while biallelic loss-of-function variants cause early-onset dementia. TREM2 undergoes alternative splicing, but its transcript repertoire and regulation in human brain remain poorly defined. We identified a novel splice isoform lacking exon 2 (Δe2) that encodes a truncated protein with altered activity. Preliminary data show that AD- and dementia-associated variants shift splicing toward Δe2, reducing functional TREM2 dosage. We will define TREM2 isoforms in human brain, functionally assess regulatory variants affecting splicing, and analyze interactions between cis-variants and trans-acting splicing factors altered in AD, using long-read RNA sequencing and high-throughput functional assays.
AMPERE (Augmented Momentary Personal Ecological Risk Evaluation)
Death by suicide is the 2nd leading cause of death among young adults in the United States. While most patients who die by suicide have had recent contact with their health care providers, the medical delivery system is poorly equipped to address this preventable issue. EMA (ecological momentary assessment) systems show promise as indicators of suicide risk and as a means of enhancing existing resources. However, little is known about how to apply these methods in the context of clinical care. The AMPERE study leverages existing work on EMAs and human-centered design principles to develop and pilot a prototype suicide risk monitoring system to support suicide risk management for adolescents and young adults (ages 16-30) within the UW Medicine Primary Care system.
Behaviors and Executive Skills in T21 (BEST21)
We are conducting a study to understand the role of problem-solving in challenging behaviors for children with Down syndrome so that we can better understand the development of and treat these behaviors. If you agree to participate, this study will involve questionnaires, some of which may be completed at home. You would also attend an in-person visit that involves measuring your child’s naturally-occurring brain activity with EEG as well as cognitive assessments. We would schedule your visit around your schedule to the best of our ability and we can schedule this visit in a location that is convenient for you (UW, home visits, etc.). Participants will receive an $80 gift card to thank them for their time.
Improving treatment strategies and clinical outcomes in patients with first-episode psychosis and substance use disorders
Our project will seek to identify factors associated with gaps in transitions of care for psychiatric inpatients who presented with substance-induced psychosis (SIP) for the first time. We will analyze historical electronic health record data of patients who were treated for psychosis at Harborview Medical Center. We will test the hypotheses that (1) treatment with long-acting injectable antipsychotics (LAI) and referrals to outpatient behavioral health are lower for patients diagnosed with first-episode SIP compared to those diagnosed with first-episode psychosis and that (2) patients diagnosed with first-episode SIP will have worse post-discharge outcomes (rehospitalization, ED utilization), in part due to lower use of LAI.
Strengthening financial literacy for people living with serious mental illness
Improved financial literacy among people living with serious mental illness (SMI) is associated with a higher quality of life, fewer hospitalizations, and better treatment adherence. Yet people living with SMI frequently express how their lack of financial knowledge has negative personal consequences and that they don’t know where to turn for assistance. This project will gather qualitative and quantitative data from people admitted to the Center for Behavioral Health and Learning, a psychiatric hospital, to understand the need and desire for a financial skills intervention and its role in discharge planning. The assessment will also seek input from family members/caregivers, representative payees/fiduciaries and experts in the community. Ultimately, we hope to create a replicable, standardized intervention that can be evaluated and implemented in inpatient settings and modified as necessary for outpatient settings.
Once-weekly GLP-1R agonist dulaglutide for treatment of fentanyl use disorder and modulation of lateral habenula activity in male and female rats
Current pharmacological treatments for fentanyl use disorder, primarily opioid replacements, have proven insufficient to stem the tide of fentanyl related suffering and deaths. Novel pharmacotherapies are desperately needed, ideally ones that are non-opioid, highly convenient, and produce minimal side effects. One promising class of drugs that meets these criteria are glucagon-like peptide 1 (GLP-1) receptor (GLP-1R) agonists. Endogenous GLP-1 is released in response to food intake, but GLP-1Rs are present in many tissues throughout the body, including brain regions involved in addiction. Early studies have shown GLP-1R agonists may reduce drug seeking. Here, we aim to determine if the long acting GLP-1R agonist dulaglutide, given once weekly, can reduce fentanyl SA for a substantial period of time (3 weeks), even after SA has been established.
Determining if activity in specific lateral habenula output pathways motivates avoidance of synthetic opioid withdrawal or cue induced reinstatement
Fentanyl abuse has reached epidemic proportions in the United States and is responsible for more than 70,000 overdose deaths each year. Avoidance of significant physical and emotional turmoil during withdrawal and exposure to drug-associated cues are two key deterrents to voluntary abstinence in those suffering from substance abuse disorder. By investigating the localized neuronal projections responsible for motivating avoidance of withdrawal, and processing reward cues, we may be able to produce targeted pharmacotherapies or genetic therapies to improve the rate of voluntary abstinence.
Default mode network impairments in comorbid anxiety and cannabis use disorders
Social anxiety disorder (SAD) is characterized by maladaptive self-focused attention (SFA), which itself is correlated with large scale brain network connectivity impairments. Cannabis use disorder (CUD) is commonly conceptualized as impaired reward processing within the ventral dopaminergic network, however, it is also implicated in connectivity disturbances in other critical cortical circuits. In the current study we will characterize the large scale brain network impairment in comorbid SAD and CUD given commonly overlapping symptoms and population prevalence
Psychosis beyond symptoms: Cognitive and genetic biomarkers of schizophrenia
Schizophrenia is a prevalent, debilitating psychiatric disorder that is diagnosed based on clinical interviews that are subjective and highly variable; in fact, two patients can have no overlapping symptoms and be diagnosed with the same disease. While cardiologists have blood tests to help diagnose heart attacks and oncologists have PET scans to find hidden cancers, psychiatrists don’t have objective diagnostic tests. This proposal will utilize machine learning to analyze cognitive tests, brain electrical activity, and genetic signatures from 1,415 patients with schizophrenia and 1,062 controls to uncover biomarkers of schizophrenia. By incorporating biomarkers into diagnostic standards, psychiatrists could one day order a simple test that could help them confidently diagnose schizophrenia and make better treatment decisions based on quantitative rather than subjective measures.
