R01MH122686

Discovery and CRISPR Validation of Genetic Factors Associated with Antipsychotic-Induced Weight Gain and Cardiometabolic Risk - Project Summary/Abstract

Antipsychotic-induced weight gain (AIWG) is of significant public health importance in mentally ill populations, potentially addressable with personalized, precision medicine. Antipsychotic medications increase body weight, thereby increasing cardiometabolic risk (CMR) conditions like type 2 diabetes and cardiovascular disease, conditions associated with accelerated cellular aging. This has contributed to a 10 to 15-year mortality gap between mentally ill individuals and the general population.

Antipsychotic medications are commonly used at all ages, but are associated with differential patterns of fat gain, whereby children gain more and older adults gain less. Numerous genome-wide association studies (GWAS) have identified key genetic factors associated with AIWG, but are limited by the use of indirect measures of body fat, like weight or body mass index (BMI), that are less well correlated with metabolic disease risk. Additionally, existing research does not fully address age-related differences in AIWG.

In response to NIH PA-17-088 "Secondary Analyses of Existing Cohorts, Data Sets and Stored Biospecimens to Address Clinical Aging Research Questions," we propose a novel approach applying population-based genetics, existing biospecimen with linked clinical data including precisely-measured adiposity and insulin sensitivity, and advanced molecular tools to identify and functionally validate key genetic determinants of AIWG and CMR across the age-span.

This approach leverages:
1) Existing population-level data from large biobanking initiatives and epidemiological studies inclusive of approximately 15,000 individuals with genetic and relevant phenotypic data,
2) Existing clinical and biospecimen data from NIH funded randomized clinical trials or RCTs characterizing the metabolic effects of antipsychotics in children, adults, and older adults with direct and precise measures of body fat, together with data from approximately 600 individuals with genetic data and additional biomarkers of metabolic risk, and
3) CRISPR based in vitro drug exposure, followed by cellular functional assays to characterize molecular mechanisms impacted by antipsychotics.

Additional sources of existing data will be available upon funding, including data on approximately 3000 individuals from large industry funded RCTs, data on up to 250,000 individuals from the Psychiatric Genetics Consortium (PGC), and data from more than 2,000 individuals from the Dutch Bipolar Cohort Study. These additional sources will be used for independent validation and replication.

This study will combine unbiased genomic methods, including array-based genotyping, GWAS and GWAS meta-analysis, CRISPR-based gene inhibition/activation screens (CRISPRi/a), and functional molecular and cellular studies on prioritized variants of interest, combined with unique clinical data to identify genetic factors and generate predictive models of weight-related physiological changes associated with accelerated aging.

This combined set of molecular techniques will allow us to build on known genetic associations while discovering new genes and genetic variants that are associated with the greatest risk for treatment-related fat gain in younger and older patients. This project will contribute to the development of a precision-based treatment algorithm that can accurately predict and prevent AIWG and cardiometabolic risk in youth, young, middle-aged, and older adults.

The results from this study will also importantly contribute to publicly available datasets and motivate future collection of similar data necessary for further validation of our results.

Washington University

THE MISSION OF THE NATIONAL INSTITUTE OF MENTAL HEALTH (NIMH) IS TO TRANSFORM THE UNDERSTANDING AND TREATMENT OF MENTAL ILLNESSES THROUGH BASIC AND CLINICAL RESEARCH, PAVING THE WAY FOR PREVENTION, RECOVERY, AND CURE. IN MAY 2020, NIMH RELEASED ITS NEW STRATEGIC PLAN FOR RESEARCH. THE NEW STRATEGIC PLAN BUILDS ON THE SUCCESSES OF PREVIOUS NIMH STRATEGIC PLANS BY PROVIDING A FRAMEWORK FOR SCIENTIFIC RESEARCH AND EXPLORATION, AND ADDRESSING NEW CHALLENGES IN MENTAL HEALTH. THE NEW STRATEGIC PLAN OUTLINES FOUR HIGH-LEVEL GOALS: GOAL 1: DEFINE THE BRAIN MECHANISMS UNDERLYING COMPLEX BEHAVIORS GOAL 2: EXAMINE MENTAL ILLNESS TRAJECTORIES ACROSS THE LIFESPAN GOAL 3: STRIVE FOR PREVENTION AND CURES GOAL 4: STRENGTHEN THE PUBLIC HEALTH IMPACT OF NIMH-SUPPORTED RESEARCH THESE FOUR GOALS FORM A BROAD ROADMAP FOR THE INSTITUTE'S RESEARCH PRIORITIES OVER THE NEXT FIVE YEARS, BEGINNING WITH THE FUNDAMENTAL SCIENCE OF THE BRAIN AND BEHAVIOR, AND EXTENDING THROUGH EVIDENCE-BASED SERVICES THAT IMPROVE PUBLIC HEALTH OUTCOMES. THE INSTITUTE'S OVERALL FUNDING STRATEGY IS TO SUPPORT A BROAD SPECTRUM OF INVESTIGATOR-INITIATED RESEARCH IN FUNDAMENTAL SCIENCE, WITH INCREASING USE OF INSTITUTE-SOLICITED INITIATIVES FOR APPLIED RESEARCH WHERE PUBLIC HEALTH IMPACT IS A SHORT-TERM MEASURE OF SUCCESS. THE NEW STRATEGIC PLAN ALSO ADDRESSES A NUMBER OF CROSS-CUTTING THEMES THAT ARE RELEVANT TO ALL RESEARCH SUPPORTED BY NIMH, THESE THEMES HIGHLIGHT AREAS WHERE NIMH-FUNDED SCIENCE MAY HAVE THE GREATEST IMPACT, BRIDGE GAPS, AND OFFER NOVEL APPROACHES TO ACCELERATE ADVANCES IN MENTAL HEALTH RESEARCH. FOR EXAMPLE, NIMH VALUES A COMPREHENSIVE RESEARCH AGENDA THAT TAKES AN INCLUSIVE APPROACH THAT ENSURES RESEARCH INTERESTS ARE VARIED, MAINTAIN DIVERSE PARTICIPATION AND PARTNERSHIPS, AND ACHIEVE RESEARCH GOALS ACROSS MULTIPLE TIMEFRAMES. THIS INCLUDES DIVERSE METHODOLOGIES, TOOLS, AND MODELS, RESEARCH ADDRESSING COMPLEX BASIC, TRANSLATIONAL, AND APPLIED QUESTIONS, RESEARCH INCLUDING BOTH SEXES AND, AS APPROPRIATE, GENETIC BACKGROUND, AND, PARTICIPANTS FROM DIVERSE RACIAL AND ETHNIC BACKGROUNDS, AND ACROSS GENDER IDENTITIES, GEOGRAPHICAL CONTEXT, SOCIOECONOMIC STATUS, NEUROTYPE, AND AGE OFFERING THE BEST POSSIBLE REPRESENTATION, FOR THE BROADEST NUMBER OF INDIVIDUALS WHO MAY ULTIMATELY BENEFIT FROM THESE SCIENTIFIC ADVANCES. TO ACCOMPLISH THE GOALS OUTLINED IN THE NEW STRATEGIC PLAN, NIMH WILL SUPPORT RESEARCH THAT AIMS: TO CHARACTERIZE THE GENOMIC, MOLECULAR, CELLULAR, AND CIRCUIT COMPONENTS CONTRIBUTING TO BRAIN ORGANIZATION AND FUNCTION, TO IDENTIFY THE DEVELOPMENTAL, FUNCTIONAL, AND REGULATORY MECHANISMS RELEVANT TO COGNITIVE, AFFECTIVE, AND SOCIAL DOMAINS, ACROSS UNITS OF ANALYSIS, AND, TO GENERATE AND VALIDATE NOVEL TOOLS, TECHNIQUES, AND MEASURES TO QUANTIFY CHANGES IN THE ACTIVITY OF MOLECULES, CELLS, CIRCUITS, AND CONNECTOMES. TO DISCOVER GENE VARIANTS AND OTHER GENOMIC ELEMENTS THAT CONTRIBUTE TO THE DEVELOPMENT OF MENTAL ILLNESSES IN DIVERSE POPULATIONS, TO ADVANCE OUR UNDERSTANDING OF THE COMPLEX ETIOLOGY OF MENTAL ILLNESSES USING MOLECULAR EPIDEMIOLOGIC APPROACHES THAT INCORPORATE INDIVIDUAL GENETIC INFORMATION IN LARGE COHORTS, TO ELUCIDATE HOW HUMAN GENETIC VARIATION AFFECTS THE COORDINATION OF MOLECULAR, CELLULAR, AND PHYSIOLOGICAL NETWORKS SUPPORTING HIGHER-ORDER FUNCTIONS AND EMERGENT PROPERTIES OF NEUROBIOLOGICAL SYSTEMS, AND, TO DEVELOP NOVEL TOOLS AND TECHNIQUES FOR THE ANALYSIS OF LARGE-SCALE GENETIC, MULTI-OMIC DATA AS IT APPLIES TO MENTAL HEALTH. TO UTILIZE CONNECTOMIC APPROACHES TO IDENTIFY BRAIN NETWORKS AND CIRCUIT COMPONENTS THAT CONTRIBUTE TO VARIOUS ASPECTS OF MENTAL FUNCTION AND DYSFUNCTION, TO DETERMINE THROUGH BRAIN-WIDE ANALYSIS HOW CHANGES IN THE PHYSIOLOGICAL PROPERTIES OF MOLECULES, CELLS, AND CIRCUITS CONTRIBUTE TO MENTAL ILLNESSES, TO DEVELOP MOLECULAR, CELLULAR, AND CIRCUIT-LEVEL BIOMARKERS OF IMPAIRED NEURAL FUNCTION IN HUMANS, AND, TO DEVELOP INNOVATIVE TECHNOLOGIES, INCLUDING NEW IMAGING, COMPUTATIONAL, PHARMACOLOGICAL, AND GENETIC TOOLS TO INTERROGATE AND MODULATE CIRCUIT ACTIVITY AND STRUCTURE ALTERED IN MENTAL ILLNESSES. TO ELUCIDATE THE MECHANISMS CONTRIBUTING TO THE TRAJECTORIES OF BRAIN DEVELOPMENT AND BEHAVIOR, AND, TO CHARACTERIZE THE EMERGENCE AND PROGRESSION OF MENTAL ILLNESSES, AND IDENTIFYING SENSITIVE PERIODS FOR OPTIMAL INTERVENTION. TO DETERMINE EARLY RISK AND PROTECTIVE FACTORS, AND RELATED MECHANISMS, TO SERVE AS NOVEL INTERVENTION GROUPS, AND, TO DEVELOP RELIABLE AND ROBUST BIOMARKERS AND ASSESSMENT TOOLS TO PREDICT ILLNESS ONSET, COURSE, AND ACROSS DIVERSE POPULATIONS. TO DEVELOP NOVEL INTERVENTIONS USING A MECHANISM-INFORMED, EXPERIMENTAL THERAPEUTICS APPROACH, AND, TO DEVELOP AND IMPLEMENT MEASUREMENT STRATEGIES TO FACILITATE MECHANISM-BASED INTERVENTION DEVELOPMENT AND TESTING. TO INVESTIGATE PERSONALIZED INTERVENTION STRATEGIES ACROSS DISEASE PROGRESSION AND DEVELOPMENT, AND, TO DEVELOP AND REFINE COMPUTATIONAL APPROACHES AND RESEARCH DESIGNS THAT CAN BE USED TO INFORM AND TEST PERSONALIZED INTERVENTIONS. TO DEVELOP AND TEST APPROACHES FOR ADAPTING, COMBINING, AND SEQUENCING INTERVENTIONS TO ACHIEVE THE GREATEST IMPACT ON THE LIVES AND FUNCTIONING OF PERSONS SEEKING CARE, TO CONDUCT EFFICIENT PRAGMATIC TRIALS THAT EMPLOY NEW TOOLS TO RAPIDLY IDENTIFY, ENGAGE, ASSESS, AND FOLLOW PARTICIPANTS IN THE CONTEXT OF ROUTINE CARE, AND, TO ENHANCE THE PRACTICAL RELEVANCE OF EFFECTIVENESS RESEARCH VIA DEPLOYMENT-FOCUSED, HYBRID, EFFECTIVENESS-IMPLEMENTATION STUDIES. TO EMPLOY ASSESSMENT PLATFORMS WITHIN HEALTHCARE SYSTEMS TO ACCURATELY ASSESS THE DISTRIBUTION AND DETERMINANTS OF MENTAL ILLNESSES AND TO INFORM STRATEGIES FOR IMPROVED SERVICES, TO OPTIMIZE REAL-WORLD DATA COLLECTION SYSTEMS TO IDENTIFY STRATEGIES FOR IMPROVING ACCESS, QUALITY, EFFECTIVENESS, AND CONTINUITY OF MENTAL HEALTH SERVICES, AND, TO COMPARE ALTERNATIVE FINANCING MODELS TO PROMOTE EFFECTIVE AND EFFICIENT CARE FOR INDIVIDUALS WITH SERIOUS EMOTIONAL DISTURBANCES AND SERIOUS MENTAL ILLNESSES. TO STRENGTHEN PARTNERSHIPS WITH KEY STAKEHOLDERS TO DEVELOP AND VALIDATE STRATEGIES FOR IMPLEMENTING, SUSTAINING, AND CONTINUOUSLY IMPROVE EVIDENCE-BASED PRACTICES, TO BUILD MODELS TO SCALE-UP EVIDENCE-BASED PRACTICES FOR USE IN PUBLIC AND PRIVATE PRIMARY CARE, SPECIALTY CARE AND OTHER SETTINGS, AND, TO DEVELOP DECISION-SUPPORT TOOLS AND TECHNOLOGIES THAT INCREASE THE EFFECTIVENESS AND CONTINUOUS IMPROVEMENT OF MENTAL HEALTH INTERVENTIONS IN PUBLIC AND PRIVATE PRIMARY CARE, SPECIALTY CARE, AND OTHER SETTINGS. TO ADAPT, VALIDATE, AND SCALE-UP PROGRAMS CURRENTLY IN USE THAT IMPROVE MENTAL HEALTH SERVICES FOR UNDERSERVED POPULATIONS, TO DEVELOP AND VALIDATE SERVICE DELIVERY MODELS THAT PROVIDE EVIDENCE-BASED CARE FOR INDIVIDUALS THROUGHOUT THE COURSE OF MENTAL ILLNESS, TO DEVELOP AND VALIDATE SYSTEMS-LEVEL STRATEGIES USING TECHNOLOGY AND OTHER APPROACHES, TO IDENTIFY, SUPPORT, AND MONITOR THE EFFECTIVENESS OF EVIDENCE-BASED CARE THROUGHOUT THE COURSE OF ILLNESS, AND, TO DEVELOP AND VALIDATE DECISION-MAKING MODELS THAT BRIDGE MENTAL HEALTH, MEDICAL, AND OTHER CARE SETTINGS TO INTEGRATE THE APPROPRIATE CARE FOR PEOPLE WITH SERIOUS MENTAL ILLNESSES AND COMORBID MEDICAL CONDITIONS.

93.242 - Mental Health Research Grants

National Institute of Mental Health (NIMH) [HHS - NIH]

Saint Louis, Missouri 63130 United States

Single Zip Code

Secondary Analyses of Existing Cohorts, Data Sets and Stored Biospecimens to Address Clinical Aging Research Questions (R01) (PA-17-088)

Amendment Since initial award the total obligations have increased 359% from $768,936 to $3,528,182.