# Genetic Risk for Serious Mental Illness and Development

> **NIH NIH R01** · UNIVERSITY OF WASHINGTON · 2022 · $690,055

## Abstract

PROJECT SUMMARY/ABSTRACT
Clinical staging is gaining traction as a potentially powerful framework for understanding the pathogenesis and
emergence of serious mental illnesses (SMI), such as schizophrenia (SCZ), bipolar disorder (BP), and severe
depression (severe-DEP), across development, and for guiding early interventions that aim to alter disease
trajectory. However, realizing the full potential of this approach requires overcoming a number of challenges.
These challenges include the imprecise boundaries between psychiatric disorders; unclear validity and
specificity of early clinical and neurobehavioral markers for predicting later illness onset; and growing
recognition that current psychiatric nosology may not map onto differences in underlying etiology in an optimal
way. Indeed, as large-scale genetic studies continue to unravel the genetic architecture of psychiatric
disorders, it has become clear that genetic risk for each disorder is complex and highly polygenic; involves
variants that span the allelic frequency range; and that individual genetic variants frequently confer risk for
multiple disorders. Leveraging genetic risk profiles to define groups of at-risk individuals and map the
progression of clinical phenotypes across development may therefore offer a more biologically valid approach
for defining the nosology of psychiatric disorders, identifying biomarkers with the greatest predictive validity
and specificity for different clinical outcomes, and optimizing early intervention. Towards this end, the current
project will investigate the relationships between genetic risk profiles and early markers of psychopathology in
the “Paisa,” a genetically and culturally homogenous population that predominates in the Andean Mountains of
Colombia. Specifically, we will build upon our existing infrastructure for large-scale studies of SMI in the region
to establish a new cohort of 3,000 children and early adolescents at elevated (n = 2,700) or low risk (n = 300)
for SMI. We will obtain DNA samples and comprehensive clinical and neurobehavioral phenotyping and will
generate common-variant based polygenic risk scores (PRS) for major psychiatric disorders, as well as rare
variant scores summarizing burden of rare damaging variants and copy number deletions. We will characterize
relationships between clinical syndromes and neurobehavioral traits in childhood (Aim 1). We will then map
relationships between common variant-based genetic risk for SMI, rare damaging variant burden, and
psychiatric diagnoses in childhood (Aim 2), as well as cognitive, motor, sensory, and psychological markers of
functioning (Aim 3). Finally, using existing state-of-the-art psychiatric electronic medical record (EMR)
databases to obtain longitudinal outcomes, we will explore genetic and clinical and neurobehavioral
characteristics associated with poor clinical outcome within 2 years. Study findings will clarify trans-diagnostic
vs. disorder-specific neurobehavioral profil...

## Key facts

- **NIH application ID:** 10443282
- **Project number:** 1R01MH127165-01A1
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Jennifer Katherine Forsyth
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $690,055
- **Award type:** 1
- **Project period:** 2022-08-01 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10443282

## Citation

> US National Institutes of Health, RePORTER application 10443282, Genetic Risk for Serious Mental Illness and Development (1R01MH127165-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10443282. Licensed CC0.

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