Genetic Risk for Serious Mental Illness and Development

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 profiles in childhood, identify clinical syndromes and neurobehavioral traits in childhood associated with genetic liability for SMI, and quantify the relative power of genetic versus clinical and neurobehavioral characteristics for predicting proximal psychiatric outcomes.