Polygenic and trans-diagnostic risk for anorexia nervosa and obsessive-compulsive disorder: Novel associations with emotional, behavioral, and cognitive dysfunction in a population-based cohort

Univ Of North Carolina Chapel Hill, Chapel Hill NC

Investigators

Linked publications & trials

Abstract

? DESCRIPTION (provided by applicant): AN and OCD are disorders of major public health importance due to their significant personal and societal costs. Patients with AN or OCD are often undetected at early stages of illness, face long periods of illness, and a significant percentage never recover. Despite years of psychiatric research, detection and prevention strategies for AN and OCD are not optimal. Recent preliminary analyses using published AN and OCD genome-wide-association-study (GWAS) data discovered that these disorders share a substantial proportion (55%) of genetic risk, confirming decades of epidemiological evidence from our group and others suggesting a shared etiology. However, the link between genetic risk for AN and OCD and the emotional, behavioral, and cognitive dysfunction that characterizes AN and OCD has not been explored. The overarching goals of our proposed analyses are: first, to develop three continuous genetic risk scores [e.g. polygenic risk scores (PRS)], to quantify anorexia nervosa (AN), and obsessive-compulsive disorder (OCD), and trans-diagnostic AN/OCD genetic risk; and second, to examine associations between these three risk scores and dimensions of emotional, behavioral, and cognitive functioning. In the proposed R21, we leverage the considerable wealth of existing data available to us through the Psychiatric Genomics Consortium (PGC), a large international network of psychiatric genetics investigators, and the Avon Longitudinal Study of Parents and Children (ALSPAC), a longitudinal population-based cohort. The PGC AN and OCD working groups include almost all available genetic data from cases with AN (~4k cases) and OCD (~3k cases). We also anticipate the addition of ~3k new independent genotyped AN cases and ~5K OCD cases to the PGC over the next year. ALSPAC includes existing genome-wide data on ~8k individuals in the longitudinal cohort combined with multiple comprehensive measures of their phenotypic outcomes. Our project has three major aims: First, using PGC data, we will calculate three polygenic risk scores (PRS)-a continuous measure quantifying the sum of cumulative risk loci for disorder pruned by linkage disequilibrium and weighted by effect size-for AN and OCD and a trans-diagnostic PRS (e.g., an AN/OCD PRS calculated where cases have AN or OCD). Second, using ALSPAC data, we will examine whether AN/OCD PRS explains dysfunction dimensionally across the population in the emotional, behavioral, and cognitive constructs known to contribute to the phenotypic overlap between AN and OCD. Finally, using ALSPAC data, we will examine whether PRS for AN or OCD predict dysfunction in emotional, behavioral, and cognitive constructs unique to AN or OCD, respectively. Results will be used in future research to align nosology with biology rather than with symptoms; examinations of biological risk factors for poor treatment outcome; and ultimately, novel approaches to tailor treatment to genetic risk and dysfunction in emotional, behavioral, and cognitive functioning.