Genetics and Pathway Analysis of Normative Cognitive Variation in the Philadelphia Neurodevelopmental Cohort

Identifying genes and cellular pathways associated with normative brain physiology and behavior promises to help understand the molecular basis of brain function and could help identify molecular therapies that target specific psychiatric symptoms with minimal side effects. Massive genotype-phenotype datasets are available to help with this endeavour, but interpreting these data is challenging due to their size and complexity. We developed a novel brain-focused gene and pathway prioritization and annotation workflow to study brain-related phenotypes, and applied it to nine tasks from the Penn Computerized Neurocognitive Test Battery from the Philadelphia Neurodevelopmental Cohort (PNC, N=3,319 individuals of European ancestry). We report genome-wide significance of variants associated with nonverbal reasoning, within the 39 end of FBLN1 gene (p=4.6x10-8), itself associated with fetal neurodevelopment and psychotic disorders. These findings suggest that nonverbal reasoning and FBLN1 variation warrant further investigation in studies of psychosis. We also perform a pathway and brain-specific gene set enrichment analysis for all tasks, mapping SNPs to genes using a large brain genome regulation database. In contrast to the few individual SNPs we find strongly associated with PNC phenotypes, multiple pathways, including organ development, cell proliferation and nervous system dysfunction, are strongly associated with a diverse set of tasks. Top-ranked genes in pathways associated with working memory are also genetically associated with diseases with working memory deficits, including schizophrenia and Parkinson9s disease. Our analysis identifies a diverse set of known drug targets, suggesting that different therapies may be effective for the same impairment, depending on the disease. We propose that pathway level information should be added to frameworks like RDoC to help build a "genes to pathways to behaviour" approach to understanding brain-related phenotypes.