M17 - POTENTIAL BRAIN MORPHOLOGY INSTABILITY FEATURES MEDIATING THE ASSOCIATION BETWEEN GENOME-WIDE HOMOZYGOSITY AND ALTERED NEUROCOGNITION

Abstract

Background Increased homozygosity has been shown to reduce fitness and predispose for a number of diseases. Across different species and traits, this broad phenomenon has often been explained by developmental instability in homozygotes, which leads to morphopathological alterations such as asymmetry and ultimately to physiological impairments. Of note, although recent studies in humans indicate that genome-wide homozygosity is associated with different neuropsychiatric/cognitive phenotypes, the underlying neurobiological mechanisms remain scarcely explored. In this study, the potential brain asymmetry alterations mediating the association between genome-wide homozygosity and altered cognition and behavior is explored in a sample of over 3600 European-ancestry individuals, from the Philadelphia Neurodevelopmental Cohort (PNC). Methods The general population sample employed here included >3600 European-ancestry individuals, aged 8-21 years, from the PNC. Genome-wide information was collected for those subjects through four different Illumina platforms (Human 610 Quad/HumanHap550 v1/HumanHap 550 v3/HumanOmniExpress from Illumina). The participants underwent psychiatric screening for a range of common symptoms characterizing various psychiatric disorders, and completed a comprehensive computerized neurocognitive battery, which measures four main domains: executive control, episodic memory, reasoning, and social cognition. High-resolution magnetic resonance imaging scans were available for a subset of >700 individuals. Estimations of genome-wide homozygosity were obtained using PLINK, and both cortical and subcortical features were obtained with FreeSurfer. Associations between runs of homozygosity and both fluctuating and directional asymmetry in brain features (subcortical volumes and cortical thickness/area/volume) were tested, adjusting for potential confounders. Interactions between homozygosity and age were also tested. Results The data indicates that specific patterns of fluctuating asymmetry of brain cortical/subcortical morphology may be associated with genome-wide homozygosity markers in the general population. Some of these putative morphopathological traits are likely mediating the associations between homozygosity and neurocognitive profiles. Discussion The potential role of random deviations in brain morphology, as indexed by both fluctuating and directional asymmetry, was examined in relation to genomic homozygosity. The findings indicate that localized bilateral brain features are suggestively related to fitness reductions, likely due to destabilizing effects of homozygosity on normal brain development. Some of these brain alterations may be mediating the previously observed associations between homozygosity and neurocognitive, neuropsychiatry and behavioral traits. Replication of these findings is expected to be completed by early autumn 2016.