T42 - Assessing Genetic Control Over Brain Morphology Variance In Psychosis: A Genome-Wide Variance-Controling Qtl (Vqtl) Neuroimaging Study

Abstract

Background Most imaging genetic studies on psychosis have relied upon conventional quantitative trait locus (QTL) analysis, which examines whether distinct allelic variants in a DNA locus are associated with the mean difference in the quantitative measure of a phenotypic trait, e.g. mean brain volumes. However, alternative genotypes can also moderate the variance heterogeneity of a phenotype, which is frequently referred to as variance-controlling QTL (vQTL). This type of genetic control has been observed across several species and traits, and is usually associated to genetic sensitivity to environmental fluctuation. This is highly relevant for an application in imaging genetics in light of the influential diathesis-stress model of psychopathology. To the best of our knowledge, no previous study has evaluated the presence of vQTLs for brain morphology. Methods Participants: The sample analyzed so far consists of 504 individuals recruited through the ongoing Thematically Organized Psychosis (TOP) study, which includes 216 healthy controls (HC), and 288 patients with psychosis (SZ: 143, BD: 145). Patients were diagnosed using the structured clinical interview for DSM-IV (SCID) by trained clinicians. Genetic data: The participants were genotyped with the Affymetrix Genome-Wide Human SNP Array 6.0 (Affymetrix Inc, Santa Clara, CA, USA). Quality control was performed using PLINK. Brain imaging: Magnetic resonance imaging (MRI) structural data were acquired using a 3D T1-weighted magnetization prepared rapid acquisition gradient echo (MPRAGE) sequence, and the T1-weighted scans were processed using FreeSurfer, to obtain estimated of cortical thickness/area/volume and subcortical volumes. vQTL assessment: The relationship between genome-wide single nucleotide polymorphism (SNP) variants and the phenotypic variance of each brain feature of interest was assessed by means of double generalized linear models, and multiple testing adjustments were later performed. Results Exploratory analyses revealed no significant between-group differences in variance for the brain features considered. Genome-wide vQTL analyses indicated that the population variance of features such as cerebellar volume and temporal pole cortical thickness could be under partial genetic control. Replication of these findings and diagnose-genotype interaction tests are currently being implemented and are expected to be competed by early autumn 2016. Discussion The findings suggest that inter-individual variability in brain morphometry may be influenced by specific genetic variants. Carriers of those genotypes may be particularly susceptible to brain deficits and psychopathology after exposure to pathogenic environments and, simultaneously, have increased likelihood of benefiting from enriched/non-adverse experiences.