Genome-Wide Association Studies Of Smooth Pursuit Eye Movements Across Psychotic Disorders: Preliminary Findings From The B-Snip Sample

Abstract

Background Smooth pursuit eye movement dysfunctions are regarded as intermediate phenotypes for psychotic disorders. They include first, impairments of sensorimotor processing during pursuit initiation and second, deficits of sustained pursuit maintenance implicating different functional brain systems. Here we were interested in genetic alterations specifically related to these pursuit deficits. Methods Pursuit performance was assessed in 849 participants (schizophrenia N=230, schizoaffective disorder N=155, psychotic bipolar disorder N=206, and healthy controls N=258) of the Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP) study. Participants were 18-65 years of age and without significant neurological disorder, recent substance abuse or dependence. A mixed modeling GWAS approach (EMMAX) was performed using genotyping assessed with the PsychChip (287,637 SNPs with MAF>0.01 passing standard GWAS QC criteria). Eye acceleration (measure of sensorimotor processing) and sustained maintenance gain (measure of cognitive control) were modeled as quantitative trait phenotypes in relation to genetic data while controlling for genetically-derived ancestry measures, age, and sex. Probands and controls were grouped together for primary analyses stratified by the top two genetically-derived ancestry groups with follow-up studies in proband or control categories. Results Genome-wide associations (p Discussion Protocadherin 12 (PCDH12) encodes a member of the cadherin family of proteins previously identified for involvement in neurodevelopment and brain morphology in both schizophrenia and bipolar disorder. By disturbing fast axonal guidance and synaptic specificity, variation in this gene may impact neuronal signaling needed for sensorimotor processing. CABLES1 encodes a protein involved in cell cycle regulation and has been identified as an important component of neural development and interhemispheric connections needed for predictive control of sustained pursuit. Relationships between neurodevelopment related genes and smooth pursuit genotypes represent novel findings that may give insights into the behavioral/neurophysiological consequences of genetic variation in these systems and its alterations in severe mental illness. Other genes implicated in our association studies represent novel relationships requiring further study.