Abstract
Eye movement deviations, particularly deficits of initial sensorimotor processing and sustained pursuit maintenance, and antisaccade inhibition errors, are established intermediate phenotypes for psychotic disorders. We here studied eye movement measures of 849 participants from the Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP) study (schizophrenia N=230, schizoaffective disorder N=155, psychotic bipolar disorder N=206 and healthy controls N=258) as quantitative phenotypes in relation to genetic data, while controlling for genetically derived ancestry measures, age and sex. A mixed-modeling genome-wide association studies approach was used including ~4.4 million genotypes (PsychChip and 1000 Genomes imputation). Across participants, sensorimotor processing at pursuit initiation was significantly associated with a single nucleotide polymorphism in IPO8 (12p11.21, P=8 × 10−11), whereas suggestive associations with sustained pursuit maintenance were identified with SNPs in SH3GL2 (9p22.2, P=3 × 10−8). In participants of predominantly African ancestry, sensorimotor processing was also significantly associated with SNPs in PCDH12 (5q31.3, P=1.6 × 10−10), and suggestive associations were observed with NRSN1 (6p22.3, P=5.4 × 10−8) and LMO7 (13q22.2, P=7.3x10−8), whereas antisaccade error rate was significantly associated with a non-coding region at chromosome 7 (P=6.5 × 10−9). Exploratory pathway analyses revealed associations with nervous system development and function for 40 top genes with sensorimotor processing and pursuit maintenance (P=4.9 × 10−2–9.8 × 10−4). Our findings suggest novel patterns of genetic variation relevant for brain systems subserving eye movement control known to be impaired in psychotic disorders. They include genes involved in nuclear trafficking and gene silencing (IPO8), fast axonal guidance and synaptic specificity (PCDH12), transduction of nerve signals (NRSN1), retinal degeneration (LMO7), synaptic glutamate release (SH3GL2), and broader nervous system development and function.
Highlights
We report a genome-wide association studies (GWAS) evaluating genetic associations with three eye movement phenotypes representing (1) initial sensorimotor processing, (2) sustained pursuit and (3) voluntary inhibitory control in probands with psychosis and controls from the Bipolar and Schizophrenia Network on Intermediate Phenotypes (B-SNIP) sample, with additional exploratory pathway analyses to identify biological networks implicated by top findings
Participants, we found suggestive associations of sustained pursuit maintenance with a region in the SH3GL2 gene encoding Endophilin A1.71 Previous studies in schizophrenia suggest that SH3GL2 is differentially expressed in gray matter of prefrontal cortex in psychosis patients compared to controls.[72,73]
We identified regions of interest for further study including some novel findings in addition to suggestive associations that are consistent with prior disease risk studies
Summary
Deviations of eye movement control are established neurophysiological intermediate phenotypes for psychotic disorders that may be useful for advancing gene discovery in psychiatry.[1]Impairments are seen in a reduced ability to accurately track slowly moving objects with the eyes[2] and to voluntarily suppress a reflexive saccade to a peripheral target on antisaccade tasks.[3,4] Consistent with multiple lines of evidence indicating shared neurobiological alterations and genetic vulnerability across schizophrenia spectrum and psychotic bipolar disorders,[5,6,7,8,9] comparable eye movement deficits have been demonstrated across these groups in first-episode and chronically ill patients, and in their relatives indicating disturbances in brain systems subserving pursuit initiation and maintenance, and inhibitory control.[2,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27] We recently reported both smooth pursuit impairments and antisaccade inhibition errors in a large cohort of clinically stabilized psychotic disorder cases and their relatives as part of the Bipolar and Schizophrenia Network on Intermediate Phenotypes (B-SNIP) Consortium Study.[28,29,30] We found that the initiation of a pursuit movement, which depends on rapid sensorimotor processing, was disturbed in probands and their relatives, while pursuit maintenance, dependent on cognitive predictions of target motion and the most widely used phenotype in prior genetic studies, was mostly impaired in probands.[29]. How these intermediate phenotypes are related to genetic variation across the genome has to date not been comprehensively studied
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