11. Extended Association Studies of Smooth Pursuit and Antisaccade Eye Movements: Findings From the B-SNIP Study. (20th March 2017)

• Record Type: Journal Article
• Authors: Lencer, Rebekka; Mills, Lauren J.; Alliey-Rodriguez, Ney; Reilly, James L.; Sprenger, Andreas; McDowell, Jennifer E.; Shafee, Rebecca; McCarroll, Steve A.; Keshavan, Matcheri S.; Pearlson, Godfrey D.; Tamminga, Carol A.; Clementz, Brett A.; Gershon, Elliot S.; Sweeney, John A.; Bishop, Jeffrey R.
• Is Part Of: Schizophrenia bulletin. Volume 43(2017)Supplement 1
• Page Start: S10
• Page End: S11
• Publication Date: 2017-03-20
• Subjects: Schizophrenia -- Periodicals; Schizophrenia -- Research -- Periodicals; 616.898005
• DOI: 10.1093/schbul/sbx021.030
• Languages: English
• ISSNs: 0586-7614

Abstract

Abstract: Background: Eye movement dysfunctions represent well-established endophenotypes for psychotic disorders. They include impairments of sensorimotor processing, deficits of sustained pursuit maintenance under top-down control, and inhibition errors during antisaccades. How these endophenotypes may be related to genetic variations is not well understood. Methods: 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 were characterized for initial eye acceleration (measure of sensorimotor processing), sustained pursuit maintenance gain (measure of cognitive control), and antisaccade error rate (measure of inhibitory control). A mixed modeling GWAS approach (EMMAX) was used including ~4.3 million genotypes assessed with the PsychChip and 1000 Genomes imputation. Eye movement measures 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: The most robust associations with sensorimotor processing were identified with SNPs in IPO8 (ch12) across participants ( P = 8 × 10-11). In participants of predominantly African ancestry (AA) we additionally observed an association with PCDH12 (ch5) and NRSN1 (ch6). In participants with predominating Caucasian ancestry (CA) sensorimotor measures were most robustly associated with a SNP in CYB5R3 (ch22, P = 8 × 10-10). Association with sustained pursuit maintenance was identified with a SNP in SH3GL2 (ch9) across all participants ( P = 3 × 10-8). In AA participants, we additionally identified associations of pursuit maintenance with a SNP in TMPRSS5 (ch11) and antisaccade error rate with an SNP in chromosome 7. Conclusion: These association findings may give insights into the behavioral/ neurophysiological consequences of genetic variation in systems for eye movement control and their alterations in severe mental illness. Protocadherin 12 (PCDH12) has been suggested for involvement in neurodevelopment and brain morphology in psychotic disorders. By disturbing fast axonal guidance and synaptic specificity, variation in this gene may impact neuronal signaling needed for sensorimotor processing. Variation in Neurensin 1 (NRSN1) may impact processing speed and thus initial eye acceleration by disturbances in transduction of nerve signals and growth. By regulating intracellular signaling and neurotransmitter release, Endophilin-A1 (SH3GL2) may impact sustained pursuit maintenance. Other genes implicated in our association studies represent novel relationships requiring further study.