Abstract
Schizophrenia is a heterogeneous disorder with substantial heritability. The use of endophenotypes may help clarify its aetiology. Measures from the smooth pursuit and antisaccade eye movement tasks have been identified as endophenotypes for schizophrenia in twin and family studies. However, the genetic basis of the overlap between schizophrenia and these oculomotor markers is largely unknown. Here, we tested whether schizophrenia polygenic risk scores (PRS) were associated with oculomotor performance in the general population. Analyses were based on the data of 2956 participants (aged 30-95) of the Rhineland Study, a community-based cohort study in Bonn, Germany. Genotyping was performed on Omni-2.5 exome arrays. Using summary statistics from a recent meta-analysis based on the two largest schizophrenia genome-wide association studies to date, we quantified genetic risk for schizophrenia by creating PRS at different p value thresholds for genetic markers. We examined associations between PRS and oculomotor performance using multivariable regression models. Higher PRS were associated with higher antisaccade error rate and latency, and lower antisaccade amplitude gain. PRS showed inconsistent patterns of association with smooth pursuit velocity gain and were not associated with saccade rate during smooth pursuit or performance on a prosaccade control task. There is an overlap between genetic determinants of schizophrenia and oculomotor endophenotypes. Our findings suggest that the mechanisms that underlie schizophrenia also affect oculomotor function in the general population.
Highlights
Schizophrenia is a heterogeneous disorder with substantial heritability
polygenic risk scores (PRS) was positively associated with antisaccade error rate irrespective of inclusion criteria, but sensitivity analysis at pT = 5 × 10−8 and pT = 0.1 was not significant
Our sensitivity analysis showed that applying clumping and applying the genomewide significant threshold obscured the association between PRS and antisaccade error rate that we found when we used PRS based on only the pre-specified single nucleotide polymorphisms (SNPs)
Summary
Schizophrenia is a heterogeneous disorder with substantial heritability. The use of endophenotypes may help clarify its aetiology. We tested whether schizophrenia polygenic risk scores (PRS) were associated with oculomotor performance in the general population. There are many SNPs that do not reach the genome-wide significant threshold in a GWAS (5 × 10−8) but that could explain in sum a substantial proportion of genetic variance (International Schizophrenia Consortium, 2009). Another reason for this may be that schizophrenia is highly heterogeneous and encompasses a multitude of different syndromes that do not necessarily have a common biological basis (Braff, Freedman, Schork, & Gottesman, 2007)
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