Heritability and molecular genetic basis of antisaccade eye tracking error rate: A genome‐wide association study

The hunt for endophenotypes that may index the genetic liability for mental disorders is currently of great interest in psychology and psychiatry. Nowhere is this search more marked than schizophrenia, and with good reason given its high heritability and the significant public health impact associated with its often-chronic course and consequent psychosocial debilitation. Indeed, countless studies have been published documenting various deleterious outcomes associated with schizophrenia such as developmental abnormalities, impaired role functioning, cognitive deficits, and deviations in brain structure and processes. More recently, stimulated by progress stemming from the human genome project, scientists have applied new, potentially powerful molecular genetic strategies to identify genetic variants underpinning schizophrenia. While some intriguing results have been published (e.g., Greenwood et al., 2013; Smoller et al., 2013), much work is needed to flesh out the genetic influence on schizophrenia. Of considerable interest is what additional etiological insights might be gained by examining the molecular genetic basis of associated psychophysiological measures that appear to tap into the genetic liability for schizophrenia. Indeed, there have already been notable attempts along these lines (e.g., Consortium on the Genetics of Schizophrenia [COGS]; Greenwood et al., 2011) using candidate gene and whole genome linkage studies (Greenwood et al., 2011, 2013), as well as initiatives that provide the stimulus for such research (e.g., Research Domain Criteria [RDoC]; Insel et al., 2010). However, genome-wide association studies (GWAS) of schizophrenia-related endophenotypes represent an underexploited opportunity to identify genetic variants linked to the disorder. This is due in part to the difficulty in collecting laboratory data from the large sample sizes required for genetic analyses. However, it remains unclear how large such samples need to be. Because endophenotypes are linked to brain processes that are posited to be more proximal to the effects of genes influencing psychopathology, there is a priori reason to believe that the effects of genetic variants may be detectable using samples considerably smaller than those used in GWAS with clinical diagnostic phenotypes (for examples, see the concluding comments in Iacono, Malone, Vaidyanathan, & Vrieze, 2014). Among the various criteria proposed for endophenotypes, of particular importance is evidence of stability over time, heritability, cosegregation with the illness, appearance in unaffected relatives, and ability to predict the development of disorder in longitudinal research (Braff et al., 2008; Gottesman & Gould, 2003; Iacono, 1985; Iacono & Malone, 2011)—which several psychophysiological indices satisfy easily. Thus, a GWAS of endophenotypes seems an appropriate next step in attempting to understand potential causal factors implicated in mental disorders. Here, we take this next step by testing one schizophrenia-related endophenotype—antisaccade error—using GWAS methodology in a community-based sample of 4,469 individuals. In the antisaccade task, subjects are required to suppress the natural tendency to direct their gaze in pursuit of a centered fixation stimulus that appears to move abruptly to the right or left of their visual field. Their task is to inhibit the natural tendency to generate prosaccades towards the target while directing their gaze in the opposite direction (producing an antisaccade). The subject thus has to suppress a prepotent response and make an appropriate eye movement in the opposite direction. The inability to suppress this response is posited to be an indicator of deficits in executive control (Munoz & Everling, 2004).