Antisaccade performance in schizophrenia patients, their first-degree biological relatives, and community comparison subjects: data from the COGS study.

The antisaccade task is a widely used technique to measure failure of inhibition, an important cause of cognitive and clinical abnormalities found in schizophrenia. Although antisaccade performance, which reflects the ability to inhibit prepotent responses, is a putative schizophrenia endophenotype, researchers have not consistently reported the expected differences between first-degree relatives and comparison groups. Schizophrenia participants (n=219) from the large Consortium on the Genetics of Schizophrenia (COGS) sample (n=1078) demonstrated significant deficits on an overlap version of the antisaccade task compared to their first-degree relatives (n=443) and community comparison subjects (CCS; n=416). Although mean antisaccade performance of first-degree relatives was intermediate between schizophrenia participants and CCS, a linear mixed-effects model adjusting for group, site, age, and gender found no significant performance differences between the first-degree relatives and CCS. However, admixture analyses showed that two components best explained the distributions in all three groups, suggesting two distinct doses of an etiological factor. Given the significant heritability of antisaccade performance, the effects of a genetic polymorphism is one possible explanation of our results.

[1]  Benedikt Reuter,et al.  Distinct Neural Correlates for Volitional Generation and Inhibition of Saccades , 2010, Journal of Cognitive Neuroscience.

[2]  D. Bates,et al.  Mixed-Effects Models in S and S-PLUS , 2001 .

[3]  P. Michie,et al.  A Multivariate Electrophysiological Endophenotype, from a Unitary Cohort, Shows Greater Research Utility than Any Single Feature in the Western Australian Family Study of Schizophrenia , 2006, Biological Psychiatry.

[4]  S. Dollfus,et al.  Are eye movement abnormalities indicators of genetic vulnerability to schizophrenia? , 2005, European psychiatry.

[5]  S Zisook,et al.  Saccadic system functioning among schizophrenia patients and their first-degree biological relatives. , 1994, Journal of abnormal psychology.

[6]  B. Clementz,et al.  Neurophysiology and neuroanatomy of reflexive and volitional saccades: Evidence from studies of humans , 2008, Brain and Cognition.

[7]  J. Daléry,et al.  Poor performance in smooth pursuit and antisaccadic eye-movement tasks in healthy siblings of patients with schizophrenia , 2001, Psychiatry Research.

[8]  G. A. Miller,et al.  Misunderstanding analysis of covariance. , 2001, Journal of abnormal psychology.

[9]  I. Gottesman,et al.  The endophenotype concept in psychiatry: etymology and strategic intentions. , 2003, The American journal of psychiatry.

[10]  R. Freedman,et al.  Admixture analysis of smooth pursuit eye movements in probands with schizophrenia and their relatives suggests gain and leading saccades are potential endophenotypes. , 2002, Psychophysiology.

[11]  P. Fitzgerald,et al.  The Relationship Between Cortical Inhibition, Antipsychotic Treatment, and the Symptoms of Schizophrenia , 2009, Biological Psychiatry.

[12]  Michael F. Green,et al.  Abnormal Auditory N100 Amplitude: A Heritable Endophenotype in First-Degree Relatives of Schizophrenia Probands , 2008, Biological Psychiatry.

[13]  David A. Lewis,et al.  Impaired prefrontal inhibition in schizophrenia: relevance for cognitive dysfunction , 2002, Physiology & Behavior.

[14]  S. Hutton,et al.  The antisaccade task as a research tool in psychopathology: a critical review. , 2006, Psychophysiology.

[15]  Michael F. Green,et al.  The Consortium on the Genetics of Endophenotypes in Schizophrenia: model recruitment, assessment, and endophenotyping methods for a multisite collaboration. , 2006, Schizophrenia bulletin.

[16]  R Freedman,et al.  Age Diminishes Performance on an Antisaccade Eye Movement Task , 1997, Neurobiology of Aging.

[17]  S. Barash,et al.  Switching of sensorimotor transformations: antisaccades and parietal cortex. , 2006, Novartis Foundation symposium.

[18]  P. E. Hallett,et al.  Primary and secondary saccades to goals defined by instructions , 1978, Vision Research.

[19]  Matti S. Hämäläinen,et al.  Where left becomes right: A magnetoencephalographic study of sensorimotor transformation for antisaccades , 2007, NeuroImage.

[20]  I. Gottesman,et al.  Psychiatric endophenotypes and the development of valid animal models , 2006, Genes, brain, and behavior.

[21]  N. Schork,et al.  Advances in endophenotyping schizophrenia , 2008, World psychiatry : official journal of the World Psychiatric Association.

[22]  M. Leboyer,et al.  Admixture analysis of age at onset in schizophrenia , 2004, Schizophrenia Research.

[23]  H. Coon,et al.  Linkage of a composite inhibitory phenotype to a chromosome 22q locus in eight Utah families. , 1999, American journal of medical genetics.

[24]  Philip D. Harvey,et al.  Is schizophrenia a syndrome of accelerated aging? , 2008, Schizophrenia bulletin.

[25]  Philip D. Harvey,et al.  Six-year follow-up study of cognitive and functional status across the lifespan in schizophrenia: a comparison with Alzheimer's disease and normal aging. , 2001, The American journal of psychiatry.

[26]  T. Sharma,et al.  Lack of association between prepulse inhibition and antisaccadic deficits in chronic schizophrenia: implications for identification of schizophrenia endophenotypes. , 2005, Journal of Psychiatric Research.

[27]  Clayton E. Curtis,et al.  Saccadic disinhibition in schizophrenia patients and their first-degree biological relatives , 2001, Experimental Brain Research.

[28]  R. Murray,et al.  Saccadic eye movements in families multiply affected with schizophrenia: the Maudsley Family Study. , 1998, The American journal of psychiatry.

[29]  Arthur Falek,et al.  Schizophrenia and genetics: A twin study vantage point. , 1976 .

[30]  Michael F. Green,et al.  Initial heritability analyses of endophenotypic measures for schizophrenia: the consortium on the genetics of schizophrenia. , 2007, Archives of general psychiatry.

[31]  P. Sachdev,et al.  Long-term outcome of late-onset schizophrenia: 5-year follow-up study , 2003, British Journal of Psychiatry.

[32]  S. Luck,et al.  The Construct of Attention in Schizophrenia , 2008, Biological Psychiatry.

[33]  R. Freedman,et al.  Familial transmission of two independent saccadic abnormalities in schizophrenia , 1998, Schizophrenia Research.

[34]  Jellinger Ka Dementia as a complication of schizophrenia , 2001 .

[35]  Robert Freedman,et al.  Deconstructing schizophrenia: an overview of the use of endophenotypes in order to understand a complex disorder. , 2006, Schizophrenia bulletin.

[36]  Paul Mitchell,et al.  Major genetic effects in glaucoma: commingling analysis of optic disc parameters in an older Australian population. , 2009, Investigative ophthalmology & visual science.

[37]  M. Leboyer,et al.  Admixture analysis of age at first suicide attempt. , 2009, Journal of psychiatric research.

[38]  Roderick J. A. Little,et al.  Statistical Analysis with Missing Data: Little/Statistical Analysis with Missing Data , 2002 .

[39]  Deniz S. Ones,et al.  Eye movement dysfunction in first-degree relatives of patients with schizophrenia: A meta-analytic evaluation of candidate endophenotypes , 2008, Brain and Cognition.

[40]  J. Nurnberger,et al.  Diagnostic interview for genetic studies. Rationale, unique features, and training. NIMH Genetics Initiative. , 1994, Archives of general psychiatry.

[41]  W. Berrettini Genetic bases for endophenotypes in psychiatric disorders , 2005, Dialogues in clinical neuroscience.

[42]  W M Grove,et al.  Saccadic disinhibition in patients with acute and remitted schizophrenia and their first-degree biological relatives. , 2001, The American journal of psychiatry.

[43]  A. Addington,et al.  The neurodevelopmental model of schizophrenia: update 2005 , 2005, Molecular Psychiatry.

[44]  W. Iacono,et al.  Error rate on the antisaccade task: heritability and developmental change in performance among preadolescent and late-adolescent female twin youth. , 2002, Psychophysiology.

[45]  S. Rabe-Hesketh,et al.  Smooth pursuit and antisaccade eye movements in siblings discordant for schizophrenia. , 2004, Journal of psychiatric research.

[46]  B. Turetsky,et al.  Neurophysiological endophenotypes of schizophrenia: the viability of selected candidate measures. , 2006, Schizophrenia bulletin.

[47]  D. Rubin,et al.  Statistical Analysis with Missing Data , 1988 .

[48]  Clayton E. Curtis,et al.  Antisaccade performance is impaired in medically and psychiatrically healthy biological relatives of schizophrenia patients , 2004, Schizophrenia Research.

[49]  R. Delorme,et al.  Admixture analysis of age at onset in obsessive–compulsive disorder , 2005, Psychological Medicine.

[50]  E. Sigurdsson,et al.  Investigation of a genetically homogenous Icelandic sample , 2008 .

[51]  T. Shinkai,et al.  Admixture analysis of Age at Onset in Schizophrenia: Genetic Association Study of 45 candidate loci , 2012, Schizophrenia Research.

[52]  S. Hutton Cognitive control of saccadic eye movements , 2008, Brain and Cognition.

[53]  H. Coon,et al.  Measuring liability for schizophrenia using optimized antisaccade stimulus parameters. , 1999, Psychophysiology.

[54]  S. Everling,et al.  The antisaccade: a review of basic research and clinical studies , 1998, Neuropsychologia.

[55]  Robert Freedman,et al.  The genetics of sensory gating deficits in schizophrenia , 2003, Current psychiatry reports.

[56]  B. Christensen,et al.  The role of cortical inhibition in the pathophysiology and treatment of schizophrenia , 2007, Brain Research Reviews.

[57]  J. Ott,et al.  Detection of rare major genes in lipid levels , 1979, Human Genetics.

[58]  G. Lettre,et al.  Genetic regulation of adult stature , 2009, Current opinion in pediatrics.

[59]  Daniel W. Hommer,et al.  A quantitative analysis of saccades and smooth pursuit during visual pursuit tracking A comparison of schizophrenics with normals and substance abusing controls , 1992, Schizophrenia Research.

[60]  Michael F. Green,et al.  Successful multi-site measurement of antisaccade performance deficits in schizophrenia , 2007, Schizophrenia Research.

[61]  Thomas Nyffeler,et al.  Inhibitory control of the human dorsolateral prefrontal cortex during the anti‐saccade paradigm − a transcranial magnetic stimulation study , 2007, The European journal of neuroscience.

[62]  Niels G. Waller The Scale for the Assessment of Negative Symptoms , 1995 .

[63]  Y. Friedlander,et al.  Inheritance of LDL peak particle diameter: Results from a segregation analysis in Israeli families , 1999, Genetic epidemiology.

[64]  Daniel R Weinberger,et al.  On the Plausibility of “The Neurodevelopmental Hypothesis” of Schizophrenia , 1996, Neuropsychopharmacology.

[65]  N. Mendell,et al.  Antisaccade performance in biological relatives of schizophrenia patients: a meta-analysis , 2004, Schizophrenia Research.

[66]  D. Ffytche,et al.  Decomposing the neural correlates of antisaccade eye movements using event-related FMRI. , 2008, Cerebral cortex.

[67]  C. Klein,et al.  The gap effect in pro-saccades and anti-saccades in psychometric schizotypes , 2000, Biological Psychology.

[68]  O. Krastoshevsky,et al.  Does performance on the standard antisaccade task meet the co-familiality criterion for an endophenotype? , 2008, Brain and Cognition.

[69]  C. Pierrot-Deseilligny,et al.  Decisional role of the dorsolateral prefrontal cortex in ocular motor behaviour. , 2003, Brain : a journal of neurology.