Neurobiological deficits that serve as informative endophenotype markers have been demonstrated in schizophrenia by a number of different paradigms. Neurophysiological deficits are prominent in P50 event related suppression, prepulse inhibition (PPI) of the startle response, and the antisaccade (AS) task for eye movement dysfunction. Neurocognitive deficits in schizophrenia are revealed by poor performance on the CPT, verbal memory, and tests of working memory. Each of these deficits has also been demonstrated in clinically unaffected relatives of schizophrenia patients, which is evidence that they may reflect part of the heritable risk for the illness. This conclusion is reinforced by findings of deficits in non-psychotic, unmedicated schizophrenia patients, and schizotypal patients. The null hypothesis is that all 6 deficits reflect a single, common underlying heritable dysfunction in all schizophrenia patients. A test of that hypothesis requires measurement of all of these deficits in the same group of schizophrenia patient probands and their relatives. If they are all manifestations of the same genetic dysfunction (although perhaps expressed in different brain areas), then a multivariate analysis would show that they all contribute to a single dimension in both relatives and schizophrenia patients. An alternative hypothesis is that only one or a small subset of deficits is present in each family, which is consistent with the heterogeneity found in current genetic linkage studies. In that case, the multivariate analysis would show the different measures or subsets of them loading onto different dimensions. Schizophrenia itself is likely to be the result of multiple deficits in any individual. Therefore, the analysis is performed in the same cohort of schizophrenia patient probands and their relatives to take advantage of Mendel's second law, which holds that genetically independent deficits segregate independently. Hence, although schizophrenia patient probands themselves have multiple deficits, if the deficits are caused by different genetic factors, then they will segregate to different groups of relatives. This 7 site collaborative RO1 project will gather a combined total of 420 pedigrees (1680 subjects) and 525 normal subjects over 5 years (each site will contribute 1/7th of these totals). Findings of heritable deficits in specific measures will be used to guide the next generation of studies of the genetics of schizophrenia.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-GNM (02))
Program Officer
Lehner, Thomas
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Washington
Schools of Medicine
United States
Zip Code
Swerdlow, Neal R; Light, Gregory A; Thomas, Michael L et al. (2018) Deficient prepulse inhibition in schizophrenia in a multi-site cohort: Internal replication and extension. Schizophr Res 198:6-15
Thomas, Michael L; Green, Michael F; Hellemann, Gerhard et al. (2017) Modeling Deficits From Early Auditory Information Processing to Psychosocial Functioning in Schizophrenia. JAMA Psychiatry 74:37-46
Millard, Steven P; Shofer, Jane; Braff, David et al. (2016) Prioritizing schizophrenia endophenotypes for future genetic studies: An example using data from the COGS-1 family study. Schizophr Res 174:1-9
Greenwood, Tiffany A; Light, Gregory A; Swerdlow, Neal R et al. (2016) Gating Deficit Heritability and Correlation With Increased Clinical Severity in Schizophrenia Patients With Positive Family History. Am J Psychiatry 173:385-91
Greenwood, Tiffany A; Lazzeroni, Laura C; Calkins, Monica E et al. (2016) Genetic assessment of additional endophenotypes from the Consortium on the Genetics of Schizophrenia Family Study. Schizophr Res 170:30-40
Light, Gregory A; Swerdlow, Neal R; Thomas, Michael L et al. (2015) Validation of mismatch negativity and P3a for use in multi-site studies of schizophrenia: characterization of demographic, clinical, cognitive, and functional correlates in COGS-2. Schizophr Res 163:63-72
Stone, William S; Mesholam-Gately, Raquelle I; Braff, David L et al. (2015) California Verbal Learning Test-II performance in schizophrenia as a function of ascertainment strategy: comparing the first and second phases of the Consortium on the Genetics of Schizophrenia (COGS). Schizophr Res 163:32-7
Radant, Allen D; Millard, Steven P; Braff, David L et al. (2015) Robust differences in antisaccade performance exist between COGS schizophrenia cases and controls regardless of recruitment strategies. Schizophr Res 163:47-52
Turetsky, Bruce I; Dress, Erich M; Braff, David L et al. (2015) The utility of P300 as a schizophrenia endophenotype and predictive biomarker: clinical and socio-demographic modulators in COGS-2. Schizophr Res 163:53-62
Seidman, Larry J; Hellemann, Gerhard; Nuechterlein, Keith H et al. (2015) Factor structure and heritability of endophenotypes in schizophrenia: findings from the Consortium on the Genetics of Schizophrenia (COGS-1). Schizophr Res 163:73-9

Showing the most recent 10 out of 36 publications