The Consortium on the Genetics of Schizophrenia (COGS-2) is a 6-site collaborative linked R01 study that aims to understand the genetic architecture of functionally important quantitative neurophysiological and neurocognitive endophenotypes and the qualitative phenotype of schizophrenia in 2,000 patients and 1,000 community comparison subjects (CCS). During the initial support period, the COGS-1 project developed a robust research platform for subject recruitment, careful clinical characterization, acquisition, quality assurance, and analysis of these endophenotypes in probands (N=305), clinically unaffected family members (N=1,014) and CCS (N=505). In addition, COGS-1 developed novel statistical genetics methods that take full advantage of the unique findings that have emerged to date. The COGS-2 renewal will extend the use of the original 3 neurophysiological and 3 neurocognitive endophenotypes, as well as additional heritable endophenotypes derived from COGS-1 using the Computerized Neurocognitive Battery (CNB). Given the increased importance of the relationship of these endophenotypes to functional outcome, COGS-2 will also add a functional status assessment battery, consisting of observer-based, surrogate and real-world functional status. COGS-2 will complete the originally proposed linkage analysis in the COGS-1 sample, as well as conduct a candidate gene study from the COGS-1 database using the custom COGS 1536 SNP Chip. COGS-2 will focus on ascertaining, testing and obtaining DNA from new samples of 2,000 schizophrenia patients and 1,000 CCS recruited via Specific Aim 1.
In Specific Aim 2, a genome wide association study (GWAS) using the current and most informative platform at the Center for Inherited Disease Research (CIDR) will be performed using the COGS-2 case-control data on the 9 COGS-2 quantitative endophenotypes and the qualitative diagnosis of schizophrenia. A complementary association study, using many strong-inference derived SNPs not included in the CIDR platform, will utilize the COGS SNP Chip array (94 candidate genes, 1536 SNPs) to assess SNP and copy-number variations (CNVs) associated with endophenotype deficits in schizophrenia as well as schizophrenia itself.
In Specific Aim 3, SNPs and CNVs associated with these endophenotypes and schizophrenia will be compared with those in publicly available databases (e.g., GAIN, CATIE, BROAD). Furthermore, we will continue to develop the COGS platform and related innovative statistical genetics methods to identify and interrogate crucial genetic data in order to enhance the search for schizophrenia vulnerability genes, enhance the endophenotype strategy and ultimately identify molecular targets for the treatment and improved function of schizophrenia patients.

Public Health Relevance

Schizophrenia is a devastating brain disorder that strikes young adults and carries with it a profound and devastating disease burden, often for the lifetime of the patient. The Consortium on the Genetics of Schizophrenia ("COGS-2") project entitled, "The Genetics of Endophenotypes and Schizophrenia", examines the genetic basis of impairments in core neurophysiological and neurocognitive processes in schizophrenia patients. Once we understand the genetic architecture of these abnormalities, new medications that aim to improve the functioning and quality of life of schizophrenia patients can be developed.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH065707-08
Application #
8220793
Study Section
Special Emphasis Panel (ZRG1-PSE-E (60))
Program Officer
Senthil, Geetha
Project Start
2003-05-01
Project End
2014-01-31
Budget Start
2012-02-01
Budget End
2013-01-31
Support Year
8
Fiscal Year
2012
Total Cost
$338,059
Indirect Cost
$69,758
Name
University of California Los Angeles
Department
None
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Horan, William P; Wynn, Jonathan K; Hajcak, Greg et al. (2016) Distinct patterns of dysfunctional appetitive and aversive motivation in bipolar disorder versus schizophrenia: An event-related potential study. J Abnorm Psychol 125:576-87
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
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
Wynn, Jonathan K; Roach, Brian J; Lee, Junghee et al. (2015) EEG findings of reduced neural synchronization during visual integration in schizophrenia. PLoS One 10:e0119849
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
Horan, William P; Reise, Steven P; Kern, Robert S et al. (2015) Structure and correlates of self-reported empathy in schizophrenia. J Psychiatr Res 66-67:60-6
Wynn, Jonathan K; Jimenez, Amy M; Roach, Brian J et al. (2015) Impaired target detection in schizophrenia and the ventral attentional network: Findings from a joint event-related potential-functional MRI analysis. Neuroimage Clin 9:95-102
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
Nuechterlein, Keith H; Green, Michael F; Calkins, Monica E et al. (2015) Attention/vigilance in schizophrenia: performance results from a large multi-site study of the Consortium on the Genetics of Schizophrenia (COGS). Schizophr Res 163:38-46

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