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1.
World Psychiatry. 2008 Feb;7(1):11-8.

Advances in endophenotyping schizophrenia.

Author information

1
Department of Psychiatry, University of California at San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0804, USA.

Abstract

The search for the genetic architecture of schizophrenia has employed multiple, often converging strategies. One such strategy entails the use of tracing the heritability and neurobiology of endophenotypes. Endophenotypes are quantifiable traits not visible to the eye, which are thought to reflect an intermediate place on the path from genes to disorder. Endophenotype abnormalities in domains such as neurophysiology or neurocognition occur in schizophrenia patients as well as their clinically "unaffected" relatives, and reflect polymorphisms in the DNA of schizophrenia spectrum subjects which create vulnerability to developing schizophrenia. By identifying the single nucleotide polymorphisms (SNPs) associated with endophenotypes in schizophrenia, psychiatric neuroscientists can select new strong inference based molecular targets for the treatment of schizophrenia.

KEYWORDS:

Schizophrenia; endophenotypes; neurocognition; neurophysiology; vulnerability genes

3.
Schizophr Bull. 2007 Jan;33(1):33-48. Epub 2006 Oct 11.

The Consortium on the Genetics of Endophenotypes in Schizophrenia: model recruitment, assessment, and endophenotyping methods for a multisite collaboration.

Author information

1
Neuropsychiatry Section, Department of Psychiatry, University of Pennsylvania, 10 Gates, 3400 Spruce St, Philadelphia, PA 19104, USA. mcalkins@bbl.med.upenn.edu

Abstract

BACKGROUND:

The Consortium on the Genetics of Schizophrenia (COGS) is an ongoing, National Institute of Mental Health-funded, 7-site collaboration investigating the occurrence and genetic architecture of quantitative endophenotypes related to schizophrenia. The purpose of this article is to provide a description of the COGS structure and methods, including participant recruitment and assessment.

METHODS:

The hypothesis-driven recruitment strategy ascertains families that include a proband with a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition diagnosis of schizophrenia, and at least one unaffected full sibling available for genotyping and endophenotyping, along with parents available for genotyping and (optional depending on age) endophenotyping. The family structure is selected to provide contrast in quantitative endophenotypic traits and thus to maximize the power of the planned genetic analyses. Probands are recruited from many sources including clinician referrals, local National Alliance for the Mentally Ill chapters, and advertising via the media. All participants undergo a standardized protocol that includes clinical characterization, a blood draw for genotyping, and endophenotype assessments (P50 suppression, prepulse inhibition, antisaccade performance, continuous performance tasks, letter-number span, verbal memory, and a computerized neurocognitive battery). Investigators participate in weekly teleconferences to coordinate and evaluate recruitment, clinical assessment, endophenotyping, and continuous quality control of data gathering and analyses. Data integrity is maintained through use of a highly quality-assured, centralized web-based database.

RESULTS:

As of February 2006, 355 families have been enrolled and 688 participants have been endophenotyped, including schizophrenia probands (n = 154, M:F = 110:44), first-degree biological relatives (n = 343, M:F = 151:192), and community comparison subjects (n = 191, M:F = 81:110).

DISCUSSION:

Successful multisite genetics collaborations must institute standardized methodological criteria for assessment and recruitment that are clearly defined, well communicated, and uniformly applied. In parallel, studies utilizing endophenotypes require strict adherence to criteria for cross-site data acquisition, equipment calibration and testing and software equivalence, and continuous quality assurance for many measures obtained across sites. This report describes methods and presents the structure of the COGS as a model of multisite endophenotype genetic studies. It also provides demographic information after the first 2 years of data collection on a sample for whom the behavioral data and genetics of endophenotype performance will be fully characterized in future articles. Some issues discussed in the reviews that follow reflect the challenges of evaluating endophenotypes in studies of the genetic architecture of endophenotypes in schizophrenia.

PMID:
17035358
PMCID:
PMC2632302
DOI:
10.1093/schbul/sbl044
[Indexed for MEDLINE]
Free PMC Article
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4.
Schizophr Res. 2002 Mar 1;54(1-2):47-57.

Endophenotyping schizotypy: a prelude to genetic studies within the schizophrenia spectrum.

Author information

1
Department of Psychiatry, University of California-San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0804, USA.

Abstract

Schizophrenia is a complex genetic disease with a prevalence rate of 1% in the general population. Schizotypal personality disorder (SPD) occurs in up to 3% of the population, and these subjects are phenomenologically and perhaps genotypically related to schizophrenia. The diagnosis of SPD was empirically derived based on the symptoms of individuals with a genetic relationship to schizophrenia patients and SPD may be a more common phenotypic expression of a schizophrenia-related diathesis than is schizophrenia itself. Family-genetic studies have determined that (1) relatives of schizophrenic patients have an increased risk of SPD and (2) relatives of SPD subjects have increased the rates of both schizophrenia and SPD. Because SPD subjects do not typically have the confounding effects of a chronic illness, long-term hospitalization or chronic neuroleptic treatment, they are ideal for the study of the proposed trait-related vulnerability markers in schizophrenia spectrum individuals. The study of vulnerability markers in SPD subjects has become increasingly important because it provides a means of assessing phenotypic traits that may not be evident clinically. By combining multiple inhibitory/gating information processing measures, it may be possible to identify a subgroup of SPD subjects with multiple inhibitory deficits who are phenotypically most similar to patients with schizophrenia. Composite phenotypes can also be developed, which increase the probability of identifying the complex genetic architecture of schizophrenia spectrum disorders, which interact with nongenetic protective and exacerbating factors.

PMID:
11853978
[Indexed for MEDLINE]
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