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


CONCLUSIONS
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.
Calkins
Monica E
ME
Neuropsychiatry Section, Department of Psychiatry, University of Pennsylvania, 10 Gates, 3400 Spruce St, Philadelphia, PA 19104, USA. mcalkins@bbl.med.upenn.edu
Dobie
Dorcas J
DJ
Cadenhead
Kristin S
KS
Olincy
Ann
A
Freedman
Robert
R
Green
Michael F
MF
Greenwood
Tiffany A
TA
Gur
Raquel E
RE
Gur
Ruben C
RC
Light
Gregory A
GA
Mintz
Jim
J
Nuechterlein
Keith H
KH
Radant
Allen D
AD
Schork
Nicholas J
NJ
Seidman
Larry J
LJ
Siever
Larry J
LJ
Silverman
Jeremy M
JM
Stone
William S
WS
Swerdlow
Neal R
NR
Tsuang
Debby W
DW
Tsuang
Ming T
MT
Turetsky
Bruce I
BI
Braff
David L
DL
D003299:Cooperative Behavior; D003625:Data Collection; D036281:Genetic Research; D005838:Genotype; D006801:Humans; D008957:Models, Genetic; D015337:Multicenter Studies as Topic; D018579:Patient Selection; D010375:Pedigree; D010641:Phenotype; D012109:Research Support as Topic; D012559:Schizophrenia / Q000175:diagnosis / Q000235:genetics*; D035781:Siblings