title: Genetic assessment of additional endophenotypes from the Consortium on the Genetics of Schizophrenia Family Study.
abstract: The Consortium on the Genetics of Schizophrenia Family Study (COGS-1) has previously reported our efforts to characterize the genetic architecture of 12 primary endophenotypes for schizophrenia. We now report the characterization of 13 additional measures derived from the same endophenotype test paradigms in the COGS-1 families. Nine of the measures were found to discriminate between schizophrenia patients and controls, were significantly heritable (31 to 62%), and were sufficiently independent of previously assessed endophenotypes, demonstrating utility as additional endophenotypes. Genotyping via a custom array of 1536 SNPs from 94 candidate genes identified associations for CTNNA2, ERBB4, GRID1, GRID2, GRIK3, GRIK4, GRIN2B, NOS1AP, NRG1, and RELN across multiple endophenotypes. An experiment-wide p value of 0.003 suggested that the associations across all SNPs and endophenotypes collectively exceeded chance. Linkage analyses performed using a genome-wide SNP array further identified significant or suggestive linkage for six of the candidate endophenotypes, with several genes of interest located beneath the linkage peaks (e.g., CSMD1, DISC1, DLGAP2, GRIK2, GRIN3A, and SLC6A3). While the partial convergence of the association and linkage likely reflects differences in density of gene coverage provided by the distinct genotyping platforms, it is also likely an indication of the differential contribution of rare and common variants for some genes and methodological differences in detection ability. Still, many of the genes implicated by COGS through endophenotypes have been identified by independent studies of common, rare, and de novo variation in schizophrenia, all converging on a functional genetic network related to glutamatergic neurotransmission that warrants further investigation.
authors.affiliation: Department of Psychiatry, University of California San Diego, La Jolla, CA, United States. Electronic address: tgreenwood@ucsd.edu.
authors.forename: Tiffany A
authors.initials: TA
authors.lastname: Greenwood
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, United States.
authors.forename: Laura C
authors.initials: LC
authors.lastname: Lazzeroni
authors.affiliation: Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, United States.
authors.forename: Monica E
authors.initials: ME
authors.lastname: Calkins
authors.affiliation: Department of Psychiatry, University of Colorado Health Sciences Center, Denver, CO, United States.
authors.forename: Robert
authors.initials: R
authors.lastname: Freedman
authors.affiliation: Department of Psychiatry and Biobehavioral Sciences, University of California Los Angeles, Los Angeles, CA, United States; VA Greater Los Angeles Healthcare System, Los Angeles, CA, United States.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Green
authors.affiliation: Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, United States.
authors.forename: Raquel E
authors.initials: RE
authors.lastname: Gur
authors.affiliation: Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, United States.
authors.forename: Ruben C
authors.initials: RC
authors.lastname: Gur
authors.affiliation: Department of Psychiatry, University of California San Diego, La Jolla, CA, United States; VISN-22 Mental Illness, Research, Education and Clinical Center (MIRECC), VA San Diego Healthcare System, United States.
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Light
authors.affiliation: Department of Psychiatry and Biobehavioral Sciences, University of California Los Angeles, Los Angeles, CA, United States.
authors.forename: Keith H
authors.initials: KH
authors.lastname: Nuechterlein
authors.affiliation: Department of Psychiatry, University of Colorado Health Sciences Center, Denver, CO, United States.
authors.forename: Ann
authors.initials: A
authors.lastname: Olincy
authors.affiliation: Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, United States; VA Puget Sound Health Care System, Seattle, WA, United States.
authors.forename: Allen D
authors.initials: AD
authors.lastname: Radant
authors.affiliation: Department of Psychiatry, Harvard Medical School, Boston, MA, United States; Massachusetts Mental Health Center Public Psychiatry Division of the Beth Israel Deaconess Medical Center, Boston, MA, United States.
authors.forename: Larry J
authors.initials: LJ
authors.lastname: Seidman
authors.affiliation: Department of Psychiatry, The Mount Sinai School of Medicine, New York, NY, United States; James J. Peters VA Medical Center, New York, NY, United States.
authors.forename: Larry J
authors.initials: LJ
authors.lastname: Siever
authors.affiliation: Department of Psychiatry, The Mount Sinai School of Medicine, New York, NY, United States; James J. Peters VA Medical Center, New York, NY, United States.
authors.forename: Jeremy M
authors.initials: JM
authors.lastname: Silverman
authors.affiliation: Department of Psychiatry, Harvard Medical School, Boston, MA, United States; Massachusetts Mental Health Center Public Psychiatry Division of the Beth Israel Deaconess Medical Center, Boston, MA, United States.
authors.forename: William S
authors.initials: WS
authors.lastname: Stone
authors.affiliation: Department of Biostatistics, University of California Los Angeles School of Public Health, Los Angeles, CA, United States.
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Sugar
authors.affiliation: Department of Psychiatry, University of California San Diego, La Jolla, CA, United States.
authors.forename: Neal R
authors.initials: NR
authors.lastname: Swerdlow
authors.affiliation: Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, United States; VA Puget Sound Health Care System, Seattle, WA, United States.
authors.forename: Debby W
authors.initials: DW
authors.lastname: Tsuang
authors.affiliation: Department of Psychiatry, University of California San Diego, La Jolla, CA, United States; Center for Behavioral Genomics, Institute for Genomic Medicine, University of California San Diego, La Jolla, CA, United States; Harvard Institute of Psychiatric Epidemiology and Genetics, Boston, MA, United States.
authors.forename: Ming T
authors.initials: MT
authors.lastname: Tsuang
authors.affiliation: Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, United States.
authors.forename: Bruce I
authors.initials: BI
authors.lastname: Turetsky
authors.affiliation: Department of Psychiatry, University of California San Diego, La Jolla, CA, United States; VISN-22 Mental Illness, Research, Education and Clinical Center (MIRECC), VA San Diego Healthcare System, United States.
authors.forename: David L
authors.initials: DL
authors.lastname: Braff
mesh_terms: D058068:Endophenotypes; D005190:Family; D020022:Genetic Predisposition to Disease; D006801:Humans; D000091042:Reelin Protein; D012559:Schizophrenia / Q000235:genetics* / Q000503:physiopathology*
keywords: Association; Endophenotype; Genetics; Heritability; Linkage; Schizophrenia