title: Comparison of the heritability of schizophrenia and endophenotypes in the COGS-1 family study.
abstract: BACKGROUND
  Twin and multiplex family studies have established significant heritability for schizophrenia (SZ), often summarized as 81%. The Consortium on the Genetics of Schizophrenia (COGS-1) family study was designed to deconstruct the genetic architecture of SZ using neurocognitive and neurophysiological endophenotypes, for which heritability estimates ranged from 18% to 50% (mean = 30%). This study assessed the heritability of SZ in these families to determine whether there is a "heritability gap" between the diagnosis and related endophenotypes.
  
  
  METHODS
  Nuclear families (N = 296) with a SZ proband, an unaffected sibling, and both parents (n = 1366 subjects; mean family size = 4.6) underwent comprehensive endophenotype and clinical characterization. The Family Interview for Genetic Studies was administered to all participants and used to obtain convergent psychiatric symptom information for additional first-degree relatives of interviewed subjects (N = 3304 subjects; mean family size = 11.2). Heritability estimates of psychotic disorders were computed for both nuclear and extended families.
  
  
  RESULTS
  The heritability of SZ was 31% and 44% for nuclear and extended families. The inclusion of bipolar disorder increased the heritability to 37% for the nuclear families. When major depression was added, heritability estimates dropped to 34% and 20% for nuclear and extended families, respectively.
  
  
  CONCLUSIONS
  Endophenotypes and psychotic disorders exhibit comparable levels of heritability in the COGS-1 family sample. The ascertainment of families with discordant sibpairs to increase endophenotypic contrast may underestimate diagnostic heritability relative to other studies. However, population-based studies also report significantly lower heritability estimates for SZ. Collectively, these findings support the importance of endophenotype-based strategies and the dimensional view of psychosis.
authors.affiliation: Department of Psychiatry, University of California San Diego, La Jolla, CA; VISN-22 Mental Illness, Research, Education and Clinical Center, San Diego Healthcare System La Jolla, CA; glight@ucsd.edu.
authors.forename: Gregory
authors.initials: G
authors.lastname: Light
authors.affiliation: Department of Psychiatry, University of California San Diego, La Jolla, CA;
authors.forename: Tiffany A
authors.initials: TA
authors.lastname: Greenwood
authors.affiliation: Department of Psychiatry, University of California San Diego, La Jolla, CA;
authors.forename: Neal R
authors.initials: NR
authors.lastname: Swerdlow
authors.affiliation: Department of Psychiatry, University of Pennsylvania, Philadelphia, PA;
authors.forename: Monica E
authors.initials: ME
authors.lastname: Calkins
authors.affiliation: Department of Psychiatry, University of Colorado Health Sciences Center, Denver, CO;
authors.forename: Robert
authors.initials: R
authors.lastname: Freedman
authors.affiliation: Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, CA; VA Greater Los Angeles Healthcare System, Los Angeles, CA;
authors.forename: Michael F
authors.initials: MF
authors.lastname: Green
authors.affiliation: Department of Psychiatry, University of Pennsylvania, Philadelphia, PA;
authors.forename: Raquel E
authors.initials: RE
authors.lastname: Gur
authors.affiliation: Department of Psychiatry, University of Pennsylvania, Philadelphia, PA;
authors.forename: Ruben C
authors.initials: RC
authors.lastname: Gur
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA;
authors.forename: Laura C
authors.initials: LC
authors.lastname: Lazzeroni
authors.affiliation: Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, CA;
authors.forename: Keith H
authors.initials: KH
authors.lastname: Nuechterlein
authors.affiliation: Department of Psychiatry, University of Colorado Health Sciences Center, Denver, CO;
authors.forename: Ann
authors.initials: A
authors.lastname: Olincy
authors.affiliation: Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA; VA Puget Sound Health Care System, Seattle, WA;
authors.forename: Allen D
authors.initials: AD
authors.lastname: Radant
authors.affiliation: Department of Psychiatry, Harvard Medical School, Boston, MA; Massachusetts Mental Health Center Public Psychiatry, Division of the Beth Israel Deaconess Medical Center, Boston, MA;
authors.forename: Larry J
authors.initials: LJ
authors.lastname: Seidman
authors.affiliation: Department of Psychiatry, Mount Sinai School of Medicine, New York, NY; James J. Peters VA Medical Center, New York, NY;
authors.forename: Larry J
authors.initials: LJ
authors.lastname: Siever
authors.affiliation: Department of Psychiatry, Mount Sinai School of Medicine, New York, NY; James J. Peters VA Medical Center, New York, NY;
authors.forename: Jeremy M
authors.initials: JM
authors.lastname: Silverman
authors.affiliation: Department of Psychiatry, University of California San Diego, La Jolla, CA;
authors.forename: Joyce
authors.initials: J
authors.lastname: Sprock
authors.affiliation: Department of Psychiatry, Harvard Medical School, Boston, MA; Massachusetts Mental Health Center Public Psychiatry, Division of the Beth Israel Deaconess Medical Center, Boston, MA;
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;
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Sugar
authors.affiliation: Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA; VA Puget Sound Health Care System, Seattle, WA;
authors.forename: Debby W
authors.initials: DW
authors.lastname: Tsuang
authors.affiliation: Department of Psychiatry, University of California San Diego, La Jolla, CA; Center for Behavioral Genomics, Institute for Genomic Medicine, University of California San Diego, La Jolla, CA; Harvard Institute of Psychiatric Epidemiology and Genetics, Boston, MA.
authors.forename: Ming T
authors.initials: MT
authors.lastname: Tsuang
authors.affiliation: Department of Psychiatry, University of Pennsylvania, Philadelphia, PA;
authors.forename: Bruce I
authors.initials: BI
authors.lastname: Turetsky
authors.affiliation: Department of Psychiatry, University of California San Diego, La Jolla, CA;
authors.forename: David L
authors.initials: DL
authors.lastname: Braff
mesh_terms: D000328:Adult; D058068:Endophenotypes; D005190:Family; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009679:Nuclear Family; D011618:Psychotic Disorders / Q000235:genetics* / Q000503:physiopathology; D012559:Schizophrenia / Q000235:genetics* / Q000503:physiopathology
keywords: biomarkers; cognition; endophenotypes; heritability; psychosis; schizophrenia