Gregory Light1, Tiffany A Greenwood2, Neal R Swerdlow2, Monica E Calkins3, Robert Freedman4, Michael F Green5, Raquel E Gur3, Ruben C Gur3, Laura C Lazzeroni6, Keith H Nuechterlein7, Ann Olincy4, Allen D Radant8, Larry J Seidman9, Larry J Siever10, Jeremy M Silverman10, Joyce Sprock2, William S Stone9, Catherine A Sugar11, Debby W Tsuang8, Ming T Tsuang12, Bruce I Turetsky3, David L Braff2. 1. 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. 2. Department of Psychiatry, University of California San Diego, La Jolla, CA; 3. Department of Psychiatry, University of Pennsylvania, Philadelphia, PA; 4. Department of Psychiatry, University of Colorado Health Sciences Center, Denver, CO; 5. Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, CA; VA Greater Los Angeles Healthcare System, Los Angeles, CA; 6. Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA; 7. Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, CA; 8. Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA; VA Puget Sound Health Care System, Seattle, WA; 9. Department of Psychiatry, Harvard Medical School, Boston, MA; Massachusetts Mental Health Center Public Psychiatry, Division of the Beth Israel Deaconess Medical Center, Boston, MA; 10. Department of Psychiatry, Mount Sinai School of Medicine, New York, NY; James J. Peters VA Medical Center, New York, NY; 11. Department of Biostatistics, University of California, Los Angeles School of Public Health, Los Angeles, CA; 12. 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.
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. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center 2014.
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. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center 2014.
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