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Comparison of the heritability of schizophrenia and endophenotypes in the COGS-1 family study.
- Calkins, Monica;
- Freedman, Robert;
- Green, Michael;
- Gur, Raquel;
- Gur, Ruben;
- Lazzeroni, Laura;
- Nuechterlein, Keith;
- Olincy, Ann;
- Radant, Allen;
- Seidman, Larry;
- Siever, Larry;
- Silverman, Jeremy;
- Sprock, Joyce;
- Stone, William;
- Sugar, Catherine;
- Tsuang, Debby;
- Greenwood, Tiffany;
- Turetsky, Bruce;
- Braff, David;
- Light, Gregory;
- Swerdlow, Neal;
- Tsuang, Ming
Published Web Location
https://doi.org/10.1093/schbul/sbu064Abstract
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.
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