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.Key words: schizophrenia, psychosis, endophenotypes, cognition, biomarkers, heritability相似文献
We evaluated the discrepancy of endophenotypic performance between probands with schizophrenia and unaffected siblings by paternal age at proband birth, a possible marker for de novo mutations. Pairs of schizophrenia probands and unaffected siblings (N=220 pairs) were evaluated on 11 neuropsychological or neurophysiological endophenotypes previously identified as heritable. For each endophenotype, the sibling-minus-proband differences were transformed to standardized scores. Then for each pair, the average discrepancy was calculated from its standardized scores. We tested the hypothesis that the discrepancy is associated with paternal age, controlling for the number of endophenotypes shared between proband and his or her sibling, and proband age, which were both associated with paternal age. The non-significant association between the discrepancy and paternal age was in the opposite direction from the hypothesis. Of the 11 endophenotypes only sensori-motor dexterity was significant, but in the opposite direction. Eight other endophenotypes were also in the opposite direction, but not significant. The results did not support the hypothesized association of increased differences between sibling/proband pairs with greater paternal age. A possible explanation is that the identification of heritable endophenotypes was based on samples for which schizophrenia was attributable to inherited rather than de novo/non-inherited causes. 相似文献
Mutations in the beta-myosin heavy chain gene are believed to cause hypertrophic cardiomyopathy (HCM) by acting as dominant negative alleles. In contrast, a truncated cardiac troponin T (TnT) that causes HCM implies that altered stoichiometry of contractile proteins may also cause cardiac hypertrophy. Wild-type and HCM-mutant (truncated) TnT were studied in a novel quail myotube expression system. Unexpectedly, antibody staining demonstrated incorporation of both forms of human cardiac TnT into the sarcomeres of quail myotubes. Functional studies of wild type and mutant transfected myotubes of normal appearance revealed that calcium-activated force of contraction was normal upon incorporation of wild type TnT, but greatly diminished for the mutant TnT. These findings indicate that HCM-causing mutations in TnT and beta-myosin heavy chain share abnormalities in common, acting as dominant negative alleles that impair contractile performance. This diminished force output is the likely stimulus for hypertrophy in the human heart. 相似文献
Bullying is associated with a heightened risk for poor outcomes, including psychosis. This study aimed to replicate previous findings on bullying prevalence in clinical high-risk (CHR) individuals, to assess the longitudinal course of clinical and functional variables between bullied and non-bullied CHR and the association of bullying with premorbid functioning, clinical outcome, transition to psychosis and risk of violence.
Methods
The sample consisted of 691 CHR participants and 96 healthy controls. Participants reported whether they had experienced bullying and how long it had lasted. Assessments included DSM-5 diagnoses, attenuated psychotic symptoms, negative symptoms, social and role functioning, depression, stress, premorbid functioning, and risk of violence. The bullied and non-bullied CHR groups were compared at baseline and further longitudinally on clinical and functioning variables and transition to psychosis.
Results
Bullying was more prevalent among CHR individuals than healthy controls. Bullied CHR had a higher prevalence of PTSD and more severe depression and stress at baseline than non-bullied CHR. There was no impact of bullying on clinical and functional variables over time. Bullying was not related to final clinical status or transition to psychosis. However, bullied participants had poorer premorbid functioning and a greater risk of violence.
Conclusion
While bullying may not impact the likelihood of CHR individuals to transition to psychosis, it may be a risk factor for development of the at-risk state and may be related to a greater risk of violence. Future studies should consider bullying perpetration among CHR individuals.
Cardiac hypertrophy, either compensated or decompensated, is associated with cardiomyocyte contractile dysfunction from depressed sarcoplasmic reticulum (SR) Ca(2+) cycling. Normalization of Ca(2+) cycling by ablation or inhibition of the SR inhibitor phospholamban (PLN) has prevented cardiac failure in experimental dilated cardiomyopathy and is a promising therapeutic approach for human heart failure. However, the potential benefits of restoring SR function on primary cardiac hypertrophy, a common antecedent of human heart failure, are unknown. We therefore tested the efficacy of PLN ablation to correct hypertrophy and contractile dysfunction in two well-characterized and highly relevant genetic mouse models of hypertrophy and cardiac failure, Galphaq overexpression and human familial hypertrophic cardiomyopathy mutant myosin binding protein C (MyBP-C(MUT)) expression. In both models, PLN ablation normalized the characteristically prolonged cardiomyocyte Ca(2+) transients and enhanced unloaded fractional shortening with no change in SR Ca(2+) pump content. However, there was no parallel improvement in in vivo cardiac function or hypertrophy in either model. Likewise, the activation of JNK and calcineurin associated with Galphaq overexpression was not affected. Thus, PLN ablation normalized contractility in isolated myocytes, but failed to rescue the cardiomyopathic phenotype elicited by activation of the Galphaq pathway or MyBP-C mutations. 相似文献