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Principal components of heritability from neurocognitive domains differ between families with schizophrenia and control subjects.

ABSTRACT: Various measures of neurocognitive function show mean differences among individuals with schizophrenia (SZ), their relatives, and population controls. We use eigenvector transformations that maximize heritability of multiple neurocognitive measures, namely principal components of heritability (PCH), and evaluate how they distribute in SZ families and controls.African-Americans with SZ or schizoaffective disorder (SZA) (n = 514), their relatives (n = 1092), and adult controls (n = 300) completed diagnostic interviews and computerized neurocognitive tests. PCH were estimated from 9 neurocognitive domains. Three PCH, PCH1-PCH3, were modeled to determine if status (SZ, relative, and control), other psychiatric covariates, and education were significant predictors of mean values. A small-scale linkage analysis was also conducted in a subset of the sample.PCH1, PCH2, and PCH3 account for 72% of the genetic variance. PCH1 represents 8 of 9 neurocognitive domains, is most highly correlated with spatial processing and emotion recognition, and has unadjusted heritability of 68%. The means for PCH1 differ significantly among SZ, their relatives, and controls. PCH2, orthogonal to PCH1, is most closely correlated with working memory and has an unadjusted heritability of 45%. Mean PCH2 is different only between SZ families and controls. PCH3 apparently represents a heritable component of neurocognition similar across the 3 diagnostic groups. No significant linkage evidence to PCH1-PCH3 or individual neurocognitive measures was discovered.PCH1 is highly heritable and genetically correlated with SZ. It should prove useful in future genetic analyses. Mean PCH2 differentiates SZ families and controls but not SZ and unaffected family members.

SUBMITTER: Wiener H

PROVIDER: S-EPMC3576168 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature

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Principal components of heritability from neurocognitive domains differ between families with schizophrenia and control subjects.

Wiener Howard H Klei Lambertus L Calkins Monica M Wood Joel J Nimgaonkar Vishwajit V Gur Ruben R Bradford L DiAnne LD Richard Jan J Edwards Neil N Savage Robert R Kwentus Joseph J Allen Trina T McEvoy Joseph J Santos Alberto A Gur Raquel R Devlin Bernie B Go Rodney R

Schizophrenia bulletin 20120110 2

<h4>Objective</h4>Various measures of neurocognitive function show mean differences among individuals with schizophrenia (SZ), their relatives, and population controls. We use eigenvector transformations that maximize heritability of multiple neurocognitive measures, namely principal components of heritability (PCH), and evaluate how they distribute in SZ families and controls.<h4>Methods</h4>African-Americans with SZ or schizoaffective disorder (SZA) (n = 514), their relatives (n = 1092), and a ...[more]

PMID: 22234486

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Project description:To decipher gene regulatory networks, we used systematic suppression of 97 transcription factors (TFs) and 7 other genes with shRNA in mouse embryonic stem (ES) cells, followed by global gene expression profiling. Meta-analysis of these data together with the earlier data obtained by the induction of 50 TFs and the existing genome-wide data on TF binding sites identified the sets of regulated target genes for 23 TFs. Principal component analysis shows different roles of two groups of TFs that are active in ES cells: Pou5f1 and Sox2 support the expression of their target genes and prevent the upregulation of trophectoderm-related genes, whereas Esrrb, Sall4, Nanog, Gbx2, Grhl2, Mtf2, Aff1, Tcfap4, and Cdc5l support the expression of targets of Esrrb, including glycolysis genes, and prevent upregulation of targets of Trp53 and Polycomb TFs. If TFs from the second group are downregulated while Pou5f1 and Sox2 are still active, then the cell state changes towards epiblast lineages. Sequences for shRNA were designed to target 3 untranslated region of genes (Supplementary Table S8). Gene expression change was checked with real time qPCR (Supplementary Figure S7) and Westerm blot. ES cells (ES[MC1R(20)], passage 20) were cultured without feeders and were co-transfected with 1.6 g of shRNA expression vector and 0.4 g of pPyCAG-EGFP-IP carrying expression cassettes for puromycin resistant genes and EGFP using Effectene (Qiagen). Transfected cells were cultured in presence of 1.5 g/ml of puromycin and were harvested at 72 h after transfection. Mock cells were treated with transfection reagent without DNA and cultured in the absence of puromycin. Experiments were done in 3 replications with 2 of them used for gene expression profiling with microarrays. Total RNA was isolated by TRIzol (Invitrogen) after 2 days. Cy3-CTP labeled sample targets were prepared with total RNA by Low RNA Input Fluorescent Linear Amplification Kit (Agilent). Cy5-CTP labeled reference target was Stratagene Universal Mouse Reference RNA. Note that the processed data in the paper, which is also attached as GSE26520_Table_data.txt.gz, is slightly different from the values columns in each sample. The original processed data are normalized with a batch method, as the new batches of arrays added in the set. The value columns in this submission reflect full normalization as described in the data processing fields in each sample.

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Principal components of heritability from neurocognitive domains differ between families with schizophrenia and control subjects.

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Principal components of heritability from neurocognitive domains differ between families with schizophrenia and control subjects.

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