6 research outputs found
Integrative functional genomic analysis of human brain development and neuropsychiatric risks
To broaden our understanding of human neurodevelopment, we profiled transcriptomic and epigenomic landscapes across brain regions and/or cell types for the entire span of prenatal and postnatal development. Integrative analysis revealed temporal, regional, sex, and cell type-specific dynamics.We observed a global transcriptomic cup-shaped pattern, characterized by a late fetal transition associated with sharply decreased regional differences and changes in cellular composition and maturation, followed by a reversal in childhood-adolescence, and accompanied by epigenomic reorganizations. Analysis of gene coexpression modules revealed relationships with epigenomic regulation and neurodevelopmental processes. Genes with genetic associations to brain-based traits and neuropsychiatric disorders (including MEF2C, SATB2, SOX5, TCF4, and TSHZ3) converged in a small number of modules and distinct cell types, revealing insights into neurodevelopment and the genomic basis of neuropsychiatric risks
Contributions of common genetic variants to risk of schizophrenia among individuals of African and Latino ancestry
Schizophrenia is a common, chronic and debilitating neuropsychiatric syndrome affecting tens of millions of individuals worldwide. While rare genetic variants play a role in the etiology of schizophrenia, most of the currently explained liability is within common variation, suggesting that variation predating the human diaspora out of Africa harbors a large fraction of the common variant attributable heritability. However, common variant association studies in schizophrenia have concentrated mainly on cohorts of European descent. We describe genome-wide association studies of 6152 cases and 3918 controls of admixed African ancestry, and of 1234 cases and 3090 controls of Latino ancestry, representing the largest such study in these populations to date. Combining results from the samples with African ancestry with summary statistics from the Psychiatric Genomics Consortium (PGC) study of schizophrenia yielded seven newly genome-wide significant loci, and we identified an additional eight loci by incorporating the results from samples with Latino ancestry. Leveraging population differences in patterns of linkage disequilibrium, we achieve improved fine-mapping resolution at 22 previously reported and 4 newly significant loci. Polygenic risk score profiling revealed improved prediction based on trans-ancestry meta-analysis results for admixed African (Nagelkerke’s R2 = 0.032; liability R2 = 0.017; P < 10−52), Latino (Nagelkerke’s R2 = 0.089; liability R2 = 0.021; P < 10−58), and European individuals (Nagelkerke’s R2 = 0.089; liability R2 = 0.037; P < 10−113), further highlighting the advantages of incorporating data from diverse human populations
Screening for mutations in the peripheral myelin genes PMP22, MPZ and Cx32 in Russian Charcot-Marie-Tooth neuropathy patients
Supplementary Material for: Transcriptional Gene Silencing of the Autism-Associated Long Noncoding RNA MSNP1AS in Human Neural Progenitor Cells
<p>The long noncoding RNA <i>MSNP1AS</i> (moesin pseudogene 1,
antisense) is a functional element that was previously associated with
autism spectrum disorder (ASD) with genome-wide significance. Expression
of <i>MSNP1AS</i> was increased 12-fold in the cerebral cortex of
individuals with ASD and 22-fold in individuals with a genome-wide
significantly associated ASD genetic marker on chromosome 5p14.1.
Overexpression of <i>MSNP1AS</i> in human neuronal cells caused
decreased expression of moesin protein, which is involved in neuronal
process stability. In this study, we hypothesize that <i>MSNP1AS</i>
knockdown impacts global transcriptome levels. We transfected the human
neural progenitor cell line SK- N-SH with constructs that caused a 50%
suppression of <i>MSNP1AS</i> expression. After 24 h, cells were
harvested for total RNA isolation. Strand-specific RNA sequencing
analysis indicated altered expression of 1,352 genes, including altered
expression of 318 genes following correction for multiple comparisons.
Expression of the <i>OAS2</i> gene was increased >150-fold, a result
that was validated by quantitative PCR. Gene ontology analysis of the
318 genes with altered expression following correction for multiple
comparisons indicated that upregulated genes were significantly enriched
for genes involved in immune response, and downregulated genes were
significantly enriched for genes involved in chromatin remodeling. These
data indicate multiple transcriptional and translational functions of <i>MSNP1AS</i>
that impact ASD-relevant biological processes. Chromatin remodeling and
immune response are biological processes implicated by genes with rare
mutations associated with ASD. Our data suggest that the functional
elements implicated by association of common genetic variants impact the
same biological processes, suggesting a possible shared common
molecular pathway of ASD.</p