Article

Genetic control of human brain transcript expression in Alzheimer disease.

Neurogenomics Division, Translational Genomics Research Institute, Phoenix, AZ 85004, USA.
The American Journal of Human Genetics (Impact Factor: 11.2). 05/2009; 84(4):445-58. DOI: 10.1016/j.ajhg.2009.03.011
Source: PubMed

ABSTRACT We recently surveyed the relationship between the human brain transcriptome and genome in a series of neuropathologically normal postmortem samples. We have now analyzed additional samples with a confirmed pathologic diagnosis of late-onset Alzheimer disease (LOAD; final n = 188 controls, 176 cases). Nine percent of the cortical transcripts that we analyzed had expression profiles correlated with their genotypes in the combined cohort, and approximately 5% of transcripts had SNP-transcript relationships that could distinguish LOAD samples. Two of these transcripts have been previously implicated in LOAD candidate-gene SNP-expression screens. This study shows how the relationship between common inherited genetic variants and brain transcript expression can be used in the study of human brain disorders. We suggest that studying the transcriptome as a quantitative endo-phenotype has greater power for discovering risk SNPs influencing expression than the use of discrete diagnostic categories such as presence or absence of disease.

0 Bookmarks
 · 
171 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Statins effectively lower LDL cholesterol levels in large studies and the observed interindividual response variability may be partially explained by genetic variation. Here we perform a pharmacogenetic meta-analysis of genome-wide association studies (GWAS) in studies addressing the LDL cholesterol response to statins, including up to 18,596 statin-treated subjects. We validate the most promising signals in a further 22,318 statin recipients and identify two loci, SORT1/CELSR2/PSRC1 and SLCO1B1, not previously identified in GWAS. Moreover, we confirm the previously described associations with APOE and LPA. Our findings advance the understanding of the pharmacogenetic architecture of statin response.
    Nature Communications 10/2014; · 10.74 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The availability of genome-wide expression data for the blood-brain barrier is an invaluable resource that has recently enabled the discovery of several genes and pathways involved in the development and maintenance of the blood-brain barrier, particularly in rodent models. The broad distribution of published data sets represents a viable starting point for the molecular dissection of the blood-brain barrier and will further direct the discovery of novel mechanisms of blood-brain barrier formation and function. Technical advances in purifying brain endothelial cells, the key cell that forms the critical barrier, have allowed for greater specificity in gene expression comparisons with other central nervous system cell types, and more systematic characterizations of the molecular composition of the blood-brain barrier. Nevertheless, our understanding of how the blood-brain barrier changes during aging and disease is underrepresented. Blood-brain barrier data sets from a wider range of experimental paradigms and species, including invertebrates and primates, would be invaluable for investigating the function and evolution of the blood-brain barrier. Newer technologies in gene expression profiling, such as RNA-sequencing, now allow for finer resolution of transcriptomic changes, including isoform specificity and RNA-editing. As our field continues to utilize more advanced expression profiling in its ongoing efforts to elucidate the blood-brain barrier, including in disease and drug delivery, we will continue to see rapid advances in our understanding of the molecular mediators of barrier biology. We predict that the recently published data sets, combined with forthcoming genomic and proteomic blood-brain barrier data sets, will continue to fuel the molecular genetic revolution of.
    Frontiers in neuroscience. 01/2014; 8:355.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: IntroductionNeurodegenerative diseases share common pathologic features including neuroinflammation, mitochondrial dysfunction and protein aggregation, suggesting common underlying mechanisms of neurodegeneration. We undertook a meta-analysis of public gene expression data for neurodegenerative diseases to identify a common transcriptional signature of neurodegeneration.ResultsUsing 1,270 post-mortem central nervous system tissue samples from 13 patient cohorts covering four neurodegenerative diseases, we identified 243 differentially expressed genes, which were similarly dysregulated in 15 additional patient cohorts of 205 samples including seven neurodegenerative diseases. This gene signature correlated with histologic disease severity. Metallothioneins featured prominently among differentially expressed genes, and functional pathway analysis identified specific convergent themes of dysregulation. MetaCore network analyses revealed various novel candidate hub genes (e.g. STAU2). Genes associated with M1-polarized macrophages and reactive astrocytes were strongly enriched in the meta-analysis data. Evaluation of genes enriched in neurons revealed 70 down-regulated genes, over half not previously associated with neurodegeneration. Comparison with aging brain data (3 patient cohorts, 221 samples) revealed 53 of these to be unique to neurodegenerative disease, many of which are strong candidates to be important in neuropathogenesis (e.g. NDN, NAP1L2). ENCODE ChIP-seq analysis predicted common upstream transcriptional regulators not associated with normal aging (REST, RBBP5, SIN3A, SP2, YY1, ZNF143, IKZF1). Finally, we removed genes common to neurodegeneration from disease-specific gene signatures, revealing uniquely robust immune response and JAK-STAT signaling in amyotrophic lateral sclerosis.Conclusions Our results implicate pervasive bioenergetic deficits, M1-type microglial activation and gliosis as unifying themes of neurodegeneration, and identify numerous novel genes associated with neurodegenerative processes.
    Acta neuropathologica communications. 09/2014; 2(1):93.

Full-text (2 Sources)

Download
38 Downloads
Available from
May 16, 2014