A survey of genetic human cortical gene expression

Myers, Amanda; Gibbs, J. Raphael; Webster, Jennifer; Rohrer, Kristen; Zhao, Alice; Marlowe, Lauren; Kaleem, Mona; Leung, Doris G.; Bryden, Leslie; Nath, Priti; Zismann, Victoria; Joshipura, Keta; Huentelman, Matthew J.; Hu-Lince, Diane; Coon, Keith D.; Craig, David W.; Pearson, John V.; Holmans, Peter Alan; Heward, Christopher B.; Reiman, Eric M.; Stephan, Dietrich A.; Hardy, John

doi:10.1038/ng.2007.16

Cited by 453 publications

(535 citation statements)

References 19 publications

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“…For this, a human brain sample was used with gene expression level estimates for 14 077 transcripts in 193 individuals. 12 In testing TOMM40 and APOE against the base set, we observed very strong correlation of TOMM40 to PSEN2 (P¼1.3Â10 À13 , r 2 ¼0.24) and a weaker association of APOE to APP (P¼4.5Â10 À7 , r 2 ¼0.12). The other correlations were not significant at a¼0.05.…”

mentioning

confidence: 77%

Genome-wide pathway analysis implicates intracellular transmembrane protein transport in Alzheimer disease

et al. 2010

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We developed and implemented software for the analysis of genome-wide association studies in the context of biological pathway enrichment and have here applied our algorithm to the study of Alzheimer disease (AD). Using genome-wide association data in a large French population, we observed a highly significant enrichment of genes involved in intracellular protein transmembrane transport, including several mitochondrial proteins and nucleoporins. An intriguing aspect of these findings is the implication that TOMM40, the channel-forming subunit of the translocase of the mitochondrial outer membrane complex, and a gene generally considered to be indiscernible from APOE because of linkage disequilibrium, may itself contribute to Alzheimer pathology. Results provide an indication that protein trafficking, in particular across the nuclear and mitochondrial membranes, may contribute to risk for AD.

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confidence: 77%

Genome-wide pathway analysis implicates intracellular transmembrane protein transport in Alzheimer disease

et al. 2010

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“…This study used only variable-based models without loops, and its primary results were models with only one predicting SNP. This simple analysis detected associations between SNP alleles and binned gene expression values, replicating and extending SNP-gene expression associations in a public data set [16]. Only the data from SNPs and expression values from the published positive cis-acting (local) SNP-gene expression associations were included.…”

Section: Results: a Real Data Examplementioning

confidence: 99%

“…That study employed only simple variable-based models without loops, but it successfully replicated and extended SNP-gene expression associations in a public dataset [16].…”

Section: B-systems Analysismentioning

confidence: 99%

Reconstructability of Epistatic Functions

Zwick¹,

Fusion²,

Wilmot³

2012

J Mol Eng Syst Biol

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Background: Reconstructability Analysis (RA) has been used to detect epistasis in genomic data; in that work, even the simplest RA models (variable-based models without loops) gave performance superior to two other methods. A follow-on theoretical study showed that RA also offers higher-resolution models, namely variable-based models with loops and state-based models, likely to be even more effective in modeling epistasis, and also described several mathematical approaches to classifying types of epistasis. Methods: The present paper extends this second study by discussing a non-standard use of RA: the analysis of epistasis in quantitative as opposed to nominal variables; such quantitative variables are, for example, encountered in genetic characterizations of gene expression, e.g., eQTL data. Three methods are investigated for applying variable-and state-based RA to quantitative dependent variables: (i) k-systems analysis, which treats continuous function values as pseudofrequencies, (ii) b-systems analysis, which derives continuous values from binned DVs using expected value calculations, and (iii) u-systems analysis, which treats continuous function values as pseudo-utilities subject to a lottery. These methods are demonstrated and compared on synthetic data. Results: The three methods of k-, b-, and u-systems analyses, both variable-based and state-based, are then applied to a published SNP dataset. A preliminary search is done with b-systems analysis, followed by more refined k-and u-systems searches. The analyses suggest candidates for epistatic interactions that affect the level of gene expression. As in the synthetic data studies, state-based RA is more powerful than variable-based RA. Conclusions: While the previous RA studies looked at epistasis in nominal (or discretized) data, this paper shows that RA can also analyze epistasis in quantitative expression data without discretizing this data. Since RA can also model epistasis in frequency distributions and detect linkage disequilibrium, its successful application here also to continuous functions shows that it offers a flexible methodology for the analysis of genomic interaction effects.

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“…To identify eQTL effects, eQTL databases were analyzed (Borel et al., 2011; Dimas et al., 2009; Dixon et al., 2007; Fehrmann et al., 2011; Greenawalt et al., 2011; Grundberg et al., 2009; GTEx Consortium, 2015; Kim, Cho, Lee, & Webster, 2012; Kirsten et al., 2015; Mehta et al., 2013; Myers et al., 2007; Ramasamy et al., 2014; Schadt et al., 2008; Schröder et al., 2011; Veyrieras et al., 2008; Westra et al., 2013; Xia et al., 2012; Zeller et al., 2010). We only considered SNPs identified in brain or blood tissue and eQTLs had to be replicated in at least one study.…”

Section: Methodsmentioning

confidence: 99%

ATP2C2andDYX1C1are putative modulators of dyslexia‐related MMR

et al. 2017

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BackgroundDyslexia is a specific learning disorder affecting reading and spelling abilities. Its prevalence is ~5% in German‐speaking individuals. Although the etiology of dyslexia largely remains to be determined, comprehensive evidence supports deficient phonological processing as a major contributing factor. An important prerequisite for phonological processing is auditory discrimination and, thus, essential for acquiring reading and spelling skills. The event‐related potential Mismatch Response (MMR) is an indicator for auditory discrimination capabilities with dyslexics showing an altered late component of MMR in response to auditory input.MethodsIn this study, we comprehensively analyzed associations of dyslexia‐specific late MMRs with genetic variants previously reported to be associated with dyslexia‐related phenotypes in multiple studies comprising 25 independent single‐nucleotide polymorphisms (SNPs) within 10 genes.ResultsFirst, we demonstrated validity of these SNPs for dyslexia in our sample by showing that additional inclusion of a polygenic risk score improved prediction of impaired writing compared with a model that used MMR alone. Secondly, a multifactorial regression analysis was conducted to uncover the subset of the 25 SNPs that is associated with the dyslexia‐specific late component of MMR. In total, four independent SNPs within DYX1C1 and ATP2C2 were found to be associated with MMR stronger than expected from multiple testing. To explore potential pathomechanisms, we annotated these variants with functional data including tissue‐specific expression analysis and eQTLs.ConclusionOur findings corroborate the late component of MMR as a potential endophenotype for dyslexia and support tripartite relationships between dyslexia‐related SNPs, the late component of MMR and dyslexia.

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A survey of genetic human cortical gene expression

Cited by 453 publications

References 19 publications

Genome-wide pathway analysis implicates intracellular transmembrane protein transport in Alzheimer disease

Genome-wide pathway analysis implicates intracellular transmembrane protein transport in Alzheimer disease

Reconstructability of Epistatic Functions

ATP2C2andDYX1C1are putative modulators of dyslexia‐related MMR

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