Colin Smith

Publications (4)27 Total impact

• Article: Resolving the polymorphism-in-probe problem is critical for correct interpretation of expression QTL studies.

  Adaikalavan Ramasamy, Daniah Trabzuni, J Raphael Gibbs, Allissa Dillman, Dena G Hernandez, Sampath Arepalli, Robert Walker, Colin Smith, Gigaloluwa Peter Ilori, Andrey A Shabalin, Yun Li, Andrew B Singleton, Mark R Cookson, John Hardy, Mina Ryten, Michael E Weale
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  ABSTRACT: Polymorphisms in the target mRNA sequence can greatly affect the binding affinity of microarray probe sequences, leading to false-positive and false-negative expression quantitative trait locus (QTL) signals with any other polymorphisms in linkage disequilibrium. We provide the most complete solution to this problem, by using the latest genome and exome sequence reference data to identify almost all common polymorphisms (frequency >1% in Europeans) in probe sequences for two commonly used microarray panels (the gene-based Illumina Human HT12 array, which uses 50-mer probes, and exon-based Affymetrix Human Exon 1.0 ST array, which uses 25-mer probes). We demonstrate the impact of this problem using cerebellum and frontal cortex tissues from 438 neuropathologically normal individuals. We find that although only a small proportion of the probes contain polymorphisms, they account for a large proportion of apparent expression QTL signals, and therefore result in many false signals being declared as real. We find that the polymorphism-in-probe problem is insufficiently controlled by previous protocols, and illustrate this using some notable false-positive and false-negative examples in MAPT and PRICKLE1 that can be found in many eQTL databases. We recommend that both new and existing eQTL data sets should be carefully checked in order to adequately address this issue.
  Nucleic Acids Research 02/2013; · 8.03 Impact Factor
• Article: Age-associated changes in gene expression in human brain and isolated neurons.

  Azad Kumar, J Raphael Gibbs, Alexandra Beilina, Allissa Dillman, Ravindran Kumaran, Daniah Trabzuni, Mina Ryten, Robert Walker, Colin Smith, Bryan J Traynor, John Hardy, Andrew B Singleton, Mark R Cookson
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  ABSTRACT: Previous studies have suggested that there are genes whose expression levels are associated with chronological age. However, which genes show consistent age association across studies, and which are specific to a given organism or tissue remains unresolved. Here, we reassessed this question using 2 independently ascertained series of human brain samples from 2 anatomic regions, the frontal lobe of the cerebral cortex and cerebellum. Using microarrays to estimate gene expression, we found 60 associations between expression and chronological age that were statistically significant and were replicated in both series in at least 1 tissue. There were a greater number of significant associations in the frontal cortex compared with the cerebellum. We then repeated the analysis in a subset of samples using laser capture microdissection to isolate Purkinje neurons from the cerebellum. We were able to replicate 5 gene associations from either frontal cortex or cerebellum in the Purkinje cell dataset, suggesting that there is a subset of genes which have robust changes with aging. Of these, the most consistent and strongest association was with expression of RHBDL3, a rhomboid protease family member. We confirmed several hits using an independent technique (quantitative reverse transcriptase polymerase chain reaction) and in an independent published sample series that used a different array platform. We also interrogated larger patterns of age-related gene expression using weighted gene correlation network analysis. We found several modules that showed significant associations with chronological age and, of these, several that showed negative associations were enriched for genes encoding components of mitochondria. Overall, our results show that there is a distinct and reproducible gene signature for aging in the human brain.
  Neurobiology of aging 11/2012; · 5.94 Impact Factor
• Article: MAPT expression and splicing is differentially regulated by brain region: relation to genotype and implication for tauopathies.

  Daniah Trabzuni, Selina Wray, Jana Vandrovcova, Adaikalavan Ramasamy, Robert Walker, Colin Smith, Connie Luk, J Raphael Gibbs, Allissa Dillman, Dena G Hernandez, Sampath Arepalli, Andrew B Singleton, Mark R Cookson, Alan M Pittman, Rohan de Silva, Michael E Weale, John Hardy, Mina Ryten
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  ABSTRACT: The MAPT (microtubule-associated protein tau) locus is one of the most remarkable in neurogenetics due not only to its involvement in multiple neurodegenerative disorders, including progressive supranuclear palsy, corticobasal degeneration, Parksinson's disease and possibly Alzheimer's disease, but also due its genetic evolution and complex alternative splicing features which are, to some extent, linked and so all the more intriguing. Therefore, obtaining robust information regarding the expression, splicing and genetic regulation of this gene within the human brain is of immense importance. In this study, we used 2011 brain samples originating from 439 individuals to provide the most reliable and coherent information on the regional expression, splicing and regulation of MAPT available to date. We found significant regional variation in mRNA expression and splicing of MAPT within the human brain. Furthermore, at the gene level, the regional distribution of mRNA expression and total tau protein expression levels were largely in agreement, appearing to be highly correlated. Finally and most importantly, we show that while the reported H1/H2 association with gene level expression is likely to be due to a technical artefact, this polymorphism is associated with the expression of exon 3-containing isoforms in human brain. These findings would suggest that contrary to the prevailing view, genetic risk factors for neurodegenerative diseases at the MAPT locus are likely to operate by changing mRNA splicing in different brain regions, as opposed to the overall expression of the MAPT gene.
  Human Molecular Genetics 06/2012; 21(18):4094-103. · 7.64 Impact Factor
• Article: Integration of GWAS SNPs and tissue specific expression profiling reveal discrete eQTLs for human traits in blood and brain.

  Dena G Hernandez, Mike A Nalls, Matthew Moore, Sean Chong, Allissa Dillman, Daniah Trabzuni, J Raphael Gibbs, Mina Ryten, Sampath Arepalli, Michael E Weale, Alan B Zonderman, Juan Troncoso, Richard O'Brien, Robert Walker, Colin Smith, Stefania Bandinelli, Bryan J Traynor, John Hardy, Andrew B Singleton, Mark R Cookson
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  ABSTRACT: Genome-wide association studies have nominated many genetic variants for common human traits, including diseases, but in many cases the underlying biological reason for a trait association is unknown. Subsets of genetic polymorphisms show a statistical association with transcript expression levels, and have therefore been nominated as expression quantitative trait loci (eQTL). However, many tissue and cell types have specific gene expression patterns and so it is not clear how frequently eQTLs found in one tissue type will be replicated in others. In the present study we used two appropriately powered sample series to examine the genetic control of gene expression in blood and brain. We find that while many eQTLs associated with human traits are shared between these two tissues, there are also examples where blood and brain differ, either by restricted gene expression patterns in one tissue or because of differences in how genetic variants are associated with transcript levels. These observations suggest that design of eQTL mapping experiments should consider tissue of interest for the disease or other traits studied.
  Neurobiology of Disease 03/2012; 47(1):20-8. · 5.40 Impact Factor