Erin L. Heinzen 1 , Dongliang Ge 1 , Kenneth D. Cronin 1 , Jessica M. Maia 1 , Kevin V. Shianna 1 , Willow N. Gabriel 1 , Kathleen A. Welsh-Bohmer 2 , Christine M. Hulette 2 , Thomas N. Denny 3 , David B. Goldstein 1 *
1 Institute for Genome Sciences & Policy, Center for Human Genome Variation, Duke University, Durham, North Carolina, United States of America, 2 Joseph and Kathleen Bryan Alzheimer's Disease Research Center, Duke University, Durham, North Carolina, United States of America, 3 Human Vaccine Institute, Duke University, Durham, North Carolina, United States of AmericaPLoS Biol 6(12): e1 doi:10.1371/journal.pbio.1000001
Numerous genome-wide screens for polymorphisms that influence gene expression have provided key insights into the genetic control of transcription. Despite this work, the relevance of specific polymorphisms to in vivo expression and splicing remains unclear. We carried out the first genome-wide screen, to our knowledge, for SNPs that associate with alternative splicing and gene expression in human primary cells, evaluating 93 autopsy-collected cortical brain tissue samples with no defined neuropsychiatric condition and 80 peripheral blood mononucleated cell samples collected from living healthy donors. We identified 23 high confidence associations with total expression and 80 with alternative splicing as reflected by expression levels of specific exons. Fewer than 50% of the implicated SNPs however show effects in both tissue types, reflecting strong evidence for distinct genetic control of splicing and expression in the two tissue types. The data generated here also suggest the possibility that splicing effects may be responsible for up to 13 out of 84 reported genome-wide significant associations with human traits. These results emphasize the importance of establishing a database of polymorphisms affecting splicing and expression in primary tissue types and suggest that splicing effects may be of more phenotypic significance than overall gene expression changes.Funding. This work was funded in part by the Institute for Genome Sciences and Policy at Duke University, the Center for HIV-AIDS Vaccine Immunology, the Bryan Alzheimer's Disease Research Center (NIA, AG028377), and a pilot grant from the Kathleen Price Bryan Alzheimer's Disease Research Center. The tissue specimens used in this study were kindly provided by the National NeuroAIDS Tissue Consortium (NNTC), the Kathleen Price Bryan Brain Bank (KPBBB) at Duke University, Layton Aging & Alzheimer's Disease Center at Oregon Health and Science University, and the Duke Human Vaccine Institute.
Competing interests. The authors have declared that no competing interests exist.
Academic Editor: Edison Liu, Genome Institute of Singapore, Singapore
Citation: Heinzen EL, Ge D, Cronin KD, Maia JM, Shianna KV, et al. (2008) Tissue-Specific Genetic Control of Splicing: Implications for the Study of Complex Traits. PLoS Biol 6(12): e1 doi:10.1371/journal.pbio.1000001
Abbreviations : eQTL, expression quantitative trait locus; LD, linkage disequilibrium; MAF, minor allele frequency; PBMC, peripheral blood mononucleated cell; sQTL, splicing quantitative trait locus
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These authors contributed equally to this work.