Tissue-specific genetic control of splicing: implications for the study of complex traits.
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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.
Polymorphism, Single Nucleotide
Principal Component Analysis
Quantitative Trait Loci
Quantitative Trait, Heritable
Regulatory Sequences, Nucleic Acid
Reproducibility of Results
Reverse Transcriptase Polymerase Chain Reaction
Published Version (Please cite this version)10.1371/journal.pbio.1000001
Publication InfoHeinzen, Erin L; Ge, Dongliang; Cronin, Kenneth D; Maia, Jessica M; Shianna, Kevin V; Gabriel, Willow N; ... Goldstein, David B (2008). Tissue-specific genetic control of splicing: implications for the study of complex traits. PLoS Biol, 6(12). pp. e1. 10.1371/journal.pbio.1000001. Retrieved from https://hdl.handle.net/10161/14735.
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Professor in Medicine
Thomas N. Denny, MSc, M.Phil, is the Chief Operating Officer of the Duke Human Vaccine Institute (DHVI) and the Center for HIV/AIDS Vaccine Immunology (CHAVI), and a Professor of Medicine in the Department of Medicine at Duke University Medical Center. He is also an Affiliate Member of the Duke Global Health Institute. He has recently been appointed to the Duke University Fuqua School of Business Health Sector Advisory Council. Previously, he was an Associate Professor of Pathology, Laboratory M
Adjunct Professor in the Department of Molecular Genetics and Microbiology
Assistant Professor of Pathology
Dr. Hulette is interested in Autopsy Neuropathology and Education Technology innovation.
This author no longer has a Scholars@Duke profile, so the information shown here reflects their Duke status at the time this item was deposited.
Professor in Psychiatry and Behavioral Sciences
Dr. Kathleen Welsh-Bohmer is a Professor of Psychiatry with a secondary appointment in the Department of Neurology. Clinically trained as a neuropsychologist, Dr. Welsh-Bohmer's research activities have been focused around developing effective prevention and treatment strategies to delay the onset of cognitive disorders occurring in later life. From 2006 through 2018 she directed the Joseph and Kathleen Bryan Alzheimer’s Center
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