Tissue-specific genetic control of splicing: implications for the study of complex traits.

Abstract

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.

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Citation

Published Version (Please cite this version)

10.1371/journal.pbio.1000001

Publication Info

Heinzen, Erin L, Dongliang Ge, Kenneth D Cronin, Jessica M Maia, Kevin V Shianna, Willow N Gabriel, Kathleen A Welsh-Bohmer, Christine M Hulette, et al. (2008). Tissue-specific genetic control of splicing: implications for the study of complex traits. PLoS Biol, 6(12). p. e1. 10.1371/journal.pbio.1000001 Retrieved from https://hdl.handle.net/10161/14735.

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Scholars@Duke

Welsh-Bohmer

Kathleen Anne Welsh-Bohmer

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 in the Department of Neurology. She also oversaw the neuropsychology scientific operations of a ground-breaking Phase III global clinical trial to delay the onset of early clinical symptoms of Alzheimer’s disease entitled the “TOMMORROW” study (Takeda Pharmaceutical Company funded) which concluded in 2018.

Currently, she directs the Alzheimer's disease therapeutic area within the Duke Clinical Research Institute and she collaborates actively with VeraSci, a Durham based company, to develop reliable digital cognitive and functional assessment tools of early Alzheimer's disease and related dementias.  The methods her team is developing are informed by advances in neuroscience and technology and fill an information void in early pre-clinical Alzheimer's disease. Her work has implications for clinical practice and for the acceleration of global clinical trials aimed at the prevention of Alzheimer’s disease and related dementias.

Denny

Thomas Norton Denny

Professor in Medicine

Thomas N. Denny, MSc, M.Phil, is the Chief Operating Officer of the Duke Human Vaccine Institute (DHVI), Associate Dean for Duke Research and Discovery @RTP, 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. Previously, he served on the Health Sector Advisory Council of the Duke University Fuquay School of Business. Prior to joining Duke, he was an Associate Professor of Pathology, Laboratory Medicine and Pediatrics, Associate Professor of Preventive Medicine and Community Health and Assistant Dean for Research in Health Policy at the New Jersey Medical School, Newark, New Jersey. He has served on numerous committees for the NIH over the last two decades and currently is the principal investigator of an NIH portfolio in excess of 65 million dollars. Mr. Denny was a 2002-2003 Robert Wood Johnson Foundation Health Policy Fellow at the Institute of Medicine of the National Academies (IOM). As a fellow, he served on the US Senate Health, Education, Labor and Pensions Committee with legislation/policy responsibilities in global AIDS, bioterrorism, clinical trials/human subject protection and vaccine related-issues.

As the Chief Operating Officer of the DHVI, Mr. Denny has senior oversight of the DHVI research portfolio and the units/teams that support the DHVI mission. He has extensive international experience and previously was a consultant to the U.S. Centers for Disease Control and Prevention (CDC) for the President’s Emergency Plan for AIDS Relief (PEPFAR) project to oversee the development of an HIV and Public Health Center of Excellence laboratory network in Guyana. In September 2004, the IOM appointed him as a consultant to their Board on Global Health Committee studying the options for overseas placement of U.S. health professionals and the development of an assessment plan for activities related to the 2003 PEPFAR legislative act. In the 1980s, Mr. Denny helped establish a small laboratory in the Republic of Kalmykia (former Soviet Union) to improve the care of children with HIV/AIDS and served as a Board Member of the Children of Chernobyl Relief Fund Foundation. In 2005, Mr. Denny was named a consulting medical/scientific officer to the WHO Global AIDS Program in Geneva. He has also served as program reviewers for the governments of the Netherlands and South Africa as well as an advisor to several U.S. biotech companies. He currently serves as the Chair of the Scientific Advisory Board for Grid Biosciences.

Mr. Denny has authored and co-authored more than 200 peer-reviewed papers and serves on the editorial board of Communications in Cytometry and Journal of Clinical Virology. He holds an M.Sc in Molecular and Biomedical Immunology from the University of East London and a degree in Medical Law (M.Phil) from the Institute of Law and Ethics in Medicine, School of Law, University of Glasgow. In 1991, he completed a course of study in Strategic Management at The Wharton School, University of Pennsylvania. In 1993, he completed the Program for Advanced Training in Biomedical Research Management at Harvard School of Public Health. In December 2005, he was inducted as a Fellow into the College of Physicians of Philadelphia, the oldest medical society in the US.

While living in New Jersey, Mr. Denny was active in his community, gaining additional experience from two publicly elected positions. In 2000, Mr. Denny was selected by the New Jersey League of Municipalities to Chair the New Jersey Community Mental Health Citizens’ Advisory Board and Mental Health Planning Council as a gubernatorial appointment.

David Benjamin Goldstein

Adjunct Professor in the Department of Molecular Genetics and Microbiology

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