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Challenges in Translating GWAS Results to Clinical Care

Clinical genetic testing for Mendelian disorders is standard of care in many cases; however, it is less clear to what extent and in which situations clinical genetic testing may improve preventive efforts, diagnosis and/or prognosis of complex disease. One challenge is that much of the reported rese...

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Autores principales: Scheinfeldt, Laura B., Schmidlen, Tara J., Gerry, Norman P., Christman, Michael F.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5000665/
https://www.ncbi.nlm.nih.gov/pubmed/27527156
http://dx.doi.org/10.3390/ijms17081267
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author Scheinfeldt, Laura B.
Schmidlen, Tara J.
Gerry, Norman P.
Christman, Michael F.
author_facet Scheinfeldt, Laura B.
Schmidlen, Tara J.
Gerry, Norman P.
Christman, Michael F.
author_sort Scheinfeldt, Laura B.
collection PubMed
description Clinical genetic testing for Mendelian disorders is standard of care in many cases; however, it is less clear to what extent and in which situations clinical genetic testing may improve preventive efforts, diagnosis and/or prognosis of complex disease. One challenge is that much of the reported research relies on tag single nucleotide polymorphisms (SNPs) to act as proxies for assumed underlying functional variants that are not yet known. Here we use coronary artery disease and melanoma as case studies to evaluate how well reported genetic risk variants tag surrounding variants across population samples in the 1000 Genomes Project Phase 3 data. We performed a simulation study where we randomly assigned a “functional” variant and evaluated how often this simulated functional variant was correctly tagged in diverse population samples. Our results indicate a relatively large error rate when generalizing increased genetic risk of complex disease across diverse population samples, even when generalizing within geographic regions. Our results further highlight the importance of including diverse populations in genome-wide association studies. Future work focused on identifying functional variants will eliminate the need for tag SNPs; however, until functional variants are known, caution should be used in the interpretation of genetic risk for complex disease using tag SNPs.
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spelling pubmed-50006652016-09-01 Challenges in Translating GWAS Results to Clinical Care Scheinfeldt, Laura B. Schmidlen, Tara J. Gerry, Norman P. Christman, Michael F. Int J Mol Sci Article Clinical genetic testing for Mendelian disorders is standard of care in many cases; however, it is less clear to what extent and in which situations clinical genetic testing may improve preventive efforts, diagnosis and/or prognosis of complex disease. One challenge is that much of the reported research relies on tag single nucleotide polymorphisms (SNPs) to act as proxies for assumed underlying functional variants that are not yet known. Here we use coronary artery disease and melanoma as case studies to evaluate how well reported genetic risk variants tag surrounding variants across population samples in the 1000 Genomes Project Phase 3 data. We performed a simulation study where we randomly assigned a “functional” variant and evaluated how often this simulated functional variant was correctly tagged in diverse population samples. Our results indicate a relatively large error rate when generalizing increased genetic risk of complex disease across diverse population samples, even when generalizing within geographic regions. Our results further highlight the importance of including diverse populations in genome-wide association studies. Future work focused on identifying functional variants will eliminate the need for tag SNPs; however, until functional variants are known, caution should be used in the interpretation of genetic risk for complex disease using tag SNPs. MDPI 2016-08-04 /pmc/articles/PMC5000665/ /pubmed/27527156 http://dx.doi.org/10.3390/ijms17081267 Text en © 2016 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC-BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Scheinfeldt, Laura B.
Schmidlen, Tara J.
Gerry, Norman P.
Christman, Michael F.
Challenges in Translating GWAS Results to Clinical Care
title Challenges in Translating GWAS Results to Clinical Care
title_full Challenges in Translating GWAS Results to Clinical Care
title_fullStr Challenges in Translating GWAS Results to Clinical Care
title_full_unstemmed Challenges in Translating GWAS Results to Clinical Care
title_short Challenges in Translating GWAS Results to Clinical Care
title_sort challenges in translating gwas results to clinical care
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5000665/
https://www.ncbi.nlm.nih.gov/pubmed/27527156
http://dx.doi.org/10.3390/ijms17081267
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