Serveur d'exploration sur les relations entre la France et l'Australie

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Fine-Mapping of Common Genetic Variants Associated with Colorectal Tumor Risk Identified Potential Functional Variants

Identifieur interne : 000621 ( Pmc/Curation ); précédent : 000620; suivant : 000622

Fine-Mapping of Common Genetic Variants Associated with Colorectal Tumor Risk Identified Potential Functional Variants

Auteurs : Mengmeng Du [États-Unis] ; Shuo Jiao [États-Unis] ; Stephanie A. Bien [États-Unis] ; Manish Gala [États-Unis] ; Goncalo Abecasis [États-Unis] ; Stephane Bezieau [France] ; Hermann Brenner [Allemagne] ; Katja Butterbach [Allemagne] ; Bette J. Caan [États-Unis] ; Christopher S. Carlson [États-Unis] ; Graham Casey [États-Unis] ; Jenny Chang-Claude [Allemagne] ; David V. Conti [États-Unis] ; Keith R. Curtis [États-Unis] ; David Duggan [États-Unis] ; Steven Gallinger [Canada] ; Robert W. Haile [États-Unis] ; Tabitha A. Harrison [États-Unis] ; Richard B. Hayes [États-Unis] ; Michael Hoffmeister [Allemagne] ; John L. Hopper [Australie] ; Thomas J. Hudson [Canada] ; Mark A. Jenkins [Australie] ; Sébastien Küry [France] ; Loic Le Marchand [États-Unis] ; Suzanne M. Leal [États-Unis] ; Polly A. Newcomb [États-Unis] ; Deborah A. Nickerson [États-Unis] ; John D. Potter [États-Unis, Nouvelle-Zélande] ; Robert E. Schoen [États-Unis] ; Fredrick R. Schumacher [États-Unis] ; Daniela Seminara [États-Unis] ; Martha L. Slattery [États-Unis] ; Li Hsu [États-Unis] ; Andrew T. Chan [États-Unis] ; Emily White [États-Unis] ; Sonja I. Berndt [États-Unis] ; Ulrike Peters [États-Unis]

Source :

RBID : PMC:4933364

Abstract

Genome-wide association studies (GWAS) have identified many common single nucleotide polymorphisms (SNPs) associated with colorectal cancer risk. These SNPs may tag correlated variants with biological importance. Fine-mapping around GWAS loci can facilitate detection of functional candidates and additional independent risk variants. We analyzed 11,900 cases and 14,311 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium and the Colon Cancer Family Registry. To fine-map genomic regions containing all known common risk variants, we imputed high-density genetic data from the 1000 Genomes Project. We tested single-variant associations with colorectal tumor risk for all variants spanning genomic regions 250-kb upstream or downstream of 31 GWAS-identified SNPs (index SNPs). We queried the University of California, Santa Cruz Genome Browser to examine evidence for biological function. Index SNPs did not show the strongest association signals with colorectal tumor risk in their respective genomic regions. Bioinformatics analysis of SNPs showing smaller P-values in each region revealed 21 functional candidates in 12 loci (5q31.1, 8q24, 11q13.4, 11q23, 12p13.32, 12q24.21, 14q22.2, 15q13, 18q21, 19q13.1, 20p12.3, and 20q13.33). We did not observe evidence of additional independent association signals in GWAS-identified regions. Our results support the utility of integrating data from comprehensive fine-mapping with expanding publicly available genomic databases to help clarify GWAS associations and identify functional candidates that warrant more onerous laboratory follow-up. Such efforts may aid the eventual discovery of disease-causing variant(s).


Url:
DOI: 10.1371/journal.pone.0157521
PubMed: 27379672
PubMed Central: 4933364

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Le document en format XML

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<nlm:aff id="aff015">
<addr-line>Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia</addr-line>
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<wicri:regionArea>School of Public Health, University of Washington, Seattle, WA</wicri:regionArea>
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<addr-line>Centre for Public Health Research, Massey University, Wellington, New Zealand</addr-line>
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<wicri:regionArea>Centre for Public Health Research, Massey University, Wellington</wicri:regionArea>
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<name sortKey="Schoen, Robert E" sort="Schoen, Robert E" uniqKey="Schoen R" first="Robert E." last="Schoen">Robert E. Schoen</name>
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<name sortKey="Schumacher, Fredrick R" sort="Schumacher, Fredrick R" uniqKey="Schumacher F" first="Fredrick R." last="Schumacher">Fredrick R. Schumacher</name>
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<name sortKey="Seminara, Daniela" sort="Seminara, Daniela" uniqKey="Seminara D" first="Daniela" last="Seminara">Daniela Seminara</name>
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<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Division of Cancer Control and Population Sciences, National Cancer Institute, Bethesda, MD</wicri:regionArea>
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<name sortKey="Slattery, Martha L" sort="Slattery, Martha L" uniqKey="Slattery M" first="Martha L." last="Slattery">Martha L. Slattery</name>
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<addr-line>Department of Internal Medicine, University of Utah Health Sciences Center, Salt Lake City, UT, United States of America</addr-line>
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<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Internal Medicine, University of Utah Health Sciences Center, Salt Lake City, UT</wicri:regionArea>
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<name sortKey="Hsu, Li" sort="Hsu, Li" uniqKey="Hsu L" first="Li" last="Hsu">Li Hsu</name>
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</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA</wicri:regionArea>
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<country xml:lang="fr">États-Unis</country>
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<name sortKey="Du, Mengmeng" sort="Du, Mengmeng" uniqKey="Du M" first="Mengmeng" last="Du">Mengmeng Du</name>
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<addr-line>Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
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<addr-line>Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United States of America</addr-line>
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<name sortKey="Jiao, Shuo" sort="Jiao, Shuo" uniqKey="Jiao S" first="Shuo" last="Jiao">Shuo Jiao</name>
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<nlm:aff id="aff002">
<addr-line>Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA</wicri:regionArea>
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<addr-line>Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA</wicri:regionArea>
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</nlm:aff>
<country xml:lang="fr">États-Unis</country>
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<country xml:lang="fr">États-Unis</country>
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<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI</wicri:regionArea>
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<name sortKey="Bezieau, Stephane" sort="Bezieau, Stephane" uniqKey="Bezieau S" first="Stephane" last="Bezieau">Stephane Bezieau</name>
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</nlm:aff>
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<wicri:regionArea>Service de Génétique Médicale, CHU Nantes, Nantes</wicri:regionArea>
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<nlm:aff id="aff007">
<addr-line>Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany</addr-line>
</nlm:aff>
<country xml:lang="fr">Allemagne</country>
<wicri:regionArea>Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg</wicri:regionArea>
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<affiliation wicri:level="1">
<nlm:aff id="aff008">
<addr-line>German Cancer Consortium (DKTK), Heidelberg, Germany</addr-line>
</nlm:aff>
<country xml:lang="fr">Allemagne</country>
<wicri:regionArea>German Cancer Consortium (DKTK), Heidelberg</wicri:regionArea>
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<nlm:aff id="aff007">
<addr-line>Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany</addr-line>
</nlm:aff>
<country xml:lang="fr">Allemagne</country>
<wicri:regionArea>Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg</wicri:regionArea>
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<name sortKey="Caan, Bette J" sort="Caan, Bette J" uniqKey="Caan B" first="Bette J." last="Caan">Bette J. Caan</name>
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<nlm:aff id="aff009">
<addr-line>Division of Research, Kaiser Permanente Medical Care Program of Northern California, Oakland, CA, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
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<nlm:aff id="aff002">
<addr-line>Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA</wicri:regionArea>
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<name sortKey="Casey, Graham" sort="Casey, Graham" uniqKey="Casey G" first="Graham" last="Casey">Graham Casey</name>
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<nlm:aff id="aff010">
<addr-line>Keck School of Medicine, University of Southern California, Los Angeles, CA, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Keck School of Medicine, University of Southern California, Los Angeles, CA</wicri:regionArea>
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<name sortKey="Chang Claude, Jenny" sort="Chang Claude, Jenny" uniqKey="Chang Claude J" first="Jenny" last="Chang-Claude">Jenny Chang-Claude</name>
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<nlm:aff id="aff011">
<addr-line>Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany</addr-line>
</nlm:aff>
<country xml:lang="fr">Allemagne</country>
<wicri:regionArea>Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg</wicri:regionArea>
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<nlm:aff id="aff010">
<addr-line>Keck School of Medicine, University of Southern California, Los Angeles, CA, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Keck School of Medicine, University of Southern California, Los Angeles, CA</wicri:regionArea>
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<nlm:aff id="aff002">
<addr-line>Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA</wicri:regionArea>
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<name sortKey="Duggan, David" sort="Duggan, David" uniqKey="Duggan D" first="David" last="Duggan">David Duggan</name>
<affiliation wicri:level="1">
<nlm:aff id="aff012">
<addr-line>Translational Genomics Research Institute, Phoenix, Arizona, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Translational Genomics Research Institute, Phoenix, Arizona</wicri:regionArea>
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<nlm:aff id="aff013">
<addr-line>Department of Surgery, Mount Sinai Hospital, Toronto, ON, Canada</addr-line>
</nlm:aff>
<country xml:lang="fr">Canada</country>
<wicri:regionArea>Department of Surgery, Mount Sinai Hospital, Toronto, ON</wicri:regionArea>
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<name sortKey="Haile, Robert W" sort="Haile, Robert W" uniqKey="Haile R" first="Robert W." last="Haile">Robert W. Haile</name>
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<nlm:aff id="aff010">
<addr-line>Keck School of Medicine, University of Southern California, Los Angeles, CA, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Keck School of Medicine, University of Southern California, Los Angeles, CA</wicri:regionArea>
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<name sortKey="Harrison, Tabitha A" sort="Harrison, Tabitha A" uniqKey="Harrison T" first="Tabitha A." last="Harrison">Tabitha A. Harrison</name>
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<nlm:aff id="aff002">
<addr-line>Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA</wicri:regionArea>
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<name sortKey="Hayes, Richard B" sort="Hayes, Richard B" uniqKey="Hayes R" first="Richard B." last="Hayes">Richard B. Hayes</name>
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<nlm:aff id="aff014">
<addr-line>Division of Epidemiology, Department of Population Health, New York University School of Medicine, New York, NY, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Division of Epidemiology, Department of Population Health, New York University School of Medicine, New York, NY</wicri:regionArea>
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<name sortKey="Hoffmeister, Michael" sort="Hoffmeister, Michael" uniqKey="Hoffmeister M" first="Michael" last="Hoffmeister">Michael Hoffmeister</name>
<affiliation wicri:level="1">
<nlm:aff id="aff007">
<addr-line>Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany</addr-line>
</nlm:aff>
<country xml:lang="fr">Allemagne</country>
<wicri:regionArea>Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg</wicri:regionArea>
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<name sortKey="Hopper, John L" sort="Hopper, John L" uniqKey="Hopper J" first="John L." last="Hopper">John L. Hopper</name>
<affiliation wicri:level="1">
<nlm:aff id="aff015">
<addr-line>Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia</addr-line>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria</wicri:regionArea>
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<name sortKey="Hudson, Thomas J" sort="Hudson, Thomas J" uniqKey="Hudson T" first="Thomas J." last="Hudson">Thomas J. Hudson</name>
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<nlm:aff id="aff016">
<addr-line>Ontario Institute for Cancer Research, Toronto, ON, Canada</addr-line>
</nlm:aff>
<country xml:lang="fr">Canada</country>
<wicri:regionArea>Ontario Institute for Cancer Research, Toronto, ON</wicri:regionArea>
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<affiliation wicri:level="1">
<nlm:aff id="aff017">
<addr-line>Departments of Medical Biophysics and Molecular Genetics, University of Toronto, Toronto, ON, Canada</addr-line>
</nlm:aff>
<country xml:lang="fr">Canada</country>
<wicri:regionArea>Departments of Medical Biophysics and Molecular Genetics, University of Toronto, Toronto, ON</wicri:regionArea>
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<name sortKey="Jenkins, Mark A" sort="Jenkins, Mark A" uniqKey="Jenkins M" first="Mark A." last="Jenkins">Mark A. Jenkins</name>
<affiliation wicri:level="1">
<nlm:aff id="aff015">
<addr-line>Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia</addr-line>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Kury, Sebastien" sort="Kury, Sebastien" uniqKey="Kury S" first="Sébastien" last="Küry">Sébastien Küry</name>
<affiliation wicri:level="1">
<nlm:aff id="aff006">
<addr-line>Service de Génétique Médicale, CHU Nantes, Nantes, France</addr-line>
</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>Service de Génétique Médicale, CHU Nantes, Nantes</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Le Marchand, Loic" sort="Le Marchand, Loic" uniqKey="Le Marchand L" first="Loic" last="Le Marchand">Loic Le Marchand</name>
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<nlm:aff id="aff018">
<addr-line>Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI</wicri:regionArea>
</affiliation>
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<author>
<name sortKey="Leal, Suzanne M" sort="Leal, Suzanne M" uniqKey="Leal S" first="Suzanne M." last="Leal">Suzanne M. Leal</name>
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<nlm:aff id="aff019">
<addr-line>Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX</wicri:regionArea>
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<name sortKey="Newcomb, Polly A" sort="Newcomb, Polly A" uniqKey="Newcomb P" first="Polly A." last="Newcomb">Polly A. Newcomb</name>
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<nlm:aff id="aff002">
<addr-line>Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1">
<nlm:aff id="aff003">
<addr-line>School of Public Health, University of Washington, Seattle, WA, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>School of Public Health, University of Washington, Seattle, WA</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Nickerson, Deborah A" sort="Nickerson, Deborah A" uniqKey="Nickerson D" first="Deborah A." last="Nickerson">Deborah A. Nickerson</name>
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<nlm:aff id="aff020">
<addr-line>Genome Sciences, University of Washington, Seattle, WA, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Genome Sciences, University of Washington, Seattle, WA</wicri:regionArea>
</affiliation>
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<author>
<name sortKey="Potter, John D" sort="Potter, John D" uniqKey="Potter J" first="John D." last="Potter">John D. Potter</name>
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<nlm:aff id="aff002">
<addr-line>Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1">
<nlm:aff id="aff003">
<addr-line>School of Public Health, University of Washington, Seattle, WA, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>School of Public Health, University of Washington, Seattle, WA</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1">
<nlm:aff id="aff021">
<addr-line>Centre for Public Health Research, Massey University, Wellington, New Zealand</addr-line>
</nlm:aff>
<country xml:lang="fr">Nouvelle-Zélande</country>
<wicri:regionArea>Centre for Public Health Research, Massey University, Wellington</wicri:regionArea>
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<name sortKey="Schoen, Robert E" sort="Schoen, Robert E" uniqKey="Schoen R" first="Robert E." last="Schoen">Robert E. Schoen</name>
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<nlm:aff id="aff022">
<addr-line>Department of Medicine and Epidemiology, University of Pittsburgh Medical Center, Pittsburgh, PA, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Medicine and Epidemiology, University of Pittsburgh Medical Center, Pittsburgh, PA</wicri:regionArea>
</affiliation>
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<name sortKey="Schumacher, Fredrick R" sort="Schumacher, Fredrick R" uniqKey="Schumacher F" first="Fredrick R." last="Schumacher">Fredrick R. Schumacher</name>
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<nlm:aff id="aff010">
<addr-line>Keck School of Medicine, University of Southern California, Los Angeles, CA, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Keck School of Medicine, University of Southern California, Los Angeles, CA</wicri:regionArea>
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</author>
<author>
<name sortKey="Seminara, Daniela" sort="Seminara, Daniela" uniqKey="Seminara D" first="Daniela" last="Seminara">Daniela Seminara</name>
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<nlm:aff id="aff023">
<addr-line>Division of Cancer Control and Population Sciences, National Cancer Institute, Bethesda, MD, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Division of Cancer Control and Population Sciences, National Cancer Institute, Bethesda, MD</wicri:regionArea>
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<name sortKey="Slattery, Martha L" sort="Slattery, Martha L" uniqKey="Slattery M" first="Martha L." last="Slattery">Martha L. Slattery</name>
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<nlm:aff id="aff024">
<addr-line>Department of Internal Medicine, University of Utah Health Sciences Center, Salt Lake City, UT, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Internal Medicine, University of Utah Health Sciences Center, Salt Lake City, UT</wicri:regionArea>
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<name sortKey="Hsu, Li" sort="Hsu, Li" uniqKey="Hsu L" first="Li" last="Hsu">Li Hsu</name>
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<nlm:aff id="aff002">
<addr-line>Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Chan, Andrew T" sort="Chan, Andrew T" uniqKey="Chan A" first="Andrew T." last="Chan">Andrew T. Chan</name>
<affiliation wicri:level="1">
<nlm:aff id="aff004">
<addr-line>Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1">
<nlm:aff id="aff025">
<addr-line>Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="White, Emily" sort="White, Emily" uniqKey="White E" first="Emily" last="White">Emily White</name>
<affiliation wicri:level="1">
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<addr-line>Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1">
<nlm:aff id="aff003">
<addr-line>School of Public Health, University of Washington, Seattle, WA, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>School of Public Health, University of Washington, Seattle, WA</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Berndt, Sonja I" sort="Berndt, Sonja I" uniqKey="Berndt S" first="Sonja I." last="Berndt">Sonja I. Berndt</name>
<affiliation wicri:level="1">
<nlm:aff id="aff026">
<addr-line>Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Peters, Ulrike" sort="Peters, Ulrike" uniqKey="Peters U" first="Ulrike" last="Peters">Ulrike Peters</name>
<affiliation wicri:level="1">
<nlm:aff id="aff002">
<addr-line>Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1">
<nlm:aff id="aff003">
<addr-line>School of Public Health, University of Washington, Seattle, WA, United States of America</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>School of Public Health, University of Washington, Seattle, WA</wicri:regionArea>
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</analytic>
<series>
<title level="j">PLoS ONE</title>
<idno type="eISSN">1932-6203</idno>
<imprint>
<date when="2016">2016</date>
</imprint>
</series>
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<profileDesc>
<textClass></textClass>
</profileDesc>
</teiHeader>
<front>
<div type="abstract" xml:lang="en">
<p>Genome-wide association studies (GWAS) have identified many common single nucleotide polymorphisms (SNPs) associated with colorectal cancer risk. These SNPs may tag correlated variants with biological importance. Fine-mapping around GWAS loci can facilitate detection of functional candidates and additional independent risk variants. We analyzed 11,900 cases and 14,311 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium and the Colon Cancer Family Registry. To fine-map genomic regions containing all known common risk variants, we imputed high-density genetic data from the 1000 Genomes Project. We tested single-variant associations with colorectal tumor risk for all variants spanning genomic regions 250-kb upstream or downstream of 31 GWAS-identified SNPs (index SNPs). We queried the University of California, Santa Cruz Genome Browser to examine evidence for biological function. Index SNPs did not show the strongest association signals with colorectal tumor risk in their respective genomic regions. Bioinformatics analysis of SNPs showing smaller
<italic>P</italic>
-values in each region revealed 21 functional candidates in 12 loci (5q31.1, 8q24, 11q13.4, 11q23, 12p13.32, 12q24.21, 14q22.2, 15q13, 18q21, 19q13.1, 20p12.3, and 20q13.33). We did not observe evidence of additional independent association signals in GWAS-identified regions. Our results support the utility of integrating data from comprehensive fine-mapping with expanding publicly available genomic databases to help clarify GWAS associations and identify functional candidates that warrant more onerous laboratory follow-up. Such efforts may aid the eventual discovery of disease-causing variant(s).</p>
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<pmc article-type="research-article">
<pmc-dir>properties open_access</pmc-dir>
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<journal-id journal-id-type="nlm-ta">PLoS One</journal-id>
<journal-id journal-id-type="iso-abbrev">PLoS ONE</journal-id>
<journal-id journal-id-type="publisher-id">plos</journal-id>
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<journal-title>PLoS ONE</journal-title>
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<issn pub-type="epub">1932-6203</issn>
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<article-id pub-id-type="pmid">27379672</article-id>
<article-id pub-id-type="pmc">4933364</article-id>
<article-id pub-id-type="doi">10.1371/journal.pone.0157521</article-id>
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<subj-group subj-group-type="heading">
<subject>Research Article</subject>
</subj-group>
<subj-group subj-group-type="Discipline-v3">
<subject>Medicine and Health Sciences</subject>
<subj-group>
<subject>Oncology</subject>
<subj-group>
<subject>Cancers and Neoplasms</subject>
<subj-group>
<subject>Colorectal Cancer</subject>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
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<subject>Biology and Life Sciences</subject>
<subj-group>
<subject>Computational Biology</subject>
<subj-group>
<subject>Genome Analysis</subject>
<subj-group>
<subject>Genome-Wide Association Studies</subject>
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</subj-group>
</subj-group>
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<subject>Biology and Life Sciences</subject>
<subj-group>
<subject>Genetics</subject>
<subj-group>
<subject>Genomics</subject>
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<subject>Genome Analysis</subject>
<subj-group>
<subject>Genome-Wide Association Studies</subject>
</subj-group>
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<subject>Biology and Life Sciences</subject>
<subj-group>
<subject>Genetics</subject>
<subj-group>
<subject>Human Genetics</subject>
<subj-group>
<subject>Genome-Wide Association Studies</subject>
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</subj-group>
</subj-group>
</subj-group>
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<subject>Research and Analysis Methods</subject>
<subj-group>
<subject>Database and Informatics Methods</subject>
<subj-group>
<subject>Biological Databases</subject>
<subj-group>
<subject>Genomic Databases</subject>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
<subj-group subj-group-type="Discipline-v3">
<subject>Biology and Life Sciences</subject>
<subj-group>
<subject>Computational Biology</subject>
<subj-group>
<subject>Genome Analysis</subject>
<subj-group>
<subject>Genomic Databases</subject>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
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<subject>Biology and Life Sciences</subject>
<subj-group>
<subject>Genetics</subject>
<subj-group>
<subject>Genomics</subject>
<subj-group>
<subject>Genome Analysis</subject>
<subj-group>
<subject>Genomic Databases</subject>
</subj-group>
</subj-group>
</subj-group>
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<subject>Biology and Life Sciences</subject>
<subj-group>
<subject>Genetics</subject>
<subj-group>
<subject>Genomics</subject>
<subj-group>
<subject>Functional Genomics</subject>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
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<subject>Biology and Life Sciences</subject>
<subj-group>
<subject>Cell Biology</subject>
<subj-group>
<subject>Signal Transduction</subject>
<subj-group>
<subject>Cell Signaling</subject>
<subj-group>
<subject>Genomic Signal Processing</subject>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
<subj-group subj-group-type="Discipline-v3">
<subject>Biology and Life Sciences</subject>
<subj-group>
<subject>Genetics</subject>
<subj-group>
<subject>Genetic Loci</subject>
</subj-group>
</subj-group>
</subj-group>
<subj-group subj-group-type="Discipline-v3">
<subject>Research and Analysis Methods</subject>
<subj-group>
<subject>Database and Informatics Methods</subject>
<subj-group>
<subject>Bioinformatics</subject>
</subj-group>
</subj-group>
</subj-group>
<subj-group subj-group-type="Discipline-v3">
<subject>Biology and Life Sciences</subject>
<subj-group>
<subject>Genetics</subject>
<subj-group>
<subject>Genetic Loci</subject>
<subj-group>
<subject>Alleles</subject>
</subj-group>
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</subj-group>
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</article-categories>
<title-group>
<article-title>Fine-Mapping of Common Genetic Variants Associated with Colorectal Tumor Risk Identified Potential Functional Variants</article-title>
<alt-title alt-title-type="running-head">Fine-Mapping Common Susceptibility Loci for Colorectal Tumors</alt-title>
</title-group>
<contrib-group>
<contrib contrib-type="author" equal-contrib="yes">
<name>
<surname>Du</surname>
<given-names>Mengmeng</given-names>
</name>
<xref ref-type="aff" rid="aff001">
<sup>1</sup>
</xref>
<xref ref-type="aff" rid="aff002">
<sup>2</sup>
</xref>
<xref ref-type="corresp" rid="cor001">*</xref>
</contrib>
<contrib contrib-type="author" equal-contrib="yes">
<name>
<surname>Jiao</surname>
<given-names>Shuo</given-names>
</name>
<xref ref-type="aff" rid="aff002">
<sup>2</sup>
</xref>
</contrib>
<contrib contrib-type="author">
<contrib-id contrib-id-type="orcid" authenticated="false">http://orcid.org/0000-0002-8713-4583</contrib-id>
<name>
<surname>Bien</surname>
<given-names>Stephanie A.</given-names>
</name>
<xref ref-type="aff" rid="aff002">
<sup>2</sup>
</xref>
<xref ref-type="aff" rid="aff003">
<sup>3</sup>
</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Gala</surname>
<given-names>Manish</given-names>
</name>
<xref ref-type="aff" rid="aff004">
<sup>4</sup>
</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Abecasis</surname>
<given-names>Goncalo</given-names>
</name>
<xref ref-type="aff" rid="aff005">
<sup>5</sup>
</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Bezieau</surname>
<given-names>Stephane</given-names>
</name>
<xref ref-type="aff" rid="aff006">
<sup>6</sup>
</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Brenner</surname>
<given-names>Hermann</given-names>
</name>
<xref ref-type="aff" rid="aff007">
<sup>7</sup>
</xref>
<xref ref-type="aff" rid="aff008">
<sup>8</sup>
</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Butterbach</surname>
<given-names>Katja</given-names>
</name>
<xref ref-type="aff" rid="aff007">
<sup>7</sup>
</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Caan</surname>
<given-names>Bette J.</given-names>
</name>
<xref ref-type="aff" rid="aff009">
<sup>9</sup>
</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Carlson</surname>
<given-names>Christopher S.</given-names>
</name>
<xref ref-type="aff" rid="aff002">
<sup>2</sup>
</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Casey</surname>
<given-names>Graham</given-names>
</name>
<xref ref-type="aff" rid="aff010">
<sup>10</sup>
</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Chang-Claude</surname>
<given-names>Jenny</given-names>
</name>
<xref ref-type="aff" rid="aff011">
<sup>11</sup>
</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Conti</surname>
<given-names>David V.</given-names>
</name>
<xref ref-type="aff" rid="aff010">
<sup>10</sup>
</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Curtis</surname>
<given-names>Keith R.</given-names>
</name>
<xref ref-type="aff" rid="aff002">
<sup>2</sup>
</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Duggan</surname>
<given-names>David</given-names>
</name>
<xref ref-type="aff" rid="aff012">
<sup>12</sup>
</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Gallinger</surname>
<given-names>Steven</given-names>
</name>
<xref ref-type="aff" rid="aff013">
<sup>13</sup>
</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Haile</surname>
<given-names>Robert W.</given-names>
</name>
<xref ref-type="aff" rid="aff010">
<sup>10</sup>
</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Harrison</surname>
<given-names>Tabitha A.</given-names>
</name>
<xref ref-type="aff" rid="aff002">
<sup>2</sup>
</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Hayes</surname>
<given-names>Richard B.</given-names>
</name>
<xref ref-type="aff" rid="aff014">
<sup>14</sup>
</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Hoffmeister</surname>
<given-names>Michael</given-names>
</name>
<xref ref-type="aff" rid="aff007">
<sup>7</sup>
</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Hopper</surname>
<given-names>John L.</given-names>
</name>
<xref ref-type="aff" rid="aff015">
<sup>15</sup>
</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Hudson</surname>
<given-names>Thomas J.</given-names>
</name>
<xref ref-type="aff" rid="aff016">
<sup>16</sup>
</xref>
<xref ref-type="aff" rid="aff017">
<sup>17</sup>
</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Jenkins</surname>
<given-names>Mark A.</given-names>
</name>
<xref ref-type="aff" rid="aff015">
<sup>15</sup>
</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Küry</surname>
<given-names>Sébastien</given-names>
</name>
<xref ref-type="aff" rid="aff006">
<sup>6</sup>
</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Le Marchand</surname>
<given-names>Loic</given-names>
</name>
<xref ref-type="aff" rid="aff018">
<sup>18</sup>
</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Leal</surname>
<given-names>Suzanne M.</given-names>
</name>
<xref ref-type="aff" rid="aff019">
<sup>19</sup>
</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Newcomb</surname>
<given-names>Polly A.</given-names>
</name>
<xref ref-type="aff" rid="aff002">
<sup>2</sup>
</xref>
<xref ref-type="aff" rid="aff003">
<sup>3</sup>
</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Nickerson</surname>
<given-names>Deborah A.</given-names>
</name>
<xref ref-type="aff" rid="aff020">
<sup>20</sup>
</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Potter</surname>
<given-names>John D.</given-names>
</name>
<xref ref-type="aff" rid="aff002">
<sup>2</sup>
</xref>
<xref ref-type="aff" rid="aff003">
<sup>3</sup>
</xref>
<xref ref-type="aff" rid="aff021">
<sup>21</sup>
</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Schoen</surname>
<given-names>Robert E.</given-names>
</name>
<xref ref-type="aff" rid="aff022">
<sup>22</sup>
</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Schumacher</surname>
<given-names>Fredrick R.</given-names>
</name>
<xref ref-type="aff" rid="aff010">
<sup>10</sup>
</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Seminara</surname>
<given-names>Daniela</given-names>
</name>
<xref ref-type="aff" rid="aff023">
<sup>23</sup>
</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Slattery</surname>
<given-names>Martha L.</given-names>
</name>
<xref ref-type="aff" rid="aff024">
<sup>24</sup>
</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Hsu</surname>
<given-names>Li</given-names>
</name>
<xref ref-type="aff" rid="aff002">
<sup>2</sup>
</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Chan</surname>
<given-names>Andrew T.</given-names>
</name>
<xref ref-type="aff" rid="aff004">
<sup>4</sup>
</xref>
<xref ref-type="aff" rid="aff025">
<sup>25</sup>
</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>White</surname>
<given-names>Emily</given-names>
</name>
<xref ref-type="aff" rid="aff002">
<sup>2</sup>
</xref>
<xref ref-type="aff" rid="aff003">
<sup>3</sup>
</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Berndt</surname>
<given-names>Sonja I.</given-names>
</name>
<xref ref-type="aff" rid="aff026">
<sup>26</sup>
</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Peters</surname>
<given-names>Ulrike</given-names>
</name>
<xref ref-type="aff" rid="aff002">
<sup>2</sup>
</xref>
<xref ref-type="aff" rid="aff003">
<sup>3</sup>
</xref>
<xref ref-type="corresp" rid="cor001">*</xref>
</contrib>
</contrib-group>
<aff id="aff001">
<label>1</label>
<addr-line>Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, United States of America</addr-line>
</aff>
<aff id="aff002">
<label>2</label>
<addr-line>Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United States of America</addr-line>
</aff>
<aff id="aff003">
<label>3</label>
<addr-line>School of Public Health, University of Washington, Seattle, WA, United States of America</addr-line>
</aff>
<aff id="aff004">
<label>4</label>
<addr-line>Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States of America</addr-line>
</aff>
<aff id="aff005">
<label>5</label>
<addr-line>Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI, United States of America</addr-line>
</aff>
<aff id="aff006">
<label>6</label>
<addr-line>Service de Génétique Médicale, CHU Nantes, Nantes, France</addr-line>
</aff>
<aff id="aff007">
<label>7</label>
<addr-line>Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany</addr-line>
</aff>
<aff id="aff008">
<label>8</label>
<addr-line>German Cancer Consortium (DKTK), Heidelberg, Germany</addr-line>
</aff>
<aff id="aff009">
<label>9</label>
<addr-line>Division of Research, Kaiser Permanente Medical Care Program of Northern California, Oakland, CA, United States of America</addr-line>
</aff>
<aff id="aff010">
<label>10</label>
<addr-line>Keck School of Medicine, University of Southern California, Los Angeles, CA, United States of America</addr-line>
</aff>
<aff id="aff011">
<label>11</label>
<addr-line>Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany</addr-line>
</aff>
<aff id="aff012">
<label>12</label>
<addr-line>Translational Genomics Research Institute, Phoenix, Arizona, United States of America</addr-line>
</aff>
<aff id="aff013">
<label>13</label>
<addr-line>Department of Surgery, Mount Sinai Hospital, Toronto, ON, Canada</addr-line>
</aff>
<aff id="aff014">
<label>14</label>
<addr-line>Division of Epidemiology, Department of Population Health, New York University School of Medicine, New York, NY, United States of America</addr-line>
</aff>
<aff id="aff015">
<label>15</label>
<addr-line>Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia</addr-line>
</aff>
<aff id="aff016">
<label>16</label>
<addr-line>Ontario Institute for Cancer Research, Toronto, ON, Canada</addr-line>
</aff>
<aff id="aff017">
<label>17</label>
<addr-line>Departments of Medical Biophysics and Molecular Genetics, University of Toronto, Toronto, ON, Canada</addr-line>
</aff>
<aff id="aff018">
<label>18</label>
<addr-line>Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, United States of America</addr-line>
</aff>
<aff id="aff019">
<label>19</label>
<addr-line>Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United States of America</addr-line>
</aff>
<aff id="aff020">
<label>20</label>
<addr-line>Genome Sciences, University of Washington, Seattle, WA, United States of America</addr-line>
</aff>
<aff id="aff021">
<label>21</label>
<addr-line>Centre for Public Health Research, Massey University, Wellington, New Zealand</addr-line>
</aff>
<aff id="aff022">
<label>22</label>
<addr-line>Department of Medicine and Epidemiology, University of Pittsburgh Medical Center, Pittsburgh, PA, United States of America</addr-line>
</aff>
<aff id="aff023">
<label>23</label>
<addr-line>Division of Cancer Control and Population Sciences, National Cancer Institute, Bethesda, MD, United States of America</addr-line>
</aff>
<aff id="aff024">
<label>24</label>
<addr-line>Department of Internal Medicine, University of Utah Health Sciences Center, Salt Lake City, UT, United States of America</addr-line>
</aff>
<aff id="aff025">
<label>25</label>
<addr-line>Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, United States of America</addr-line>
</aff>
<aff id="aff026">
<label>26</label>
<addr-line>Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, United States of America</addr-line>
</aff>
<contrib-group>
<contrib contrib-type="editor">
<name>
<surname>Wang</surname>
<given-names>Junwen</given-names>
</name>
<role>Editor</role>
<xref ref-type="aff" rid="edit1"></xref>
</contrib>
</contrib-group>
<aff id="edit1">
<addr-line>Mayo Clinic Arizona, UNITED STATES</addr-line>
</aff>
<author-notes>
<fn fn-type="conflict" id="coi001">
<p>
<bold>Competing Interests: </bold>
The authors have declared that no competing interests exist.</p>
</fn>
<fn fn-type="con" id="contrib001">
<p>Conceived and designed the experiments: MD SJ SAB GA SB HB BJC CSC GC JCC DD SG RWH TAH RBH MH JLH TJH MAJ SK LLM SML PAN DAN JDP RES FRS DS MLS LH ATC EW SIB UP. Performed the experiments: DD. Analyzed the data: SJ MD SAB LH UP. Contributed reagents/materials/analysis tools: SJ KRC. Wrote the paper: MD SJ SAB UP. Collected phenotype data and biological samples and contributed these as investigators for their respective study: HB BJC GC JCC SG RWH RBH MH JLH MAJ LLM PAN JDP RES DS MLS ATC EW SIB. Critically reviewed the manuscript drafts and approved the final manuscript: MD SJ SAB MG GA SB HB KB BJC CSC GC JCC DVC KRC DD SG RWH TAR RBH MH JLH TJH MAJ SK LLM SML PAN DAN JDP RES FRS DS MLS LH ATC EW SIB UP</p>
</fn>
<corresp id="cor001">* E-mail:
<email>dumeng@mskcc.org</email>
(MD);
<email>upeters@fhcrc.org</email>
(UP)</corresp>
</author-notes>
<pub-date pub-type="epub">
<day>5</day>
<month>7</month>
<year>2016</year>
</pub-date>
<pub-date pub-type="collection">
<year>2016</year>
</pub-date>
<volume>11</volume>
<issue>7</issue>
<elocation-id>e0157521</elocation-id>
<history>
<date date-type="received">
<day>8</day>
<month>10</month>
<year>2015</year>
</date>
<date date-type="accepted">
<day>1</day>
<month>6</month>
<year>2016</year>
</date>
</history>
<permissions>
<copyright-statement>© 2016 Du et al</copyright-statement>
<copyright-year>2016</copyright-year>
<copyright-holder>Du et al</copyright-holder>
<license xlink:href="http://creativecommons.org/licenses/by/4.0/">
<license-p>This is an open access article distributed under the terms of the
<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">Creative Commons Attribution License</ext-link>
, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.</license-p>
</license>
</permissions>
<self-uri content-type="pdf" xlink:href="pone.0157521.pdf"></self-uri>
<abstract>
<p>Genome-wide association studies (GWAS) have identified many common single nucleotide polymorphisms (SNPs) associated with colorectal cancer risk. These SNPs may tag correlated variants with biological importance. Fine-mapping around GWAS loci can facilitate detection of functional candidates and additional independent risk variants. We analyzed 11,900 cases and 14,311 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium and the Colon Cancer Family Registry. To fine-map genomic regions containing all known common risk variants, we imputed high-density genetic data from the 1000 Genomes Project. We tested single-variant associations with colorectal tumor risk for all variants spanning genomic regions 250-kb upstream or downstream of 31 GWAS-identified SNPs (index SNPs). We queried the University of California, Santa Cruz Genome Browser to examine evidence for biological function. Index SNPs did not show the strongest association signals with colorectal tumor risk in their respective genomic regions. Bioinformatics analysis of SNPs showing smaller
<italic>P</italic>
-values in each region revealed 21 functional candidates in 12 loci (5q31.1, 8q24, 11q13.4, 11q23, 12p13.32, 12q24.21, 14q22.2, 15q13, 18q21, 19q13.1, 20p12.3, and 20q13.33). We did not observe evidence of additional independent association signals in GWAS-identified regions. Our results support the utility of integrating data from comprehensive fine-mapping with expanding publicly available genomic databases to help clarify GWAS associations and identify functional candidates that warrant more onerous laboratory follow-up. Such efforts may aid the eventual discovery of disease-causing variant(s).</p>
</abstract>
<funding-group>
<funding-statement>This work was supported by the following: GECCO: National Cancer Institute, National Institutes of Health, U.S. Department of Health and Human Services (U01 CA137088; R01 CA059045; U01 CA164930), M.D. is supported by grants R25 CA94880 and P30 CA008748 from the National Cancer Institute. ASTERISK: Hospital Clinical Research Program (PHRC) and supported by the Regional Council of Pays de la Loire, the Groupement des Entreprises Françaises dans la Lutte contre le Cancer (GEFLUC), the Association Anne de Bretagne Génétique and the Ligue Régionale Contre le Cancer (LRCC). COLO2&3: National Institutes of Health (R01 CA60987). CCFR: National Institutes of Health (RFA # CA-95-011) and through cooperative agreements with members of the Colon Cancer Family Registry and P.I.s. This genome wide scan was supported by the National Cancer Institute, National Institutes of Health by U01 CA122839. The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the CFRs, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government or the CFR. The following Colon CFR centers contributed data to this manuscript and were supported by National Institutes of Health: Australasian Colorectal Cancer Family Registry (U01 CA097735), Ontario Registry for Studies of Familial Colorectal Cancer (U01 CA074783), and Seattle Colorectal Cancer Family Registry (U01 CA074794). DACHS: German Research Council (Deutsche Forschungsgemeinschaft, BR 1704/6-1, BR 1704/6-3, BR 1704/6-4 and CH 117/1-1), and the German Federal Ministry of Education and Research (01KH0404 and 01ER0814). DALS: National Institutes of Health (R01 CA48998 to M.L.S.); HPFS, NHS, and PHS: HPFS by the National Institutes of Health (P01 CA 055075, UM1 CA167552, R01 137178, and P50 CA 127003), NHS by the National Institutes of Health (R01 CA137178, P01 CA 087969 and P50 CA 127003,) and PHS by the National Institutes of Health (CA42182). A.T.C. is also supported by a Damon Runyon Clinical investigator Award and K24 DK098311. MEC: National Institutes of Health (R37 CA54281, P01 CA033619, and R01 CA63464). OFCCR: National Institutes of Health, through funding allocated to the Ontario Registry for Studies of Familial Colorectal Cancer (U01 CA074783); see CCFR section above. As subset of ARCTIC, OFCCR is supported by a GL2 grant from the Ontario Research Fund, the Canadian Institutes of Health Research, and the Cancer Risk Evaluation (CaRE) Program grant from the Canadian Cancer Society Research Institute. T.J.H. is a recipient of Senior Investigator Awards from the Ontario Institute for Cancer Research, through generous support from the Ontario Ministry of Research and Innovation. PLCO: Intramural Research Program of the Division of Cancer Epidemiology and Genetics and supported by contracts from the Division of Cancer Prevention, National Cancer Institute, NIH, DHHS. Additionally, a subset of control samples were genotyped as part of the Cancer Genetic Markers of Susceptibility (CGEMS) Prostate Cancer GWAS (Yeager, M et al. Nat Genet 2007 May;39(5):645-9), Colon CGEMS pancreatic cancer scan (PanScan) (Amundadottir, L et al. Nat Genet. 2009 Sep;41(9):986-90 and Petersen, GM et al Nat Genet. 2010 Mar;42(3):224-8), and the Lung Cancer and Smoking study. The prostate and PanScan study datasets were accessed with appropriate approval through the dbGaP online resource (
<ext-link ext-link-type="uri" xlink:href="http://cgems.cancer.gov/data/">http://cgems.cancer.gov/data/</ext-link>
) accession numbers phs000207v.1p1 and phs000206.v3.p2, respectively, and the lung datasets were accessed from the dbGaP website (
<ext-link ext-link-type="uri" xlink:href="http://www.ncbi.nlm.nih.gov/gap">http://www.ncbi.nlm.nih.gov/gap</ext-link>
) through accession number phs000093 v2.p2. Funding for the Lung Cancer and Smoking study was provided by National Institutes of Health (NIH), Genes, Environment and Health Initiative (GEI) Z01 CP 010200, NIH U01 HG004446, and NIH GEI U01 HG 004438. For the lung study, the GENEVA Coordinating Center provided assistance with genotype cleaning and general study coordination, and the Johns Hopkins University Center for Inherited Disease Research conducted genotyping. PMH-CCFR: National Institutes of Health (R01 CA076366 to P.A.N.). VITAL: National Institutes of Health (K05 CA154337). WHI: The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, and HHSN271201100004C. CORECT: National Cancer Institute, National Institutes of Health under RFA # CA-09-002 (U19 CA148107). The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in CORECT, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government or CORECT. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.</funding-statement>
</funding-group>
<counts>
<fig-count count="1"></fig-count>
<table-count count="2"></table-count>
<page-count count="18"></page-count>
</counts>
<custom-meta-group>
<custom-meta id="data-availability">
<meta-name>Data Availability</meta-name>
<meta-value>For plco genetic data, the prostate and panscan study datasets can be accessed with appropriate approval through the dbgap online resource (
<ext-link ext-link-type="uri" xlink:href="http://cgems.cancer.gov/data/">http://cgems.cancer.gov/data/</ext-link>
) accession numbers phs000207v.1p1 and phs000206.v3.p2, respectively, and the lung datasets from the dbgap website (
<ext-link ext-link-type="uri" xlink:href="http://www.ncbi.nlm.nih.gov/gap">http://www.ncbi.nlm.nih.gov/gap</ext-link>
) through accession number phs000093 v2.p2. For the remaining gecco studies, genetic data is in the process of being uploaded to dbgap and will be available soon (accession number phs001078.v1.p1). While the data release is being finalized, the gecco coordinating center can assist with any data requests (contact:
<email>gecco@fredhutch.org</email>
).</meta-value>
</custom-meta>
</custom-meta-group>
</article-meta>
<notes>
<title>Data Availability</title>
<p>For plco genetic data, the prostate and panscan study datasets can be accessed with appropriate approval through the dbgap online resource (
<ext-link ext-link-type="uri" xlink:href="http://cgems.cancer.gov/data/">http://cgems.cancer.gov/data/</ext-link>
) accession numbers phs000207v.1p1 and phs000206.v3.p2, respectively, and the lung datasets from the dbgap website (
<ext-link ext-link-type="uri" xlink:href="http://www.ncbi.nlm.nih.gov/gap">http://www.ncbi.nlm.nih.gov/gap</ext-link>
) through accession number phs000093 v2.p2. For the remaining gecco studies, genetic data is in the process of being uploaded to dbgap and will be available soon (accession number phs001078.v1.p1). While the data release is being finalized, the gecco coordinating center can assist with any data requests (contact:
<email>gecco@fredhutch.org</email>
).</p>
</notes>
</front>
</pmc>
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