title: GWASeq: targeted re-sequencing follow up to GWAS.
abstract: BACKGROUND
  For the last decade the conceptual framework of the Genome-Wide Association Study (GWAS) has dominated the investigation of human disease and other complex traits. While GWAS have been successful in identifying a large number of variants associated with various phenotypes, the overall amount of heritability explained by these variants remains small. This raises the question of how best to follow up on a GWAS, localize causal variants accounting for GWAS hits, and as a consequence explain more of the so-called "missing" heritability. Advances in high throughput sequencing technologies now allow for the efficient and cost-effective collection of vast amounts of fine-scale genomic data to complement GWAS.
  
  
  RESULTS
  We investigate these issues using a colon cancer dataset. After QC, our data consisted of 1993 cases, 899 controls. Using marginal tests of associations, we identify 10 variants distributed among six targeted regions that are significantly associated with colorectal cancer, with eight of the variants being novel to this study. Additionally, we perform so-called 'SNP-set' tests of association and identify two sets of variants that implicate both common and rare variants in the etiology of colorectal cancer.
  
  
  CONCLUSIONS
  Here we present a large-scale targeted re-sequencing resource focusing on genomic regions implicated in colorectal cancer susceptibility previously identified in several GWAS, which aims to 1) provide fine-scale targeted sequencing data for fine-mapping and 2) provide data resources to address methodological questions regarding the design of sequencing-based follow-up studies to GWAS. Additionally, we show that this strategy successfully identifies novel variants associated with colorectal cancer susceptibility and can implicate both common and rare variants.
authors.affiliation: Department of Preventive Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA. Matthew.Salomon@providence.org.|Department of Molecular Oncology, John Wayne Cancer Institute at Providence Saint John's Health Center, Santa Monica, CA, USA. Matthew.Salomon@providence.org.
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Salomon
authors.affiliation: Department of Preventive Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA. sibon.li@gmail.com.
authors.forename: Wai Lok Sibon
authors.initials: WL
authors.lastname: Li
authors.affiliation: Department of Preventive Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA. cedlund@usc.edu.
authors.forename: Christopher K
authors.initials: CK
authors.lastname: Edlund
authors.affiliation: Department of Preventive Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA. jmorr@usc.edu.
authors.forename: John
authors.initials: J
authors.lastname: Morrison
authors.affiliation: Department of Preventive Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA. fortini@usc.edu.
authors.forename: Barbara K
authors.initials: BK
authors.lastname: Fortini
authors.affiliation: Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Melbourne, VIC, Australia. awin@unimelb.edu.au.
authors.forename: Aung Ko
authors.initials: AK
authors.lastname: Win
authors.affiliation: Department of Preventive Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA. dconti@med.usc.edu.
authors.forename: David V
authors.initials: DV
authors.lastname: Conti
authors.affiliation: Department of Preventive Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA. dthomas@usc.edu.
authors.forename: Duncan C
authors.initials: DC
authors.lastname: Thomas
authors.affiliation: Translational Genomics Research Institute, Phoenix, AZ, USA. dduggan@tgen.org.
authors.forename: David
authors.initials: D
authors.lastname: Duggan
authors.affiliation: Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Melbourne, VIC, Australia. daniel.buchanan@unimelb.edu.au.|Oncogenomics Group, Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Parkville, Melbourne, VIC, Australia. daniel.buchanan@unimelb.edu.au.
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Buchanan
authors.affiliation: Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Melbourne, VIC, Australia. m.jenkins@unimelb.edu.au.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Jenkins
authors.affiliation: Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Melbourne, VIC, Australia. j.hopper@unimelb.edu.au.
authors.forename: John L
authors.initials: JL
authors.lastname: Hopper
authors.affiliation: Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON, Canada. steven.gallinger@uhn.ca.
authors.forename: Steven
authors.initials: S
authors.lastname: Gallinger
authors.affiliation: University of Hawaii Cancer Center, Honolulu, HI, USA. loic@cc.hawaii.edu.
authors.forename: Loïc
authors.initials: L
authors.lastname: Le Marchand
authors.affiliation: Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. pnewcomb@fhcrc.org.
authors.forename: Polly A
authors.initials: PA
authors.lastname: Newcomb
authors.affiliation: Department of Preventive Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA. Graham.Casey@med.usc.edu.
authors.forename: Graham
authors.initials: G
authors.lastname: Casey
authors.affiliation: Department of Preventive Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA. pmarjora@usc.edu.
authors.forename: Paul
authors.initials: P
authors.lastname: Marjoram
mesh_terms: D002874:Chromosome Mapping; D003110:Colonic Neoplasms / Q000235:genetics; D019295:Computational Biology; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D017422:Sequence Analysis, DNA / Q000379:methods*