title: A resequence analysis of genomic loci on chromosomes 1q32.1, 5p15.33, and 13q22.1 associated with pancreatic cancer risk.
abstract: OBJECTIVE
  The objective of this study was to fine-map common pancreatic cancer susceptibility regions.
  
  
  METHODS
  We conducted targeted Roche-454 resequencing across 428 kb in 3 genomic regions identified in genome-wide association studies (GWAS) of pancreatic cancer, on chromosomes 1q32.1, 5p15.33, and 13q22.1.
  
  
  RESULTS
  An analytical pipeline for calling genotypes was developed using HapMap samples sequenced on chr5p15.33. Concordance to 1000 Genomes data for chr5p15.33 was greater than 96%. The concordance for chr1q32.1 and chr13q22.1 with pancreatic cancer GWAS data was greater than 99%. Between 9.2% and 19.0% of variants detected were not present in 1000 Genomes for the respective continental population. The majority of completely novel single-nucleotide polymorphisms (SNPs) were less common (minor allele frequency [MAF], ≤5%) or rare (MAF, ≤2%), illustrating the value of enlarging test sets for discovery of less common variants. Using the data set, we examined haplotype blocks across each region using a tag SNP analysis (r² > 0.8 for MAF of ≥5%) and determined that at least 196, 243, and 63 SNPs are required for fine-mapping chr1q32.1, chr5p15.33, and chr13q22.1, respectively, in European populations.
  
  
  CONCLUSIONS
  We have characterized germline variation in 3 regions associated with pancreatic cancer risk and show that targeted resequencing leads to the discovery of novel variants and improves the completeness of germline sequence variants for fine-mapping GWAS susceptibility loci.
authors.affiliation: Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Hemang
authors.initials: H
authors.lastname: Parikh
authors.forename: Jinping
authors.initials: J
authors.lastname: Jia
authors.forename: Xijun
authors.initials: X
authors.lastname: Zhang
authors.forename: Charles C
authors.initials: CC
authors.lastname: Chung
authors.forename: Kevin B
authors.initials: KB
authors.lastname: Jacobs
authors.forename: Meredith
authors.initials: M
authors.lastname: Yeager
authors.forename: Joseph
authors.initials: J
authors.lastname: Boland
authors.forename: Amy
authors.initials: A
authors.lastname: Hutchinson
authors.forename: Laura
authors.initials: L
authors.lastname: Burdett
authors.forename: Jason
authors.initials: J
authors.lastname: Hoskins
authors.forename: Harvey A
authors.initials: HA
authors.lastname: Risch
authors.forename: Rachael Z
authors.initials: RZ
authors.lastname: Stolzenberg-Solomon
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Chanock
authors.forename: Brian M
authors.initials: BM
authors.lastname: Wolpin
authors.forename: Gloria M
authors.initials: GM
authors.lastname: Petersen
authors.forename: Charles S
authors.initials: CS
authors.lastname: Fuchs
authors.forename: Patricia
authors.initials: P
authors.lastname: Hartge
authors.forename: Laufey
authors.initials: L
authors.lastname: Amundadottir
mesh_terms: D002878:Chromosomes, Human, Pair 1; D002882:Chromosomes, Human, Pair 13; D002895:Chromosomes, Human, Pair 5; D030541:Databases, Genetic; D005787:Gene Frequency; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D010190:Pancreatic Neoplasms / Q000208:ethnology / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D044469:Racial Groups / Q000235:genetics; D018570:Risk Assessment; D012307:Risk Factors; D017422:Sequence Analysis, DNA