A resequence analysis of genomic loci on chromosomes 1q32.1, 5p15.33, and 13q22.1 associated with pancreatic cancer risk

Pancreas. 2013 Mar;42(2):209-15. doi: 10.1097/MPA.0b013e318264cea5.

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.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Intramural

MeSH terms

  • Chromosomes, Human, Pair 1*
  • Chromosomes, Human, Pair 13*
  • Chromosomes, Human, Pair 5*
  • Databases, Genetic
  • Gene Frequency
  • Genetic Loci*
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Haplotypes
  • Humans
  • Linkage Disequilibrium
  • Pancreatic Neoplasms / ethnology
  • Pancreatic Neoplasms / genetics*
  • Polymorphism, Single Nucleotide*
  • Racial Groups / genetics
  • Risk Assessment
  • Risk Factors
  • Sequence Analysis, DNA*