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Title: A resequence analysis of genomic loci on chromosomes 1q32.1, 5p15.33, and 13q22.1 associated with pancreatic cancer risk.
Authors: Parikh H,  Jia J,  Zhang X,  Chung CC,  Jacobs KB,  Yeager M,  Boland J,  Hutchinson A,  Burdett L,  Hoskins J,  Risch HA,  Stolzenberg-Solomon RZ,  Chanock SJ,  Wolpin BM,  Petersen GM,  Fuchs CS,  Hartge P,  Amundadottir L
Journal: Pancreas
Date: 2013 Mar
Branches: CGR, EBP, LTG, NEB
PubMed ID: 23295781
PMC ID: PMC3618611
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.