Abstract
Genome-wide association studies (GWAS) have identified multiple common susceptibility loci for pancreatic cancer. Here we report fine-mapping and functional analysis of one such locus residing in a 610 kb gene desert on chr13q22.1 (marked by rs9543325). The closest candidate genes, KLF5, KLF12, PIBF1, DIS3 and BORA, range in distance from 265-586 kb. Sequencing three sub-regions containing the top ranked SNPs by imputation P-value revealed a 30 bp insertion/deletion (indel) variant that was significantly associated with pancreatic cancer risk (rs386772267, P=2.30×10-11, OR=1.22, 95% CI 1.15-1.28) and highly correlated to rs9543325 (r2=0.97 in the 1000 Genomes EUR population). This indel was the most significant cis-eQTL variant in a set of 222 histologically normal pancreatic tissue samples (b=0.26, P=0.004), with the insertion (risk-increasing) allele associated with reduced DIS3 expression. DIS3 encodes a catalytic subunit of the nuclear RNA exosome complex that mediates RNA processing and decay, and is mutated in several cancers. Chromosome conformation capture revealed a long range (570 kb) physical interaction between a sub-region of the risk locus, containing rs386772267, and a region ~6 kb upstream of DIS3. Finally, repressor regulatory activity and allele-specific protein binding by transcription factors of the TCF/LEF family were observed for the risk-increasing allele of rs386772267, indicating that expression regulation at this risk locus may be influenced by the Wnt signaling pathway. In conclusion, we have identified a putative functional indel variant at chr13q22.1 that associates with decreased DIS3 expression in carriers of pancreatic cancer risk-increasing alleles, and could therefore affect nuclear RNA processing and/or decay.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 4726-4738 |
| Number of pages | 13 |
| Journal | Human Molecular Genetics |
| Volume | 25 |
| Issue number | 21 |
| DOIs | |
| State | Published - 2016 |
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ASJC Scopus subject areas
- Molecular Biology
- Genetics
- Genetics(clinical)
Cite this
Functional characterization of a chr13q22.1 pancreatic cancer risk locus reveals long-range interaction and allele-specific effects on DIS3 expression. / Hoskins, Jason W.; Ibrahim, Abdisamad; Emmanuel, Mickey A.; Manmiller, Sarah M.; Wu, Yinglun; O'Neill, Maura; Jia, Jinping; Collins, Irene; Zhang, Mingfeng; Thomas, Janelle V.; Rost, Lauren M.; Das, Sudipto; Parikh, Hemang; Haake, Jefferson M.; Matters, Gail L.; Kurtz, Robert C.; Bamlet, William R.; Klein, Alison; Stolzenberg-Solomon, Rachael; Wolpin, Brian M.; Yarden, Ronit; Wang, Zhaoming; Smith, Jill; Olson, Sara H.; Andresson, Thorkell; Petersen, Gloria M; Amundadottir, Laufey T.
In: Human Molecular Genetics, Vol. 25, No. 21, 2016, p. 4726-4738.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Functional characterization of a chr13q22.1 pancreatic cancer risk locus reveals long-range interaction and allele-specific effects on DIS3 expression
AU - Hoskins, Jason W.
AU - Ibrahim, Abdisamad
AU - Emmanuel, Mickey A.
AU - Manmiller, Sarah M.
AU - Wu, Yinglun
AU - O'Neill, Maura
AU - Jia, Jinping
AU - Collins, Irene
AU - Zhang, Mingfeng
AU - Thomas, Janelle V.
AU - Rost, Lauren M.
AU - Das, Sudipto
AU - Parikh, Hemang
AU - Haake, Jefferson M.
AU - Matters, Gail L.
AU - Kurtz, Robert C.
AU - Bamlet, William R.
AU - Klein, Alison
AU - Stolzenberg-Solomon, Rachael
AU - Wolpin, Brian M.
AU - Yarden, Ronit
AU - Wang, Zhaoming
AU - Smith, Jill
AU - Olson, Sara H.
AU - Andresson, Thorkell
AU - Petersen, Gloria M
AU - Amundadottir, Laufey T.
PY - 2016
Y1 - 2016
N2 - Genome-wide association studies (GWAS) have identified multiple common susceptibility loci for pancreatic cancer. Here we report fine-mapping and functional analysis of one such locus residing in a 610 kb gene desert on chr13q22.1 (marked by rs9543325). The closest candidate genes, KLF5, KLF12, PIBF1, DIS3 and BORA, range in distance from 265-586 kb. Sequencing three sub-regions containing the top ranked SNPs by imputation P-value revealed a 30 bp insertion/deletion (indel) variant that was significantly associated with pancreatic cancer risk (rs386772267, P=2.30×10-11, OR=1.22, 95% CI 1.15-1.28) and highly correlated to rs9543325 (r2=0.97 in the 1000 Genomes EUR population). This indel was the most significant cis-eQTL variant in a set of 222 histologically normal pancreatic tissue samples (b=0.26, P=0.004), with the insertion (risk-increasing) allele associated with reduced DIS3 expression. DIS3 encodes a catalytic subunit of the nuclear RNA exosome complex that mediates RNA processing and decay, and is mutated in several cancers. Chromosome conformation capture revealed a long range (570 kb) physical interaction between a sub-region of the risk locus, containing rs386772267, and a region ~6 kb upstream of DIS3. Finally, repressor regulatory activity and allele-specific protein binding by transcription factors of the TCF/LEF family were observed for the risk-increasing allele of rs386772267, indicating that expression regulation at this risk locus may be influenced by the Wnt signaling pathway. In conclusion, we have identified a putative functional indel variant at chr13q22.1 that associates with decreased DIS3 expression in carriers of pancreatic cancer risk-increasing alleles, and could therefore affect nuclear RNA processing and/or decay.
AB - Genome-wide association studies (GWAS) have identified multiple common susceptibility loci for pancreatic cancer. Here we report fine-mapping and functional analysis of one such locus residing in a 610 kb gene desert on chr13q22.1 (marked by rs9543325). The closest candidate genes, KLF5, KLF12, PIBF1, DIS3 and BORA, range in distance from 265-586 kb. Sequencing three sub-regions containing the top ranked SNPs by imputation P-value revealed a 30 bp insertion/deletion (indel) variant that was significantly associated with pancreatic cancer risk (rs386772267, P=2.30×10-11, OR=1.22, 95% CI 1.15-1.28) and highly correlated to rs9543325 (r2=0.97 in the 1000 Genomes EUR population). This indel was the most significant cis-eQTL variant in a set of 222 histologically normal pancreatic tissue samples (b=0.26, P=0.004), with the insertion (risk-increasing) allele associated with reduced DIS3 expression. DIS3 encodes a catalytic subunit of the nuclear RNA exosome complex that mediates RNA processing and decay, and is mutated in several cancers. Chromosome conformation capture revealed a long range (570 kb) physical interaction between a sub-region of the risk locus, containing rs386772267, and a region ~6 kb upstream of DIS3. Finally, repressor regulatory activity and allele-specific protein binding by transcription factors of the TCF/LEF family were observed for the risk-increasing allele of rs386772267, indicating that expression regulation at this risk locus may be influenced by the Wnt signaling pathway. In conclusion, we have identified a putative functional indel variant at chr13q22.1 that associates with decreased DIS3 expression in carriers of pancreatic cancer risk-increasing alleles, and could therefore affect nuclear RNA processing and/or decay.
UR - http://www.scopus.com/inward/record.url?scp=85014843250&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85014843250&partnerID=8YFLogxK
U2 - 10.1093/hmg/ddw300
DO - 10.1093/hmg/ddw300
M3 - Article
C2 - 28172817
AN - SCOPUS:85014843250
VL - 25
SP - 4726
EP - 4738
JO - Human Molecular Genetics
JF - Human Molecular Genetics
SN - 0964-6906
IS - 21
ER -