Citations 2
Novel Genetic Risk Loci for Pancreatic Ductal Adenocarcinoma Identified in a Genome-wide Study of African Ancestry Individuals
Ni, Zhanmo , Zhong, Jun , McKean, David, Antwi, Samuel O. , Bracci, Paige M., Du, Mengmeng, Gallinger, Steven, Genkinger, Jeanine, Haiman, Christopher A, Hassan, Manal, Huff, Chad , Kooperberg, Charles, Kastrinos, Fay , LeMarchand, Loic, Lee, WP, Oberg, Ann L. , Park, Margaret A. , Permuth, Jennifer B., Risch, Harvey A., Scheet, Paul , Schwartz, Ann, Shu, Xie, Wolpin, Brian M. , Albanes, Demetrius, Andreotti, Gabriella , Beane-Freeman, Laura, Berndt, Sonja I, Brennan, Paul, Buring, Julie E, Cabrera, Natalia, Campa, Daniele, Chanock, Stephen J, Chung, Charles C., Eliassen, A Heather, Gaziano, J. Michael, Giles, G G, Giovannucci, Edward L, Goggins, Michael, Goodman, Phyllis J. , Hicks, Belynda, Hutchinson, Amy , Jones , Katzke, Verena, Kogevinas, Manolis, Kurtz, Robert C. , Laheru, Daniel, Lee, I, Milne, Roger, Mucci, Lorelei, Patel, Alpa V, Peruchet, Laia, Peters, Ulrike, Porta, Miquel, Rabe, Kari G. , Real, Francisco X, Ricceri, Fulvio, Rothman, Nathaniel, Sesso, Howard D. , Setiawan, Veronica W, Debra, Silverman, Southey, M C, Stampfer, M I, Um, Caroline, Visvanathan, Kala, Wentzensen, Nicolas, Willett, Walter C, Kraft, Peter, Visvanathan, Kala , Zhong, Jun , Zheng, Wei , Canzian, Federico , Malats, Nuria , Duggal, Priya , Klein, Alison P , Chaffee, Kari G. , Antwi, Samuel O , Visvanathan, Kala , Vergara, Candelaria , McKean, David , Connelly, Katelyn E. , Arslan, Alan A. , Bracci, Paige M. , Du, Mengmeng, Genkinger, Jeanine M. , Haiman, Christopher A. , Hung, Rayjean J. , Kooperberg, Charles , Lynch, Shannon M. , Moore, Steven C. , Permuth, Jennifer B. , Risch, Harvey A., Schwartz, Ann, Stolzenberg‐Solomon, Rachael Z. , Zheng, Wei , Albanes, Demetrius , Bamlet, William R. , Berndt, Sonja I. , Brennan, Paul, Buring, Julie E. , Cabrera-Castro, Natalia , Canzian, Federico , Chanock, Stephen Jacob , Chen, Yu , Gaziano, J. Michael , Giovannucci, Edward L. , Goggins, Michael , Hicks, Belynda , Katzke, Verena , Kogevinas, Manolis , Laheru, Daniel A. , Malats, Núria , Milne, Roger, Mucci, Lorelei A. , Neale, Rachel Ε. , Orlow, Irene , Peruchet‐Noray, Laia , Peters, Ulrike , Real, Francisco X. , Ricceri, Fulvio , Rothman, Nathaniel , Setiawan, Veronica Wendy , Silverman, Debra T. , Southey, Melissa C , Stampfer, Meir J. , Tobias, Geoffrey S. , Um, Caroline Y. , Wactawski‐Wende, Jean , Wentzensen, Nicolas , Yu, Kai , Duggal, Priya , Ámundadóttir, Laufey T. , Klein, Alison P.
No container title available | April 23, 2026 | Volume: No volume available | Issue: No issue available | Pages: No page available
Abstract Pancreatic cancer disproportionately affects Black individuals in the United States, but they have limited representation in genetic studies of pancreatic ductal adenocarcinoma (PDAC). To address this gap, we performed admixture mapping and genome-wide association analysis (GWAS) in genetically inferred African ancestry individuals (1,030 cases and 889 controls). Admixture mapping identified three regions with a significantly higher proportion of African ancestry in cases compared to controls (5q33.3, 10p1, 22q12.3). GWAS identified a genome-wide significant association at 5p15.33 ( CLPTM1L , rs383009:T>C, T Allele Frequency=0.51, OR:1.45, P value=1.24×10 -8 ), a locus previously associated with PDAC. Known loci at 5p15.33, 7q32.3, 8q24.21 and 7q25.1 also replicated (P value <0.01). Multi-ancestral fine-mapping identified two potential causal SNPs (rs3830069 and rs2735940) at 5p15.33. Collectively these findings identified novel PDAC risk loci and expanded our understanding of this deadly cancer in underrepresented populations, emphasizing the multifactorial nature of PDAC risk including inherited genetic and non-genetic factors. Statement of Significance To understand how genetic variation contributes to PDAC risk in Black people in North American, we studied individuals of genetically-inferred African ancestry. We identified novel risk loci and differences in the contribution of known loci. This demonstrates that ancestry-informed genetic analyses improve our understanding of PDAC risk and enhances discovery.
Different diabetes types and pancreatic ductal adenocarcinoma: a Mendelian randomization and pathway/gene-set analysis
Zhang, Ting , Mohindroo, Chirayu , Wang, Xiaoyu , Dutta, Diptavo , Liu, Jia , Katta, Shilpa, Li, Shengchao A. , Wang, Jiahui , Antwi, Samuel O. , Bracci, Paige M. , Du, Mengmeng, Gallinger, Steven , Goodman, Phyllis J. , Katzke, Verena, Patel, Alpa V. , Visvanathan, Kala , Andreotti, Gabriella , Brennan, Paul , Buring, Julie E. , Chanock, Stephen J., Chen, Yu , Giovannucci, Edward L. , Haiman, Christopher A. , Hassan, Manal M. , Holly, Elizabeth A., Jones, Miranda R. , Kraft, Peter, Kurtz, Robert C. , Ng, Kimmie , Oberg, Ann L. , Peters, Ulrike , Rabe, Kari G. , Rothman, Nathaniel , Sesso, Howard D. , Yuan, Chen, Wolpin, Brian M. , Yu, Kai , Stolzenberg‐Solomon, Rachael Z. , Mohindroo, Chirayu , Wang, Xiaoyu , Dutta, Diptavo , Liu, Jia , Li, Shengchao A , Antwi, Samuel O , Arslan, Alan A , Beane Freeman, Laura E , Canzian, Federico , Du, Mengmeng , Goodman, Phyllis J , Katzke, Verena , Kooperberg, Charles , Marchand, Loïc Le , Neale, Rachel E , Perdomo, Sandra , Shu, Xiao-Ou , Visvanathan, Kala , Van Den Eeden, Stephen K , White, Emily E. , Zheng, Wei , Albanes, Demetrius , Andreotti, Gabriella , Brennan, Paul , Buring, Julie E , Chanock, Stephen Jacob , Chen, Yu , Darst, Burcu F , Ferrari, Pietro , Giovannucci, Edward L , Goggins, Michael G , Haiman, Christopher A , Hassan, Manal M , Hung, Rayjean J , Jones, Miranda R , Kraft, Peter , Malats, Nuria , Moore, Steven C , Ng, Kimmie , Oberg, Ann L , Orlow, Irene , Peters, Ulrike , Porta, Miquel , Chaffee, Kari G. , Sánchez, Maria-Jose , Sesso, Howard D , Southey, Melissa C , Um, Caroline Y , Yarmolinsky, James , Yu, Herbert , Yuan, Chen , Zhong, Jun , Wolpin, Brian M , Risch, Harvey A , Amundadottir, Laufey , Klein, Alison P , Yu, Kai , Zhang, Haoyu , Stolzenberg-Solomon, Rachael , Zhang, Ting , Hua, Xing , Arslan, Alan A. , Freeman, Laura E. Beane , Canzian, Federico , Kooperberg, Charles , Marchand, Loı̈c Le , Neale, Rachel Ε. , Zheng, Wei , Albanes, Demetrius , Bamlet, William R. , Darst, Burcu F. , Goggins, Michael , Hung, Rayjean J. , Malats, Núria , Moore, Steven C. , Orlow, Irene , Porta, Miquel , Sánchez, María‐José , Silverman, Debra T. , Southey, Melissa C. , Um, Caroline Y. , Yu, Kai , Risch, Harvey A. , Ámundadóttir, Laufey T. , Klein, Alison P.
JNCI: Journal of the National Cancer Institute | November 8, 2025 | Volume: 118 | Issue: 3 | Pages: 437-447
Abstract Background The associations between different types of diabetes, characterized by distinct pathophysiology and genetic architecture, and pancreatic ductal adenocarcinoma (PDAC) risk are not understood. Methods We investigated associations of genetic susceptibility to type 2 diabetes (T2D), 8 T2D mechanistic clusters, type 1 diabetes (T1D), and maturity-onset diabetes of the young (MODY) with PDAC risk. We used genome-wide association study (GWAS) summary-level statistics for T2D (242 283 cases, 1 569 734 controls), T1D (18 942 cases, 501 638 controls), and PDAC (10 244 cases and 360 535 controls) in individuals of European ancestry. Results Two-sample Mendelian randomization (MR) using the Robust Adjusted Profile Score (MR-RAPS) method indicated that genetically predicted T2D was associated with PDAC risk (OR = 1.10; 95% CI = 1.05 to 1.15), particularly the T2D obesity (OR = 1.28; 95% CI = 1.15 to 1.42) and lipodystrophy (OR = 1.25; 95% CI = 1.03 to 1.51) clusters. No association was observed for T1D with PDAC risk (OR = 1.01; 95% CI = 0.99 to 1.02). Pathway/gene-set analysis using the summary-based Adaptive Rank Truncated Product (sARTP) method revealed a significant association between the MODY gene-sets and PDAC risk (P = 1.5 × 10−8), which remained after excluding 20 known PDAC GWAS loci (P = 7.6 × 10−4). HNF1A, FOXA3, and HNF4A were the top contributing genes after excluding the previously identified GWAS loci regions. Conclusions Our results from this genetic association study support that T2D, particularly the obesity and lipodystrophy mechanistic clusters, and MODY genomic susceptibility regions play a role in the etiology of PDAC.