Genome-wide association meta-analysis identifies novel GP2 gene risk variants for pancreatic cancer in the Japanese population

Yingsong Lin; Masahiro Nakatochi; Yasuyuki Hosono; Hidemi M. Ito; Yoichiro Kamatani; Akihito Inoko; Hiromi Sakamoto; Fumie Kinoshita; Yumiko Kobayashi; Hiroshi Ishii; Masato Ozaka; Takashi Sasaki; Masato Matsuyama; Naoki Sasahira; Manabu Morimoto; Satoshi Kobayashi; Taito Fukushima; Makoto Ueno; Shinichi Ohkawa; Naoto Egawa; Sawako Kuruma; Mitsuru Mori; Haruhisa Nakao; Yasushi Adachi; Masumi Okuda; Takako Osaki; Shigeru Kamiya; Chaochen Wang; Kazuo Hara; Yasuhiro Shimizu

doi:10.1038/s41467-020-16711-w

GeneticsNature CommunicationsJun 24, 2020

Peer-reviewed journal article

Genome-wide association meta-analysis identifies novel GP2 gene risk variants for pancreatic cancer in the Japanese population

Yingsong Lin iD, Masahiro Nakatochi iD, Yasuyuki Hosono, Hidemi M. Ito iD, Yoichiro Kamatani iD, Akihito Inoko iD, Hiromi Sakamoto, Fumie Kinoshita iD, Yumiko Kobayashi iD, Hiroshi Ishii iD, Masato Ozaka iD, Takashi Sasaki iD, Masato Matsuyama iD, Naoki Sasahira iD, Manabu Morimoto iD, Satoshi Kobayashi iD, Taito Fukushima iD, Makoto Ueno iD, Shinichi Ohkawa, Naoto Egawa, Sawako Kuruma iD, Mitsuru Mori iD, Haruhisa Nakao iD, Yasushi Adachi iD, Masumi Okuda iD, , Keitaro Matsuo iD

Abstract

The etiology of pancreatic cancer remains largely unknown. Here, we report the results of a meta-analysis of three genome-wide association studies (GWASs) comprising 2,039 pancreatic cancer cases and 32,592 controls, the largest sample size in the Japanese population. We identified 3 (13q12.2, 13q22.1, and 16p12.3) genome-wide significant loci (P<5.0x10-8) and 4 suggestive loci (P<1.0x10-6) for pancreatic cancer. Of these risk loci, 16p12.3 is novel; the lead SNP maps to rs78193826 (odds ratio (OR)=1.46, 95% CI=1.29-1.66, P=4.28x10-9), an Asian-specific, nonsynonymous glycoprotein 2 (GP2) gene variant predicted to be highly deleterious. Additionally, the gene-based GWAS identified a novel gene, KRT8, which is linked to exocrine pancreatic and liver diseases. The identified GP2 gene variants were pleiotropic for multiple traits, including type 2 diabetes, hemoglobin A1c (HbA1c) levels, and pancreatic cancer. Mendelian randomization analyses corroborated causality between HbA1c and pancreatic cancer. These findings suggest that GP2 gene variants are associated with pancreatic cancer susceptibility in the Japanese population, prompting further functional characterization of this locus.

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