A multilayered post-GWAS assessment on genetic susceptibility to pancreatic cancer
A multilayered post-GWAS assessment on genetic susceptibility to pancreatic cancer
ABSTRACT Pancreatic cancer (PC) is a complex disease in which both non-genetic and genetic factors interplay. To-date, 40 GWAS hits have been associated with PC risk in individuals of European descent, explaining 4.1% of the phenotypic variance. Here, we complemented a classical new PC GWAS (1D) with spatial autocorrelation analysis (2D) and Hi-C maps (3D) to gain additional insight into the inherited basis of PC. In-silico functional analysis of public genomic information allowed prioritization of potentially relevant candidate variants. We replicated 17/40 previous PC-GWAS hits and identified novel variants with potential biological functions. The spatial autocorrelation approach prioritized low MAF variants not detected by GWAS. These were further expanded via 3D interactions to 54 target regions with high functional relevance. This multi-step strategy, combined with an in-depth in-silico functional analysis, offers a comprehensive approach to advance the study of PC genetic susceptibility and could be applied to other diseases.
Costello E、Garc¨aa-Closas M、Gunter M、Rothman N、SBC/EPICURO Investigators、Beane-Freeman L、Kogevinas M、Bueno-de-Mesquita B、Goodman PJ、LeMarchand L、Li D、Neale RE、Petersen GM、Risch HA、Thornquist MD、Kleeff J、M¨￠rquez M、Mora J、Scarpa A、Amundadottir LT、Marti-Renom MA、Carrato A、Michalski CW、Gress T、Sharp L、Ilzarbe L、Crnogorac-Jurcevic T、Barber¨¤ VM、Real FX、Alonso L、Kong B、Cecchini Ll、Arnes L、Rodr¨aguez JA、Arslan AA、Klein AP、O?ˉDriscoll D、Buring J、Brennan P、Lawlor RT、Molina-Montes E、G¨?mez-Rubio P、Canzian F、Malats N、Tard¨?n A、Silverman D、L¨?pez de Maturana E、Yu J、Albanes D、Hidalgo M、Mu?oz-Bellv¨as L、Zheng W、Shu XO、Bracci PM、S¨￠nchez MJ、Stolzenberg-Solomon RZ、O?ˉRorke M、Mart¨an-Antoniano I、PanGenEU Investigators、Visvanathan K、Greenhalf W、Farr¨| A、Gaziano JM、Ye W、Chanock S、Wolpin BM、L?hr M、Balsells J、Iglesias M、Gallinger S、Lao O、Easton D、Molero X、Perea J、Dom¨anguez-Mu?oz E、Peters U、Du M
医学研究方法肿瘤学遗传学
pancreatic cancer riskgenome wide association analysisgenetic susceptibility3D genomic structureLocal Indices of Genome Spatial Autocorrelation
Costello E,Garc¨aa-Closas M,Gunter M,Rothman N,SBC/EPICURO Investigators,Beane-Freeman L,Kogevinas M,Bueno-de-Mesquita B,Goodman PJ,LeMarchand L,Li D,Neale RE,Petersen GM,Risch HA,Thornquist MD,Kleeff J,M¨￠rquez M,Mora J,Scarpa A,Amundadottir LT,Marti-Renom MA,Carrato A,Michalski CW,Gress T,Sharp L,Ilzarbe L,Crnogorac-Jurcevic T,Barber¨¤ VM,Real FX,Alonso L,Kong B,Cecchini Ll,Arnes L,Rodr¨aguez JA,Arslan AA,Klein AP,O?ˉDriscoll D,Buring J,Brennan P,Lawlor RT,Molina-Montes E,G¨?mez-Rubio P,Canzian F,Malats N,Tard¨?n A,Silverman D,L¨?pez de Maturana E,Yu J,Albanes D,Hidalgo M,Mu?oz-Bellv¨as L,Zheng W,Shu XO,Bracci PM,S¨￠nchez MJ,Stolzenberg-Solomon RZ,O?ˉRorke M,Mart¨an-Antoniano I,PanGenEU Investigators,Visvanathan K,Greenhalf W,Farr¨| A,Gaziano JM,Ye W,Chanock S,Wolpin BM,L?hr M,Balsells J,Iglesias M,Gallinger S,Lao O,Easton D,Molero X,Perea J,Dom¨anguez-Mu?oz E,Peters U,Du M.A multilayered post-GWAS assessment on genetic susceptibility to pancreatic cancer[EB/OL].(2025-03-28)[2025-05-02].https://www.biorxiv.org/content/10.1101/2020.02.11.941351.点此复制
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