Germline variation in the insulin-like growth factor pathway and risk of Barrett’s esophagus and esophageal adenocarcinoma
Authors: Dighe Shruti G , Chen Jianhong , Yan Li , He Qianchuan , Gharahkhani Puya , Onstad Lynn , Levine David M , Palles Claire , Ye Weimin , Gammon Marilie D , Iyer Prasad G , Anderson Lesley A , Liu Geoffrey , Wu Anna H , Dai James Y , Chow Wong-Ho , Risch Harvey A , Lagergren Jesper , Shaheen Nicholas J , Bernstein Leslie , Corley Douglas A , Prenen Hans , deCaestecker John , MacDonald David , Moayyedi Paul , Barr Hugh , Love Sharon B , Chegwidden Laura , Attwood Stephen , Watson Peter , Harrison Rebecca , Ott Katja , Moebus Susanne , Venerito Marino , Lang Hauke , Mayershofer Rupert , Knapp Michael , Veits Lothar , Gerges Christian , Weismüller Josef , Gockel Ines , Vashist Yogesh , Nöthen Markus M , Izbicki Jakob R , Manner Hendrik , Neuhaus Horst , Rösch Thomas , Böhmer Anne C , Hölscher Arnulf H , Anders Mario , Pech Oliver , Schumacher Brigitte , Schmidt Claudia , Schmidt Thomas , Noder Tania , Lorenz Dietmar , Vieth Michael , May Andrea , Hess Timo , Kreuser Nicole , Becker Jessica , Ell Christian , Ambrosone Christine B , Moysich Kirsten B , MacGregor Stuart , Tomlinson Ian , Whiteman David C , Jankowski Janusz , Schumacher Johannes , Vaughan Thomas L , Madeleine Margaret M , Hardie Laura J , Buas Matthew F 
Published: December 2020

Abstract
Genome-wide association studies (GWAS) of esophageal adenocarcinoma (EAC) and its precursor, Barrett’s esophagus (BE), have uncovered significant genetic components of risk, but most heritability remains unexplained. Targeted assessment of genetic variation in biologically relevant pathways using novel analytical approaches may identify missed susceptibility signals. Central obesity, a key BE/EAC risk factor, is linked to systemic inflammation, altered hormonal signaling and insulin-like growth factor (IGF) axis dysfunction. Here, we assessed IGF-related genetic variation and risk of BE and EAC. Principal component analysis was employed to evaluate pathway-level and gene-level associations with BE/EAC, using genotypes for 270 single-nucleotide polymorphisms (SNPs) in or near 12 IGF-related genes, ascertained from 3295 BE cases, 2515 EAC cases and 3207 controls in the Barrett’s and Esophageal Adenocarcinoma Consortium (BEACON) GWAS. Gene-level signals were assessed using Multi-marker Analysis of GenoMic Annotation (MAGMA) and SNP summary statistics from BEACON and an expanded GWAS meta-analysis (6167 BE cases, 4112 EAC cases, 17 159 controls). Global variation in the IGF pathway was associated with risk of BE (P = 0.0015). Gene-level associations with BE were observed for GHR (growth hormone receptor; P = 0.00046, false discovery rate q = 0.0056) and IGF1R (IGF1 receptor; P = 0.0090, q = 0.0542). These gene-level signals remained significant at q &lt; 0.1 when assessed using data from the largest available BE/EAC GWAS meta-analysis. No significant associations were observed for EAC. This study represents the most comprehensive evaluation to date of inherited genetic variation in the IGF pathway and BE/EAC risk, providing novel evidence that variation in two genes encoding cell-surface receptors, GHR and IGF1R, may influence risk of BE.