Multitrait genetic association analysis identifies 50 new risk loci for gastro-oesophageal reflux, seven new loci for Barrett's oesophagus and provides insights into clinical heterogeneity in reflux diagnosis.
Barrett's oesophagus
gastro-esophageal reflux disease
genetics
oesophageal reflux
Journal
Gut
ISSN: 1468-3288
Titre abrégé: Gut
Pays: England
ID NLM: 2985108R
Informations de publication
Date de publication:
06 2022
06 2022
Historique:
received:
19
12
2020
accepted:
13
06
2021
pubmed:
1
7
2021
medline:
10
5
2022
entrez:
30
6
2021
Statut:
ppublish
Résumé
Gastro-oesophageal reflux disease (GERD) has heterogeneous aetiology primarily attributable to its symptom-based definitions. GERD genome-wide association studies (GWASs) have shown strong genetic overlaps with established risk factors such as obesity and depression. We hypothesised that the shared genetic architecture between GERD and these risk factors can be leveraged to (1) identify new GERD and Barrett's oesophagus (BE) risk loci and (2) explore potentially heterogeneous pathways leading to GERD and oesophageal complications. We applied multitrait GWAS models combining GERD (78 707 cases; 288 734 controls) and genetically correlated traits including education attainment, depression and body mass index. We also used multitrait analysis to identify BE risk loci. Top hits were replicated in 23andMe (462 753 GERD cases, 24 099 BE cases, 1 484 025 controls). We additionally dissected the GERD loci into obesity-driven and depression-driven subgroups. These subgroups were investigated to determine how they relate to tissue-specific gene expression and to risk of serious oesophageal disease (BE and/or oesophageal adenocarcinoma, EA). We identified 88 loci associated with GERD, with 59 replicating in 23andMe after multiple testing corrections. Our BE analysis identified seven novel loci. Additionally we showed that only the obesity-driven GERD loci (but not the depression-driven loci) were associated with genes enriched in oesophageal tissues and successfully predicted BE/EA. Our multitrait model identified many novel risk loci for GERD and BE. We present strong evidence for a genetic underpinning of disease heterogeneity in GERD and show that GERD loci associated with depressive symptoms are not strong predictors of BE/EA relative to obesity-driven GERD loci.
Identifiants
pubmed: 34187846
pii: gutjnl-2020-323906
doi: 10.1136/gutjnl-2020-323906
pmc: PMC9120377
doi:
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1053-1061Subventions
Organisme : NCI NIH HHS
ID : P30 CA016672
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA133996
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK063616
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA136725
Pays : United States
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : NCI NIH HHS
ID : R01 CA100264
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA059736
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA093459
Pays : United States
Investigateurs
Rebecca Fitzgerald
(R)
Matt Buas
(M)
Marilie D Gammon
(MD)
Douglas A Corley
(DA)
Nicholas J Shaheen
(NJ)
Laura J Hardie
(LJ)
Nigel C Bird
(NC)
Brian J Reid
(BJ)
Wong-Ho Chow
(WH)
Harvey A Risch
(HA)
Weimin Ye
(W)
Geoffrey Liu
(G)
Yvonne Romero
(Y)
Leslie Bernstein
(L)
Anna H Wu
(AH)
Johannes Schumacher
(J)
Ines Gockel
(I)
Anne Bohmer
(A)
Janusz Jankowski
(J)
Claire Palles
(C)
David C Whiteman
(DC)
Michelle Agee
(M)
Stella Aslibekyan
(S)
Adam Auton
(A)
Robert K Bell
(RK)
Katarzyna Bryc
(K)
Sarah K Clark
(SK)
Sarah L Elson
(SL)
Kipper Fletez-Brant
(K)
Pierre Fontanillas
(P)
Nicholas A Furlotte
(NA)
Pooja M Gandhi
(PM)
Karl Heilbron
(K)
Barry Hicks
(B)
David A Hinds
(DA)
Karen E Huber
(KE)
Ethan M Jewett
(EM)
Yunxuan Jiang
(Y)
Aaron Kleinman
(A)
Keng-Han Lin
(KH)
Nadia K Litterman
(NK)
Marie K Luff
(MK)
Jennifer C McCreight
(JC)
Matthew H McIntyre
(MH)
Kimberly F McManus
(KF)
Joanna L Mountain
(JL)
Sahar V Mozaffari
(SV)
Priyanka Nandakumar
(P)
Elizabeth S Noblin
(ES)
Carrie Am Northover
(CA)
Jared O'Connell
(J)
Aaron A Petrakovitz
(AA)
Steven J Pitts
(SJ)
G David Poznik
(G)
J Fah Sathirapongsasuti
(J)
Anjali J Shastri
(AJ)
Janie F Shelton
(JF)
Suyash Shringarpure
(S)
Chao Tian
(C)
Joyce Y Tung
(JY)
Robert J Tunney
(RJ)
Vladimir Vacic
(V)
Xin Wang
(X)
Amir S Zare
(AS)
Informations de copyright
© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
Déclaration de conflit d'intérêts
Competing interests: Authors listed in the 23andMe Research Team are employees for the company 23andMe Co.
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