@article{c37a6253cc6b490291b25f0ceee02d92,
title = "Pleiotropic modifiers of age-related diabetes and neonatal intestinal obstruction in cystic fibrosis",
abstract = "Individuals with cystic fibrosis (CF) develop complications of the gastrointestinal tract influenced by genetic variants outside of CFTR. Cystic fibrosis-related diabetes (CFRD) is a distinct form of diabetes with a variable age of onset that occurs frequently in individuals with CF, while meconium ileus (MI) is a severe neonatal intestinal obstruction affecting ∼20% of newborns with CF. CFRD and MI are slightly correlated traits with previous evidence of overlap in their genetic architectures. To better understand the genetic commonality between CFRD and MI, we used whole-genome-sequencing data from the CF Genome Project to perform genome-wide association. These analyses revealed variants at 11 loci (6 not previously identified) that associated with MI and at 12 loci (5 not previously identified) that associated with CFRD. Of these, variants at SLC26A9, CEBPB, and PRSS1 associated with both traits; variants at SLC26A9 and CEBPB increased risk for both traits, while variants at PRSS1, the higher-risk alleles for CFRD, conferred lower risk for MI. Furthermore, common and rare variants within the SLC26A9 locus associated with MI only or CFRD only. As expected, different loci modify risk of CFRD and MI; however, a subset exhibit pleiotropic effects indicating etiologic and mechanistic overlap between these two otherwise distinct complications of CF.",
keywords = "CFRD, cystic fibrosis, cystic fibrosis-related diabetes, diabetes, genetic modifier, intestinal obstruction, meconium ileus, pleiotropy",
author = "{CF Genome Project} and Aksit, {Melis A.} and Hua Ling and Pace, {Rhonda G.} and Raraigh, {Karen S.} and Frankline Onchiri and Faino, {Anna V.} and Kymberleigh Pagel and Elizabeth Pugh and Stilp, {Adrienne M.} and Quan Sun and Blue, {Elizabeth E.} and Wright, {Fred A.} and Zhou, {Yi Hui} and Bamshad, {Michael J.} and Gibson, {Ronald L.} and Knowles, {Michael R.} and Cutting, {Garry R.} and Blackman, {Scott M.} and Elizabeth Blue and Kati Buckingham and Chong, {Jessica X.} and Michael Collaco and Hong Dang and Alice Eastman and Anna Faino and Gallins, {Paul J.} and Ronald Gibson and Beth Godwin and Gordon, {William W.} and Kurt Hetrick and Le Huang and Lam, {Anh Thu N.} and Weifang Liu and Yun Li and O'Neal, {Wanda K.} and Mark Porter and Rebekah Mikeasky and Margaret Rosenfeld and Jonathan Rosen and Adrienne Stilp and Stonebraker, {Jaclyn R.} and Jia Wen and Yingxi Yang and Peng Zhang and Yan Zhang",
note = "Funding Information: The authors would like to thank the Cystic Fibrosis Foundation for the use of CF Foundation Patient Registry data to conduct this study. Additionally, we would like to thank the subjects, care providers, and clinic coordinators at CF centers throughout the United States for their contributions to the CF Foundation Patient Registry. The authors also thank Dr. Carol Bertrand (Department of Cell Biology, University of Pittsburgh) for sharing the results of her functional studies, Anh-Thu Ngoc Lam (McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University) for assistance in preparing the samples, and Deepti Jain (Department of Biostatistics, University of Washington) for her contributions in determining the filtering strategy for rare variant association analyses. Support provided by NHLBI, through the BioData Catalyst program (award 1OT3HL142479-01, 1OT3HL142478-01, 1OT3HL142481-01, 1OT3HL142480-01, 1OT3HL147154). Funded by the Cystic Fibrosis Foundation CUTTIN18XX1, BAMSHA18XX0, and KNOWLE18XX0. The authors declare no competing interests. Funding Information: Support provided by NHLBI , through the BioData Catalyst program (award 1OT3HL142479-01 , 1OT3HL142478-01 , 1OT3HL142481-01 , 1OT3HL142480-01 , 1OT3HL147154 ). Funded by the Cystic Fibrosis Foundation CUTTIN18XX1 , BAMSHA18XX0 , and KNOWLE18XX0 . Publisher Copyright: {\textcopyright} 2022 American Society of Human Genetics",
year = "2022",
month = oct,
day = "6",
doi = "10.1016/j.ajhg.2022.09.004",
language = "English (US)",
volume = "109",
pages = "1894--1908",
journal = "American Journal of Human Genetics",
issn = "0002-9297",
publisher = "Cell Press",
number = "10",
}