Pleiotropic modifiers of age-related diabetes and neonatal intestinal obstruction in cystic fibrosis

Melis A Aksit; Hua Ling; Rhonda G Pace; Karen S Raraigh; Frankline Onchiri; Anna V Faino; Kymberleigh Pagel; Elizabeth Pugh; Adrienne M Stilp; Quan Sun; Elizabeth E Blue; Fred A Wright; Yi-Hui Zhou; Michael J Bamshad; Ronald L Gibson; Michael R Knowles; Garry R Cutting; Scott M Blackman; CF Genome Project

doi:10.1016/j.ajhg.2022.09.004

Pleiotropic modifiers of age-related diabetes and neonatal intestinal obstruction in cystic fibrosis

Am J Hum Genet. 2022 Oct 6;109(10):1894-1908. doi: 10.1016/j.ajhg.2022.09.004.

Authors

Melis A Aksit¹, Hua Ling², Rhonda G Pace³, Karen S Raraigh¹, Frankline Onchiri⁴, Anna V Faino⁴, Kymberleigh Pagel⁵, Elizabeth Pugh², Adrienne M Stilp⁶, Quan Sun⁷, Elizabeth E Blue⁸, Fred A Wright⁹, Yi-Hui Zhou¹⁰, Michael J Bamshad¹¹, Ronald L Gibson¹², Michael R Knowles³, Garry R Cutting¹, Scott M Blackman¹³; CF Genome Project

Collaborators

Affiliations

¹ McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
² Department of Genetic Medicine, Center for Inherited Disease Research, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
³ Marsico Lung Institute/UNC CF Research Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
⁴ Children's Core for Biostatistics, Epidemiology and Analytics in Research, Seattle Children's Research Institute, Seattle, WA 98101, USA.
⁵ The Institute for Computational Medicine, The Johns Hopkins University, Baltimore, MD 21218, USA.
⁶ Department of Biostatistics, University of Washington, Seattle, WA 98195, USA.
⁷ Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
⁸ Department of Medicine, Division of Medical Genetics, University of Washington, Seattle, WA 98195, USA; Brotman Baty Institute for Precision Medicine, Seattle, WA 98195, USA.
⁹ Department of Statistics, North Carolina State University, Raleigh, NC 27797, USA; Bioinformatics Research Center, North Carolina State University, Raleigh, NC 27797, USA; Department of Biological Sciences, North Carolina State University, Raleigh, NC 27797, USA.
¹⁰ Bioinformatics Research Center, North Carolina State University, Raleigh, NC 27797, USA.
¹¹ Brotman Baty Institute for Precision Medicine, Seattle, WA 98195, USA; Department of Pediatrics, Division of Genetic Medicine, University of Washington, Seattle, WA 98195, USA; Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA; Center for Clinical and Translational Research, Seattle Children's Hospital, Seattle, WA 98105, USA.
¹² Center for Clinical and Translational Research, Seattle Children's Hospital, Seattle, WA 98105, USA; Department of Pediatrics, Division of Pulmonary & Sleep Medicine, University of Washington School of Medicine/Seattle Children's Hospital, Seattle, WA, USA.
¹³ McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Division of Pediatric Endocrinology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. Electronic address: sblackman@jhmi.edu.

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.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Cystic Fibrosis Transmembrane Conductance Regulator / genetics
Cystic Fibrosis* / complications
Cystic Fibrosis* / genetics
Diabetes Mellitus* / genetics
Genome-Wide Association Study
Humans
Infant, Newborn
Infant, Newborn, Diseases*
Intestinal Obstruction* / complications
Intestinal Obstruction* / genetics

Substances

Cystic Fibrosis Transmembrane Conductance Regulator

Abstract

Publication types

MeSH terms

Substances

Grants and funding