Genetic association and transcriptome integration identify contributing genes and tissues at cystic fibrosis modifier loci

Jiafen Gong, Fan Wang, Bowei Xiao, Naim Panjwani, Fan Lin, Katherine Keenan, Julie Avolio, Mohsen Esmaeili, Lin Zhang, Gengming He, David Soave, Scott Mastromatteo, Zeynep Baskurt, Sangook Kim, Wanda K. O'Neal, Deepika Polineni, Scott Blackman, Harriet Corvol, Garry R Cutting, Mitchell Drumm & 4 others Michael R. Knowles, Johanna M. Rommens, Lei Sun, Lisa J. Strug

Research output: Contribution to journalArticle

Abstract

Cystic Fibrosis (CF) exhibits morbidity in several organs, including progressive lung disease in all patients and intestinal obstruction at birth (meconium ileus) in ~15%. Individuals with the same causal CFTR mutations show variable disease presentation which is partly attributed to modifier genes. With >6,500 participants from the International CF Gene Modifier Consortium, genome-wide association investigation identified a new modifier locus for meconium ileus encompassing ATP12A on chromosome 13 (min p = 3.83x10-10); replicated loci encompassing SLC6A14 on chromosome X and SLC26A9 on chromosome 1, (min p<2.2x10-16, 2.81x10-11, respectively); and replicated a suggestive locus on chromosome 7 near PRSS1 (min p = 2.55x10-7). PRSS1 is exclusively expressed in the exocrine pancreas and was previously associated with non-CF pancreatitis with functional characterization demonstrating impact on PRSS1 gene expression. We thus asked whether the other meconium ileus modifier loci impact gene expression and in which organ. We developed and applied a colocalization framework called the Simple Sum (SS) that integrates regulatory and genetic association information, and also contrasts colocalization evidence across tissues or genes. The associated modifier loci colocalized with expression quantitative trait loci (eQTLs) for ATP12A (p = 3.35x10-8), SLC6A14 (p = 1.12x10-10) and SLC26A9 (p = 4.48x10-5) in the pancreas, even though meconium ileus manifests in the intestine. The meconium ileus susceptibility locus on chromosome X appeared shifted in location from a previously identified locus for CF lung disease severity. Using the SS we integrated the lung disease association locus with eQTLs from nasal epithelia of 63 CF participants and demonstrated evidence of colocalization with airway-specific regulation of SLC6A14 (p = 2.3x10-4). Cystic Fibrosis is realizing the promise of personalized medicine, and identification of the contributing organ and understanding of tissue specificity for a gene modifier is essential for the next phase of personalizing therapeutic strategies.

Original languageEnglish (US)
Pages (from-to)e1008007
JournalPLoS genetics
Volume15
Issue number2
DOIs
StatePublished - Feb 1 2019

Fingerprint

Meconium
modifiers (genes)
Ileus
cystic fibrosis
Transcriptome
Cystic Fibrosis
transcriptome
chromosome
intestinal obstruction
Modifier Genes
loci
gene
Lung Diseases
Genes
Quantitative Trait Loci
X Chromosome
genes
gene expression
respiratory tract diseases
X chromosome

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research

Cite this

Genetic association and transcriptome integration identify contributing genes and tissues at cystic fibrosis modifier loci. / Gong, Jiafen; Wang, Fan; Xiao, Bowei; Panjwani, Naim; Lin, Fan; Keenan, Katherine; Avolio, Julie; Esmaeili, Mohsen; Zhang, Lin; He, Gengming; Soave, David; Mastromatteo, Scott; Baskurt, Zeynep; Kim, Sangook; O'Neal, Wanda K.; Polineni, Deepika; Blackman, Scott; Corvol, Harriet; Cutting, Garry R; Drumm, Mitchell; Knowles, Michael R.; Rommens, Johanna M.; Sun, Lei; Strug, Lisa J.

In: PLoS genetics, Vol. 15, No. 2, 01.02.2019, p. e1008007.

Research output: Contribution to journalArticle

Gong, J, Wang, F, Xiao, B, Panjwani, N, Lin, F, Keenan, K, Avolio, J, Esmaeili, M, Zhang, L, He, G, Soave, D, Mastromatteo, S, Baskurt, Z, Kim, S, O'Neal, WK, Polineni, D, Blackman, S, Corvol, H, Cutting, GR, Drumm, M, Knowles, MR, Rommens, JM, Sun, L & Strug, LJ 2019, 'Genetic association and transcriptome integration identify contributing genes and tissues at cystic fibrosis modifier loci' PLoS genetics, vol. 15, no. 2, pp. e1008007. https://doi.org/10.1371/journal.pgen.1008007
Gong, Jiafen ; Wang, Fan ; Xiao, Bowei ; Panjwani, Naim ; Lin, Fan ; Keenan, Katherine ; Avolio, Julie ; Esmaeili, Mohsen ; Zhang, Lin ; He, Gengming ; Soave, David ; Mastromatteo, Scott ; Baskurt, Zeynep ; Kim, Sangook ; O'Neal, Wanda K. ; Polineni, Deepika ; Blackman, Scott ; Corvol, Harriet ; Cutting, Garry R ; Drumm, Mitchell ; Knowles, Michael R. ; Rommens, Johanna M. ; Sun, Lei ; Strug, Lisa J. / Genetic association and transcriptome integration identify contributing genes and tissues at cystic fibrosis modifier loci. In: PLoS genetics. 2019 ; Vol. 15, No. 2. pp. e1008007.
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T1 - Genetic association and transcriptome integration identify contributing genes and tissues at cystic fibrosis modifier loci

AU - Gong, Jiafen

AU - Wang, Fan

AU - Xiao, Bowei

AU - Panjwani, Naim

AU - Lin, Fan

AU - Keenan, Katherine

AU - Avolio, Julie

AU - Esmaeili, Mohsen

AU - Zhang, Lin

AU - He, Gengming

AU - Soave, David

AU - Mastromatteo, Scott

AU - Baskurt, Zeynep

AU - Kim, Sangook

AU - O'Neal, Wanda K.

AU - Polineni, Deepika

AU - Blackman, Scott

AU - Corvol, Harriet

AU - Cutting, Garry R

AU - Drumm, Mitchell

AU - Knowles, Michael R.

AU - Rommens, Johanna M.

AU - Sun, Lei

AU - Strug, Lisa J.

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N2 - Cystic Fibrosis (CF) exhibits morbidity in several organs, including progressive lung disease in all patients and intestinal obstruction at birth (meconium ileus) in ~15%. Individuals with the same causal CFTR mutations show variable disease presentation which is partly attributed to modifier genes. With >6,500 participants from the International CF Gene Modifier Consortium, genome-wide association investigation identified a new modifier locus for meconium ileus encompassing ATP12A on chromosome 13 (min p = 3.83x10-10); replicated loci encompassing SLC6A14 on chromosome X and SLC26A9 on chromosome 1, (min p<2.2x10-16, 2.81x10-11, respectively); and replicated a suggestive locus on chromosome 7 near PRSS1 (min p = 2.55x10-7). PRSS1 is exclusively expressed in the exocrine pancreas and was previously associated with non-CF pancreatitis with functional characterization demonstrating impact on PRSS1 gene expression. We thus asked whether the other meconium ileus modifier loci impact gene expression and in which organ. We developed and applied a colocalization framework called the Simple Sum (SS) that integrates regulatory and genetic association information, and also contrasts colocalization evidence across tissues or genes. The associated modifier loci colocalized with expression quantitative trait loci (eQTLs) for ATP12A (p = 3.35x10-8), SLC6A14 (p = 1.12x10-10) and SLC26A9 (p = 4.48x10-5) in the pancreas, even though meconium ileus manifests in the intestine. The meconium ileus susceptibility locus on chromosome X appeared shifted in location from a previously identified locus for CF lung disease severity. Using the SS we integrated the lung disease association locus with eQTLs from nasal epithelia of 63 CF participants and demonstrated evidence of colocalization with airway-specific regulation of SLC6A14 (p = 2.3x10-4). Cystic Fibrosis is realizing the promise of personalized medicine, and identification of the contributing organ and understanding of tissue specificity for a gene modifier is essential for the next phase of personalizing therapeutic strategies.

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