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

PLoS Genetics
Jiafen GongLisa J Strug

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...Continue Reading

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Citations

Oct 4, 2019·The Journal of Clinical Investigation·Anh-Thu N LamGarry R Cutting
Nov 8, 2019·The Journal of Clinical Endocrinology and Metabolism·Melis A AksitScott M Blackman
Aug 1, 2020·Human Genetics·Morgan SandersJeremy W Prokop
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Oct 23, 2020·PLoS Computational Biology·Naim PanjwaniLisa J Strug
Jan 28, 2021·Genetics in Medicine : Official Journal of the American College of Medical Genetics·Yu-Chung LinLisa J Strug
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Mar 18, 2021·Biometrics·Lin Zhang, Lei Sun
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Sep 8, 2021·Frontiers in Microbiology·Gaurav AgarwalBhabesh Dutta
Oct 14, 2021·American Journal of Physiology. Cell Physiology·Alan S Verkman, Luis J V Galietta

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Datasets Mentioned

BETA
GSE32892

Methods Mentioned

BETA
genotyping
chip
PCA

Software Mentioned

PEER
SHERLOCK
Hapmap
R script
R package “ CompQuadForm ”
Simple
run
KING
normalize
R

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