@article{bdd6803984354b88ae3ddaf6e11b642b,
title = "Multi-omic analysis elucidates the genetic basis of hydrocephalus",
abstract = "We conducted PrediXcan analysis of hydrocephalus risk in ten neurological tissues and whole blood. Decreased expression of MAEL in the brain was significantly associated (Bonferroni-adjusted p < 0.05) with hydrocephalus. PrediXcan analysis of brain imaging and genomics data in the independent UK Biobank (N = 8,428) revealed that MAEL expression in the frontal cortex is associated with white matter and total brain volumes. Among the top differentially expressed genes in brain, we observed a significant enrichment for gene-level associations with these structural phenotypes, suggesting an effect on disease risk through regulation of brain structure and integrity. We found additional support for these genes through analysis of the choroid plexus transcriptome of a murine model of hydrocephalus. Finally, differential protein expression analysis in patient cerebrospinal fluid recapitulated disease-associated expression changes in neurological tissues, but not in whole blood. Our findings provide convergent evidence highlighting the importance of tissue-specific pathways and mechanisms in the pathophysiology of hydrocephalus.",
keywords = "BioVU, GWAS, PrediXcan, TWAS, UK Biobank, electronic health records, human genetics, hydrocephalus, neurodevelopmental disorders, proteomics, transcriptomics",
author = "Hale, {Andrew T.} and Lisa Bastarache and Morales, {Diego M.} and Wellons, {John C.} and Limbrick, {David D.} and Gamazon, {Eric R.}",
note = "Funding Information: A.T.H. is supported by the Vanderbilt University Medical Scientist Training Program ( T32GM007347 ) and the National Institutes of Health ( F30HL143826 and R35HG010718 ). E.R.G. is supported by the National Institutes of Health under award numbers R35HG010718 , R01HG011138 , R01GM140287 , and R01HL133559 . Funding sources for BioVU are listed at https://victr.vanderbilt.edu/pub/biovu/ . E.R.G. has also significantly benefitted from a Fellowship at Clare Hall, University of Cambridge (UK) and is grateful to the President and Fellows of the college for a stimulating intellectual home. Cerebrospinal fluid proteomic analysis was supported by the Washington University Institute of Clinical and Translational Sciences grant UL1TR002345 from the National Center for Advancing Translational Sciences (NCATS) of the National Institutes of Health (NIH). D.D.L. is also supported by a career development award ( NIH /NINDS K23NS075151). A.T.H. and E.R.G. would also like to thank the Vanderbilt Institute for Clinical and Translational Research (VICTR) for the micro-grant ( VR52639 ) supporting processing of imputation data. A.T.H. would like to thank the Surgical Outcomes Center for Kids (SOCKs) at Monroe Carell Jr. Children{\textquoteright}s Hospital for administrative support. Funding Information: A.T.H. is supported by the Vanderbilt University Medical Scientist Training Program (T32GM007347) and the National Institutes of Health (F30HL143826 and R35HG010718). E.R.G. is supported by the National Institutes of Health under award numbers R35HG010718, R01HG011138, R01GM140287, and R01HL133559. Funding sources for BioVU are listed at https://victr.vanderbilt.edu/pub/biovu/. E.R.G. has also significantly benefitted from a Fellowship at Clare Hall, University of Cambridge (UK) and is grateful to the President and Fellows of the college for a stimulating intellectual home. Cerebrospinal fluid proteomic analysis was supported by the Washington University Institute of Clinical and Translational Sciences grant UL1TR002345 from the National Center for Advancing Translational Sciences (NCATS) of the National Institutes of Health (NIH). D.D.L. is also supported by a career development award (NIH/NINDS K23NS075151). A.T.H. and E.R.G. would also like to thank the Vanderbilt Institute for Clinical and Translational Research (VICTR) for the micro-grant (VR52639) supporting processing of imputation data. A.T.H. would like to thank the Surgical Outcomes Center for Kids (SOCKs) at Monroe Carell Jr. Children's Hospital for administrative support. Conceptualization, A.T.H. and E.R.G.; methodology, A.T.H. L.B. D.D.L. and E.R.G.; investigation, A.T.H. L.B. D.M.M. D.D.L. and E.R.G.; writing ? original draft, A.T.H. and E.R.G.; writing ? review and editing, A.T.H. J.C.W. D.D.L. and E.R.G.; funding acquisition, A.T.H. and E.R.G.; supervision, E.R.G. E.R.G. receives an honorarium from the journal Circulation Research of the American Heart Association as a member of the Editorial Board. Publisher Copyright: {\textcopyright} 2021 The Author(s)",
year = "2021",
month = may,
day = "4",
doi = "10.1016/j.celrep.2021.109085",
language = "English",
volume = "35",
journal = "Cell Reports",
issn = "2211-1247",
number = "5",
}