Integration of human genetics and mutli-omics data implicates novel pathways in hydrocephalus

Abstract:

Integration of human genetics and mutli-omics data implicates novel pathways in hydrocephalus

Andrew T. Hale¹, Lisa Bastarache², Diego M. Morales³, John C. Wellons III⁴, David D. Limbrick Jr.³, Steven J. Schiff,⁵ Eric R. Gamazon^6,7

¹Medical Scientist Training Program and ²Department of Bioinformatics, Vanderbilt University School of Medicine; ³Department of Neurological Surgery, St. Louis Children’s Hospital; ⁴Division of Pediatric Neurosurgery, Monroe Carell Jr. Children’s Hospital of Vanderbilt University; ⁵Center for Neural Engineering, Departments of Neurosurgery, Engineering Science and Mechanics, and Physics, Penn State University; ⁶Division of Genetic Medicine, Vanderbilt University Medical Center; ⁷Clare Hall, University of Cambridge.

Hydrocephalus is a component of ~200 genetic syndromes and a secondary consequence of many pathologies (infection, hemorrhage, etc.). Recent studies have suggested that hydrocephalus is caused, at least in part, by abnormal neurogenesis which may lead to alterations in white matter and total brain volume. Using PrediXcan (Gamazon et al. Nature Genetics 2018), we conducted a GWAS to identify genes associated with pediatric hydrocephalus in BioVU (287 cases and 18,740 controls). We identify maelstrom (MAEL), a gene involved in DNA transposon and epigenetic regulation, as a genome-wide predictor of hydrocephalus. We then used PrediXcan to identify genes associated with white matter and total brain volumes using MRI data from 8,428 individuals in the UK Biobank (controlling for age, sex, and genetic ancestry using 40 principal components). MAEL expression is associated with decreased white matter and total brain volumes (Bonferroni-adjusted pxtagstartz 0.05), suggesting that