115. Identification of a Genome-wide Predictor of Hydrocephalus and Ventriculoperitoneal Shunt Failure in Patients of African Ancestry

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Authors: Andrew Hale; Albert Isaacs, MD; John Wellons; David Limbrick, MD, PhD; Steven Schiff, MD, PhD; Eric Gamazon (Nashville, TN)

Introduction: The genetic mechanisms underlying hydrocephalus risk and pathogenesis are complex. While many genes have been implicated in patients of European ancestry, very little is known about the genetic architecture of hydrocephalus in patients of African-descent. Here, using whole-genome genetic information linked to a deidentified electronic health record (BioVU), we explore the genetic mechanisms underlying hydrocephalus in patients of African-ancestry.

Methods: We used BioVU to identify 46 patients with communicating (n=24) or obstructive (n=22) hydrocephalus treated with ventriculoperitoneal (VP) shunt placement and 3,242 unaffected patients of African-ancestry who underwent whole-genome genotyping. We used PrediXcan, which estimates the genetically-determined component of gene expression based on common regulatory variants (i.e. allele frequency > 1%) to identify potentially-causal genes associated with hydrocephalus and VP shunt failure.

Results: We identified 815 genes that are nominally-significant (p< 0.05) predictors of hydrocephalus status. After conservative multiple-testing correction (false discovery rate< 0.05), we identify decreased expression of TMEM208 as an outlier. Furthermore, TMEM208 met the highly-stringent Bonferroni threshold for statistical-significance based on the total number of genes tested (OR= 2.07, p< 5.22x10-8), identifying TMEM208 as a genome-wide predictor of hydrocephalus. In addition, differential expression ofTMEM208 was significantly-associated with VP shunt failure (OR= 1.71, p< 6.59x10-5). Finally, pathway analysis of all nominally-associated genes (p< 0.05) revealed a marked association with inflammatory and immune-related processes. 

Conclusion: Our data identify differential expression of TMEM208 as a genome-wide predictor of hydrocephalus and VP shunt failure in patients of African-descent. The genetic and pathway associations identified here are distinct from genetic associations identified in patients of European-descent, suggesting a unique genetic basis of hydrocephalus between patients of European vs. African-descent. These data identify genetic alterations in immune-related processes that may uniquely underlie hydrocephalus in patients of African-descent.