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Elucidating the Genetics of Vaccine-Induced Febrile Seizure Through a GWAS and Exome Sequencing

  • Author(s): Rojo, Carlos
  • Advisor(s): Seielstad, Mark
  • et al.
Abstract

Despite the tremendous success of vaccination efforts across the globe, outbreaks of vaccine-preventable childhood diseases in communities around the United States are increasing. These localized outbreaks, due in part to decreased vaccination coverage, are likely the result of a public skepticism about the safety of childhood vaccinations. To help restore trust in the vaccination effort, it is important to understand a vaccine's full range of side effects. For example, an increased risk of febrile seizure has been associated with a variety of common childhood vaccines including measles-containing vaccines such as the measles, mumps, and rubella vaccines. Currently, however, the biological cause of vaccination induced febrile seizure (VIFS) remains unclear and little is known as to why only a subset of the vaccine's recipients is affected. Towards these goals, we conducted a genome-wide association study and exome sequencing analysis to survey the genetic architecture of VIFS following measles vaccination. 274 California residents, 133 of whom experienced febrile seizure post-measles vaccination and 141 matched controls, were genotyped and exome sequenced. Using the software PLINK v.1.07, 5,757,137 markers were tested for association with VIFS, which highlighted potential genes of interest in VIFS that either regulate neuronal activity or cytokine production (rs202194476 in PTPRD, p = 1.6x10-6 ; rs11186481 near SH2D4B, p = 7.7x10-6; and rs56682383 in DPYD, p = 2.4X10-5). After using the Burrows Wheeler Aligner (BWA), Picard, and the Genome Analysis Toolkit (GATK) to process the exome sequencing data, optimized sequence kernel association testing (SKAT-O) was used to implement gene-based association testing. This analysis highlighted potential genes of interests with roles in immune system regulation and apoptosis (BATF, p = 6.1x10-6; DDI2, p = 6.5x10-5; NDUFS3, p = 8.9x10-5; DEFB126, p = 2.1x10-5). As the first GWAS and exome sequencing analysis of VIFS, this study provides the first large-scale look at the underlying genetic architecture of VIFS. As such, it builds the foundation for our understanding of a serious but unexplained side effect of the common measles vaccine, which could not only help restore any lost trust in the safety of vaccination but also potentially work towards a strategy to stratify a patient's risk for developing VIFS.

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