Genetic Variation in Neisseria meningitidis Does Not Influence Disease Severity in Meningococcal Meningitis

• Published in: Frontiers in medicine Vol. 7; p. 594769
• Main Authors: Kremer, Philip H C, Lees, John A, Ferwerda, Bart, van de Ende, Arie, Brouwer, Matthijs C, Bentley, Stephen D, van de Beek, Diederik
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 11.11.2020
• Subjects: genome sequencing; genome-wide association study; Medicine; Neisseria meningitidis; severity; thrombocytes; severity; genome sequencing; Neisseria meningitidis; thrombocytes; genome-wide association study
• ISSN: 2296-858X; 2296-858X
• DOI: 10.3389/fmed.2020.594769

causes sepsis and meningitis in humans. It has been suggested that pathogen genetic variation determines variance in disease severity. Here we report results of a genome-wide association study of 486 genomes from meningococcal meningitis patients and their association with disease severity. Of 369 meningococcal meningitis patients for whom clinical data was available, 44 (12%) had unfavorable outcome and 24 (7%) died. To increase power, thrombocyte count was used as proxy marker for disease severity. Bacterial genetic variants were called as k-mers, SNPs, insertions and deletions and clusters of orthologous genes (COGs). Population-level meningococcal genetic variation did not explain variance in disease severity (unfavorable outcome or thrombocyte count) in this cohort (h = 0.0%; 95% confidence interval: 0.0-0.9). Genetic variants in the bacterial gene represented the top signal associated with thrombocyte count ( -value = 9.96e-07) but this did not reach statistical significance. We did not find an association between previously published variants in , and genes and unfavorable outcome or thrombocyte count. A power analysis based on simulated phenotypes based on real genetic data from 880 genomes showed that we would be able to detect a continuous phenotype with h > = 0.5 with the population size available in this study. This rules out a major contribution of pathogen genetic variation to disease severity in meningococcal meningitis, and shows that much larger sample sizes are required to find specific low-effect genetic variants modulating disease outcome in meningococcal meningitis.