Genetic Variation in Neisseria meningitidis Does Not Influence Disease Severity in Meningococcal Meningitis
Neisseria meningitidis 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 N. meningitidis genomes from meningococcal meningitis patients and their asso...
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| Format: | Article |
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Frontiers Media S.A.
2020-11-01
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| Series: | Frontiers in Medicine |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fmed.2020.594769/full |
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| author | Philip H. C. Kremer John A. Lees John A. Lees Bart Ferwerda Bart Ferwerda Arie van de Ende Arie van de Ende Matthijs C. Brouwer Stephen D. Bentley Diederik van de Beek |
| author_facet | Philip H. C. Kremer John A. Lees John A. Lees Bart Ferwerda Bart Ferwerda Arie van de Ende Arie van de Ende Matthijs C. Brouwer Stephen D. Bentley Diederik van de Beek |
| author_sort | Philip H. C. Kremer |
| collection | DOAJ |
| description | Neisseria meningitidis 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 N. meningitidis 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 (h2 = 0.0%; 95% confidence interval: 0.0–0.9). Genetic variants in the bacterial uppS gene represented the top signal associated with thrombocyte count (p-value = 9.96e-07) but this did not reach statistical significance. We did not find an association between previously published variants in lpxL1, fHbp, and tps genes and unfavorable outcome or thrombocyte count. A power analysis based on simulated phenotypes based on real genetic data from 880 N. meningitidis genomes showed that we would be able to detect a continuous phenotype with h2 > = 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. |
| first_indexed | 2024-12-23T04:50:04Z |
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| institution | Directory Open Access Journal |
| issn | 2296-858X |
| language | English |
| last_indexed | 2024-12-23T04:50:04Z |
| publishDate | 2020-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Medicine |
| spelling | doaj.art-cc2bc4d694084b1b9e3dd1bda447ea9c2022-12-21T17:59:29ZengFrontiers Media S.A.Frontiers in Medicine2296-858X2020-11-01710.3389/fmed.2020.594769594769Genetic Variation in Neisseria meningitidis Does Not Influence Disease Severity in Meningococcal MeningitisPhilip H. C. Kremer0John A. Lees1John A. Lees2Bart Ferwerda3Bart Ferwerda4Arie van de Ende5Arie van de Ende6Matthijs C. Brouwer7Stephen D. Bentley8Diederik van de Beek9Department of Neurology, Amsterdam Neuroscience, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, NetherlandsParasites and Microbes, Wellcome Sanger Institute, Cambridge, United KingdomDepartment of Infectious Disease Epidemiology, Medical Research Council Centre for Global Infectious Disease Analysis, Imperial College London, London, United KingdomDepartment of Neurology, Amsterdam Neuroscience, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, NetherlandsDepartment of Clinical Epidemiology, Biostatistics and Bioinformatics, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, NetherlandsDepartment of Medical Microbiology and Infection Prevention, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, NetherlandsThe Netherlands Reference Laboratory for Bacterial Meningitis, Amsterdam, NetherlandsDepartment of Neurology, Amsterdam Neuroscience, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, NetherlandsParasites and Microbes, Wellcome Sanger Institute, Cambridge, United KingdomDepartment of Neurology, Amsterdam Neuroscience, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, NetherlandsNeisseria meningitidis 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 N. meningitidis 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 (h2 = 0.0%; 95% confidence interval: 0.0–0.9). Genetic variants in the bacterial uppS gene represented the top signal associated with thrombocyte count (p-value = 9.96e-07) but this did not reach statistical significance. We did not find an association between previously published variants in lpxL1, fHbp, and tps genes and unfavorable outcome or thrombocyte count. A power analysis based on simulated phenotypes based on real genetic data from 880 N. meningitidis genomes showed that we would be able to detect a continuous phenotype with h2 > = 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.https://www.frontiersin.org/articles/10.3389/fmed.2020.594769/fullseveritygenome-wide association studygenome sequencingNeisseria meningitidisthrombocytes |
| spellingShingle | Philip H. C. Kremer John A. Lees John A. Lees Bart Ferwerda Bart Ferwerda Arie van de Ende Arie van de Ende Matthijs C. Brouwer Stephen D. Bentley Diederik van de Beek Genetic Variation in Neisseria meningitidis Does Not Influence Disease Severity in Meningococcal Meningitis Frontiers in Medicine severity genome-wide association study genome sequencing Neisseria meningitidis thrombocytes |
| title | Genetic Variation in Neisseria meningitidis Does Not Influence Disease Severity in Meningococcal Meningitis |
| title_full | Genetic Variation in Neisseria meningitidis Does Not Influence Disease Severity in Meningococcal Meningitis |
| title_fullStr | Genetic Variation in Neisseria meningitidis Does Not Influence Disease Severity in Meningococcal Meningitis |
| title_full_unstemmed | Genetic Variation in Neisseria meningitidis Does Not Influence Disease Severity in Meningococcal Meningitis |
| title_short | Genetic Variation in Neisseria meningitidis Does Not Influence Disease Severity in Meningococcal Meningitis |
| title_sort | genetic variation in neisseria meningitidis does not influence disease severity in meningococcal meningitis |
| topic | severity genome-wide association study genome sequencing Neisseria meningitidis thrombocytes |
| url | https://www.frontiersin.org/articles/10.3389/fmed.2020.594769/full |
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