HLA typing using genome wide data reveals susceptibility types for infections in a psychiatric disease enriched Ashkenazi Jewish population. 公开

Abstract

Introduction: The infections Toxoplasma gondii (T. gondii), cytomegalovirus, and herpes simplex 1 (HSV1) are common persistent infections and have been associated with schizophrenia and bipolar disorder. The major histocompatibility complex MHC (termed HLA in humans) region has been implicated in these infections and these mental illnesses. The interplay of MHC genetics, mental illness, and infection has not been systematically examined in previous research.

Methods: In a cohort of 1636 Ashkenazi Jewish individuals, we imputed 7 HLA types (A, B, C, DRB1, DQA1, DQB1, DPB1) utilizing the HIBAG software package for R. HLA types were combined with pre-existing serology data. Logistic regression modeling stratified by mental disease status was used to assess the association between these HLA alleles and the infections, controlling for age and sex. Additional stratified logistic models assessed associations between homozygosity at the imputed HLA loci and the infections controlling for age and sex.

Results: Several alleles had significant effect on infection risk after Bonferroni correction for multiple comparisons. Moreover, certain HLA haplotypes were consistently associated with increased or decreased risk of infections. The haplotypes HLA DRB*03:01~HLA DQA*05:01~HLA DQB*02:01 and HLA B*08:01~HLA C*07:01 displayed risk increasing effects for T. gondii and HSV1 that were more pronounced in mental illness free groups. Haplotypes B*38:01~HLA C*12:03 displayed protective effects against CMV and HSV1, which was also more pronounced in mental illness free groups. Homozygosity at HLA DQA correlated with decreased risk for CMV and HSV1 in the mentally ill group while homozygosity at HLA DRB correlated with increased CMV and HSV1 risk in the mentally ill group.

Conclusions: This first epidemiologic analysis of HLA types, mental illness, and selected infections identified three haplotypes that potentially have implications for generally increasing or decreasing disease risk across multiple conditions as well as several individual alleles of interest for each infection. The fact we detected the most significant effects in the mental illness free groups may indicate that the effect of HLA alleles on infection risk may be modified in schizophrenia or bipolar disorder. Additionally HLA homozygosity appears to be a contributing factor in an individual's infection risk.

Table of Contents

Abbreviations.......................................................................................1

Introduction.........................................................................................2

HLA and MHC.......................................................................................2

Toxoplamsa gondii................................................................................3

Cytomegalovirus...................................................................................4

Herpes Simplex Virus 1..........................................................................5

Schizophrenia and Bipolar Disorder........................................................6

Current Study........................................................................................8

Methods..............................................................................................10

Subjects...............................................................................................10

Immunoassay and Genotyping Measurements and cleaning.....................11

HLA Imputation...................................................................................11

Statistical Analyses..............................................................................12

Results................................................................................................16

Sample Characteristics.........................................................................16

Common Alleles..................................................................................17

Homozygosity Analysis........................................................................21

Results Tables.....................................................................................24

Discussion..........................................................................................31

Conclusions and Public Health Implications..........................................36

Appendix:..........................................................................................39

References..........................................................................................56

About this Master's Thesis

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School	Rollins School of Public Health
Department	Epidemiology
Degree	MSPH
Submission	Master's Thesis
Language	English
Research Field	Health Sciences, Public Health Health Sciences, Mental Health Health Sciences, Epidemiology
关键词	HSV1 Cytomegalovirus Imputation Toxoplasma gondii Bipolar Disorder Schizophrenia Herpes simplex virus CMV HLA MHC
Committee Chair / Thesis Advisor	Pearce, Brad, Emory University
Partnering Agencies	Emory University schools, faculty or affiliated programs

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