title: Infection and inflammation in schizophrenia and bipolar disorder: a genome wide study for interactions with genetic variation.
abstract: Inflammation and maternal or fetal infections have been suggested as risk factors for schizophrenia (SZ) and bipolar disorder (BP). It is likely that such environmental effects are contingent on genetic background. Here, in a genome-wide approach, we test the hypothesis that such exposures increase the risk for SZ and BP and that the increase is dependent on genetic variants. We use genome-wide genotype data, plasma IgG antibody measurements against Toxoplasma gondii, Herpes simplex virus type 1, Cytomegalovirus, Human Herpes Virus 6 and the food antigen gliadin as well as measurements of C-reactive protein (CRP), a peripheral marker of inflammation. The subjects are SZ cases, BP cases, parents of cases and screened controls. We look for higher levels of our immunity/infection variables and interactions between them and common genetic variation genome-wide. We find many of the antibody measurements higher in both disorders. While individual tests do not withstand correction for multiple comparisons, the number of nominally significant tests and the comparisons showing the expected direction are in significant excess (permutation p=0.019 and 0.004 respectively). We also find CRP levels highly elevated in SZ, BP and the mothers of BP cases, in agreement with existing literature, but possibly confounded by our inability to correct for smoking or body mass index. In our genome-wide interaction analysis no signal reached genome-wide significance, yet many plausible candidate genes emerged. In a hypothesis driven test, we found multiple interactions among SZ-associated SNPs in the HLA region on chromosome 6 and replicated an interaction between CMV infection and genotypes near the CTNNA3 gene reported by a recent GWAS. Our results support that inflammatory processes and infection may modify the risk for psychosis and suggest that the genotype at SZ-associated HLA loci modifies the effect of these variables on the risk to develop SZ.
authors.affiliation: McKusick Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States of America; Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD, United States of America.
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Avramopoulos
authors.affiliation: Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, United States of America.
authors.forename: Brad D
authors.initials: BD
authors.lastname: Pearce
authors.affiliation: Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD, United States of America.
authors.forename: John
authors.initials: J
authors.lastname: McGrath
authors.affiliation: Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD, United States of America.
authors.forename: Paula
authors.initials: P
authors.lastname: Wolyniec
authors.affiliation: Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD, United States of America.
authors.forename: Ruihua
authors.initials: R
authors.lastname: Wang
authors.affiliation: McKusick Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States of America.
authors.forename: Nicole
authors.initials: N
authors.lastname: Eckart
authors.affiliation: Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD, United States of America.
authors.forename: Alexandros
authors.initials: A
authors.lastname: Hatzimanolis
authors.affiliation: Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD, United States of America.
authors.forename: Fernando S
authors.initials: FS
authors.lastname: Goes
authors.affiliation: Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD, United States of America.
authors.forename: Gerald
authors.initials: G
authors.lastname: Nestadt
authors.affiliation: Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, United States of America.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Mulle
authors.affiliation: Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, United States of America; Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, United States of America.
authors.forename: Karen
authors.initials: K
authors.lastname: Coneely
authors.affiliation: Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, United States of America.
authors.forename: Myfanwy
authors.initials: M
authors.lastname: Hopkins
authors.affiliation: Bloomberg School of Public Heath, Johns Hopkins University School of Medicine, Baltimore, MD, United States of America.
authors.forename: Ingo
authors.initials: I
authors.lastname: Ruczinski
authors.affiliation: Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, United States of America.
authors.forename: Robert
authors.initials: R
authors.lastname: Yolken
authors.affiliation: Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD, United States of America.
authors.forename: Ann E
authors.initials: AE
authors.lastname: Pulver
mesh_terms: D000913:Antibodies, Protozoan / Q000378:metabolism; D000914:Antibodies, Viral / Q000378:metabolism; D001714:Bipolar Disorder / Q000150:complications / Q000235:genetics* / Q000469:parasitology / Q000821:virology; D002097:C-Reactive Protein / Q000235:genetics; D016022:Case-Control Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006801:Humans; D007249:Inflammation / Q000150:complications; D008297:Male; D010290:Parents; D020641:Polymorphism, Single Nucleotide; D012559:Schizophrenia / Q000150:complications / Q000235:genetics* / Q000469:parasitology / Q000821:virology; D014122:Toxoplasma / Q000276:immunology / Q000502:physiology; D014123:Toxoplasmosis / Q000150:complications; D014777:Virus Diseases / Q000150:complications
chemical_list: D000913:Antibodies, Protozoan; D000914:Antibodies, Viral; D002097:C-Reactive Protein