Infection and Inflammation in Schizophrenia and Bipolar Disorder: A Genome Wide Study for Interactions with Genetic Variation

• Published in: PloS one Vol. 10; no. 3; p. e0116696
• Main Authors: Avramopoulos, Dimitrios, Pearce, Brad D., McGrath, John, Wolyniec, Paula, Wang, Ruihua, Eckart, Nicole, Hatzimanolis, Alexandros, Goes, Fernando S., Nestadt, Gerald, Mulle, Jennifer, Coneely, Karen, Hopkins, Myfanwy, Ruczinski, Ingo, Yolken, Robert, Pulver, Ann E.
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 17.03.2015; Public Library of Science (PLoS)
• Subjects: Analysis; Antibodies, Protozoan - metabolism; Antibodies, Viral - metabolism; Antigens; Bipolar disorder; Bipolar Disorder - complications; Bipolar Disorder - genetics; Bipolar Disorder - parasitology; Bipolar Disorder - virology; Body mass; Body mass index; Body size; C-reactive protein; C-Reactive Protein - genetics; Case-Control Studies; Chromosome 6; Cytomegalovirus; Cytomegalovirus infections; Environmental effects; Epidemiology; Female; Fetuses; Gene expression; Genetic aspects; Genetic diversity; Genetic Predisposition to Disease; Genetic variance; Genetic Variation; Genome-Wide Association Study; Genomes; Genomics; Genotypes; Gliadin; Health aspects; Health risks; Herpes simplex; Herpes viruses; Histocompatibility antigen HLA; Humans; IgG antibody; Immunity; Immunoglobulin G; Immunoglobulins; Infection; Infections; Inflammation; Inflammation - complications; Male; Medical research; Medicine; Mental disorders; Parents; Permutations; Polymorphism, Single Nucleotide; Proteins; Psychiatry; Psychosis; Public health; Risk analysis; Risk factors; Schizophrenia; Schizophrenia - complications; Schizophrenia - genetics; Schizophrenia - parasitology; Schizophrenia - virology; Single nucleotide polymorphisms; Single-nucleotide polymorphism; Smoking; Studies; Toxoplasma - immunology; Toxoplasma - physiology; Toxoplasmosis - complications; Virus Diseases - complications; Viruses; Atlanta Georgia; United States > US; Baltimore Maryland
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0116696

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.