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

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.

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