Converging evidence implicates immune abnormalities in schizophrenia
(SCZ), and recent genome-wide association studies (GWAS) have identified
immune-related single-nucleotide polymorphisms (SNPs) associated with
SCZ. Using the conditional false discovery rate (FDR) approach, we
evaluated pleiotropy in SNPs associated with SCZ (n=21 856) and multiple
sclerosis (MS) (n=43 879), an inflammatory, demyelinating disease of
the central nervous system. Because SCZ and bipolar disorder (BD) show
substantial clinical and genetic overlap, we also investigated
pleiotropy between BD (n=16 731) and MS. We found significant genetic
overlap between SCZ and MS and identified 21 independent loci associated
with SCZ, conditioned on association with MS. This enrichment was
driven by the major histocompatibility complex (MHC). Importantly, we
detected the involvement of the same human leukocyte antigen (HLA)
alleles in both SCZ and MS, but with an opposite directionality of
effect of associated HLA alleles (that is, MS risk alleles were
associated with decreased SCZ risk). In contrast, we found no genetic
overlap between BD and MS. Considered together, our findings demonstrate
genetic pleiotropy between SCZ and MS and suggest that the MHC signals
may differentiate SCZ from BD susceptibility.Molecular Psychiatry
advance online publication, 28 January 2014
(SCZ), and recent genome-wide association studies (GWAS) have identified
immune-related single-nucleotide polymorphisms (SNPs) associated with
SCZ. Using the conditional false discovery rate (FDR) approach, we
evaluated pleiotropy in SNPs associated with SCZ (n=21 856) and multiple
sclerosis (MS) (n=43 879), an inflammatory, demyelinating disease of
the central nervous system. Because SCZ and bipolar disorder (BD) show
substantial clinical and genetic overlap, we also investigated
pleiotropy between BD (n=16 731) and MS. We found significant genetic
overlap between SCZ and MS and identified 21 independent loci associated
with SCZ, conditioned on association with MS. This enrichment was
driven by the major histocompatibility complex (MHC). Importantly, we
detected the involvement of the same human leukocyte antigen (HLA)
alleles in both SCZ and MS, but with an opposite directionality of
effect of associated HLA alleles (that is, MS risk alleles were
associated with decreased SCZ risk). In contrast, we found no genetic
overlap between BD and MS. Considered together, our findings demonstrate
genetic pleiotropy between SCZ and MS and suggest that the MHC signals
may differentiate SCZ from BD susceptibility.Molecular Psychiatry
advance online publication, 28 January 2014
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