Abstract
Background: Prepulse inhibition (PPI) of the startle response is a highly conserved form of sensorimotor gating, disruption of which is found in schizophrenia patients and their unaffected first-degree relatives. PPI can be measured in many species, and shows considerable phenotypic variation between and within rodent models. This makes PPI a useful endophenotype. Genome-wide association studies (GWAS) have been carried out to identify genetic variants underlying schizophrenia, and these suggest that schizophrenia is highly polygenic. GWAS have been unable to account for the high heritability of schizophrenia seen in family studies, partly because of the low power of GWAS due to multiple comparisons. By contrast, complementary mouse model linkage studies often have high statistical power to detect variants for behavioral traits but lower resolution, producing loci that include tens or hundreds of genes. To capitalize on the advantages of both GWAS and genetic mouse models, our study uses a cross-species approach to identify novel genes associated with PPI regulation, which thus may contribute to the PPI deficits seen in schizophrenia.Results: Using experimental data from the recombinant inbred (RI) mouse panel BXD, we identified two significant loci affecting PPI. These genomic regions contain genetic variants which influence PPI in mice and are therefore candidates that may be influencing aspects of schizophrenia in humans. We next investigated these regions in whole-genome data from the Psychiatric Genomics Consortium (PGC) schizophrenia GWAS and identify one novel candidate gene (ABPP1IP) that was significantly associated with PPI in mice and risk of schizophrenia in humans. A systems genetics approach demonstrates that APBB1IP coexpresses with several other genes related to schizophrenia in several brain regions. Gene coexpression and enrichment analysis shows clear links between APBB1IP and the immune system.Conclusion: The combination of human GWAS and mouse quantitative trait loci (QTL) from some of the largest study systems available has enabled us to identify a novel gene, APBB1IP, which influences schizophrenia in humans and PPI in mice.
Highlights
Prepulse inhibition (PPI) of the startle response is a highly conserved form of sensorimotor gating, disruption of which is found in schizophrenia patients and their unaffected first-degree relatives
We identified one gene that was significantly associated with PPI in mice and the risk of schizophrenia in humans at the genome-wide level
PPI deficits are associated with schizophrenia (Braff et al, 2001), and we, investigated genetic variation in this trait
Summary
Prepulse inhibition (PPI) of the startle response is a highly conserved form of sensorimotor gating, disruption of which is found in schizophrenia patients and their unaffected first-degree relatives. While onset typically occurs after the period of brain development that follows puberty in late adolescence or early adult life (Kirkbride et al, 2012), there is strong clinical and epidemiological evidence that schizophrenia reflects a disturbance of neurodevelopment (Owen et al, 2016) Both genetic and environmental risk factors for schizophrenia have been identified that are linked to immune function, e.g., (Murray et al, 2019), an idea that was first postulated more than a century ago (for a review see Khandaker et al, 2015). These effects could contribute to changes in mood, cognition and behavior, supported by epidemiological studies that suggest links between schizophrenia and systemic inflammation (Brown and Derkits, 2009; Miller et al, 2011; Khandaker et al, 2014)
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