Dataset Information

Deficient prepulse inhibition in schizophrenia in a multi-site cohort: Internal replication and extension.

ABSTRACT: BACKGROUND:The Consortium on the Genetics of Schizophrenia (COGS) collected case-control endophenotype and genetic information from 2457 patients and healthy subjects (HS) across 5 test sites over 3.5 years. Analysis of the first "wave" (W1) of 1400 subjects identified prepulse inhibition (PPI) deficits in patients vs. HS. Data from the second COGS "wave" (W2), and the combined W(1+2), were used to assess: 1) the replicability of PPI deficits in this design; 2) the impact of response criteria on PPI deficits; and 3) PPI in a large cohort of antipsychotic-free patients. METHODS:PPI in W2 HS (n=315) and schizophrenia patients (n=326) was compared to findings from W1; planned analyses assessed the impact of diagnosis, "wave" (1 vs. 2), and startle magnitude criteria. Combining waves allowed us to assess PPI in 120 antipsychotic-free patients, including many in the early course of illness. RESULTS:ANOVA of all W(1+2) subjects revealed robust PPI deficits in patients across "waves" (p<0.0004). Strict response criteria excluded almost 39% of all subjects, disproportionately impacting specific subgroups; ANOVA in this smaller cohort confirmed no significant effect of "wave" or "wave x diagnosis" interaction, and a significant effect of diagnosis (p<0.002). Antipsychotic-free, early-illness patients had particularly robust PPI deficits. DISCUSSION:Schizophrenia-linked PPI deficits were replicable across two multi-site "waves" of subjects collected over 3.5years. Strict response criteria disproportionately excluded older, male, non-Caucasian patients with low-normal hearing acuity. These findings set the stage for genetic analyses of PPI using the combined COGS wave 1 and 2 cohorts.

SUBMITTER: Swerdlow NR

PROVIDER: S-EPMC5700873 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Deficient prepulse inhibition in schizophrenia in a multi-site cohort: Internal replication and extension.

Swerdlow Neal R NR Light Gregory A GA Thomas Michael L ML Sprock Joyce J Calkins Monica E ME Green Michael F MF Greenwood Tiffany A TA Gur Raquel E RE Gur Ruben C RC Lazzeroni Laura C LC Nuechterlein Keith H KH Radant Allen D AD Seidman Larry J LJ Siever Larry J LJ Silverman Jeremy M JM Stone William S WS Sugar Catherine A CA Tsuang Debby W DW Tsuang Ming T MT Turetsky Bruce I BI Braff David L DL

Schizophrenia research 20170524

<h4>Background</h4>The Consortium on the Genetics of Schizophrenia (COGS) collected case-control endophenotype and genetic information from 2457 patients and healthy subjects (HS) across 5 test sites over 3.5 years. Analysis of the first "wave" (W1) of 1400 subjects identified prepulse inhibition (PPI) deficits in patients vs. HS. Data from the second COGS "wave" (W2), and the combined W(1+2), were used to assess: 1) the replicability of PPI deficits in this design; 2) the impact of response cri ...[more]

PMID: 28549722

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Project description: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.

Dataset Information

Deficient prepulse inhibition in schizophrenia in a multi-site cohort: Internal replication and extension.

Publications

Deficient prepulse inhibition in schizophrenia in a multi-site cohort: Internal replication and extension.

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