Analysis of 94 Candidate Genes and 12 Endophenotypes for Schizophrenia From the Consortium on the Genetics of Schizophrenia

Abstract

Objective We have used a custom 1,536-SNP array to interrogate 94 functionally relevant candidate genes for schizophrenia and identify associations with 12 heritable neurophysiological and neurocognitive endophenotypes collected as part of the Consortium on the Genetics of Schizophrenia (COGS). Method Variance-component association analyses of 534 genotyped subjects from 130 families were conducted using Merlin. A novel bootstrap Total Significance Test was also developed to overcome the limitations of existing genomic multiple testing methods and robustly demonstrate the presence of significant associations in the context of complex family data and possible population stratification effects. Results Associations were observed for 46 genes of potential functional significance with 3 SNPs at p<10−4, 27 SNPs at p<10−3, and 147 SNPs at p<0.01. The bootstrap analyses confirmed that the 47 SNP-endophenotype combinations with the strongest evidence of association significantly exceeded (p=0.001) that expected by chance alone with 93% of these findings expected to be true. Many of the genes interact on a molecular level, and eight genes displayed evidence for pleiotropy (e.g., NRG1 and ERBB4), revealing associations with four or more endophenotypes. Our results collectively support a strong role for genes related to glutamate signaling in mediating schizophrenia susceptibility. Conclusions This study supports the use of relevant endophenotypes and the bootstrap Total Significance Test for the identification of genetic variation underlying the etiology of schizophrenia. In addition, the observation of extensive pleiotropy for some genes and singular associations for others in our data suggests alternative, independent pathways mediating pathogenesis in the “group of schizophrenias”.

Transcription factor 4 (TCF4) and schizophrenia: integrating the animal and the human perspective

“…Schizophrenia patients and to a lesser extend also their unaffected first-degree relatives consistently display disrupted sensory and sensorimotor gating, commonly demonstrated by either lower P50 suppression of the auditory evoked potential (AEP) or reduced prepulse inhibition (PPI) of the acoustic startle response [88,89,[94][95][96][97][98][99][100]. Both measures have been shown to be heritable and to be disturbed before onset of the illness [101][102][103][104][105][106][107]. Although sensory (P50 suppression) and sensorimotor (PPI) gating are conceptually related and both were parallel suggested as useful endophenotypes of schizophrenia they are not equivalent and usually also not correlated [94,[108][109][110].…”

The genetic contribution of the NO system at the glutamatergic post-synapse to schizophrenia: Further evidence and meta-analysis

“…To this end, a Pub Med search was carried out using the keywords "(NOS1AP OR CAPON) AND schizophrenia" as well as "NOS1 AND schizophrenia", to identify all genetic studies on NOS1AP (n=24 retrieved studies) or NOS1 (n=42 retrieved) and schizophrenic disorders. Titles and abstracts were scrutinized to exclude non-genetic studies, reducing the number of included studies to Costain et al, 2010;Fang et al, 2008;Greenwood et al, 2011;Husted et al, 2010;Kremeyer et al, 2009;Miranda et al, 2006;Nicodemus et al, 2008;Wratten et al, 2009) and one on NOS1 (Fallin et al, 2005), presented family-based, but not case-control data and were therefore not integrated in the meta-analysis for methodological reasons. The remaining studies on NOS1AP (n=6; (Aberg et al, 2010;Delorme et al, 2010;Nicodemus et al, 2010;Puri et al, 2007;Puri et al, 2006;Zheng et al, 2005)) and NOS1 (n=14; (Cui et al, 2010;Donohoe et al, 2009;Kawohl et al, 2008;Nicodemus et al, 2010;O'Donoghue et al, 2012;Okumura et al, 2009;Reif et al, 2006;Reif et al, 2011;Riley et al, 2010;Rose et al, 2012;Shinkai et al, 2002;Silberberg et al, 2010;Tang et al, 2008;Wang et al, 2012)) reported on case-control association data and were scrutinized in greater detailed.…”

Neuregulin and dopamine modulation of hippocampal gamma oscillations is dependent on dopamine D4 receptors

“…Our studies showing that increases in γ oscillation power in response to NRG1 require the activity of ErbB4 and D4 receptors suggests an important nexus where genes and network activity associated with psychiatric disorders intersect in PV+ neurons. Genetic variants of NRG1 and ERBB4 constitute risk factors for schizophrenia (17) and associated endophenotypes (34), and the DRD4-7R functional variant is a risk factor for ADHD (35) and is associated with deficits in attention, working memory, and γ band activity (36). These results suggest that alterations in D4R function may underlie endophenotypes shared by both disorders.…”