Genomewide association analyses of electrophysiological endophenotypes for schizophrenia and psychotic bipolar disorders: A preliminary report

Abstract

Several event-related potentials (ERP), including P3, sensory gating (P50), and gamma oscillation, are robustly impaired in patients with schizophrenia (SCZ) and bipolar disorder (BIP). Although these ERPs are known to be heritable, little is known about the specific genetic loci involved and the degree to which they overlap with loci influencing mood and psychotic disorders. In the present study, we conducted GWAS to a) identify common variants associated with ERP endophenotypes, and b) construct polygenic risk scores (PRS) to examine overlap between genetic components of ERPs and mood and psychotic disorders. The sample consisted of 271 patients with SCZ or psychotic BIP diagnosis and 128 controls for whom ERP and genomewide data were available. GWAS were conducted using the full sample. PRS, derived from the Psychiatric Genomics Consortium (PGC) analyses of SCZ, BIP, and major depressive disorder were applied to each ERP phenotype. We identified a region on chromosome 14 that was significantly associated with sensory gating (peak SNP rs10132223, P = 1.27 × 10−9). This locus has not been previously associated with psychotic illness in PGC-GWAS. In the PRS analyses, patients with a higher load of SCZ risk alleles had reduced gamma response whereas patients with a higher load of BIP risk alleles had smaller P3 amplitude. We observed a genomewide significant locus on chromosome 14 for P50. This locus may influence P50 but not psychotic illness. Among patients with psychotic illness, PRS results indicated genetic overlap between SCZ loci and gamma oscillation and between BIP loci and P3 amplitude.

Auditory sensory gating in patients with bipolar disorders: A meta-analysis

“…Based on the title and abstract, 24 potentially eligible articles were identified. The two authors conducted a full-text review and determined that 10 articles fulfilled the inclusion criteria (Olincy and Martin, 2005;Carroll et al, 2008;Hall et al, 2008;Sanchez-Morla et al, 2008;Lijffijt et al, 2009;Patterson et al, 2009;Cabranes et al, 2013;Wang et al, 2014;Hall et al, 2015;Vuillier et al, 2015). Six of these studies consisted of more than one comparison, and thus a total of 14 and 8 individual investigations for S2/S1 ratio and S1 À S2 difference score, respectively, were included in the meta-analysis.…”

“…Bipolar disorders (BD) are characterized by uncontrolled mood fluctuation and associated with many aspects of cognitive impairments, including the sensory gating (SG) ability (Olincy and Martin, 2005;Schulze et al, 2007;Hall et al, 2015). SG, referring to the brain's ability to automatically filter out redundant sensory stimuli, is considered as a protective mechanism to prevent a flooding of irrelevant information to the higher cortical centers (Boutros and Belger, 1999).…”

“…This electrophysiological measure has been widely applied in patients with schizophrenia. Recently, the assessments of SG have received increased attention in patients with BD to identify the potential pathophysiological similarities and differences with other psychiatric diseases (Hall et al, 2015).…”

Electrophysiological Endophenotypes for Schizophrenia

“…67 While genome-wide linkage analysis showed that P50 suppression deficits in schizophrenia were linked to the site of the α7-nicotinic receptor (chromosome 15q13-14), two recent studies did not find significant associations with SNPs in the CHRNA7 region and P50 suppression. 48,69,70 The schizophrenia risk allele of another gene, transcription factor 4 (TCF4), has been shown to be significantly associated with worse P50 suppression in healthy individuals, and these gene effects were modulated by smoking behavior such that heavy smokers showed effects of TCF4 on P50 suppression than light and never smokers. 71 …”

“…COGS and Psychiatric Genomics Consortium) challenge this notion. 48,69 Larger sample sizes and uniformity of sensory gating measures (P50 ratio vs. P50 difference) are needed to understand the genetic contributions to this endophenotype. In general, conflicting findings regarding P50's state-independence, reliability, and heritability must be resolved in order for P50 to be considered a useful endophenotype of schizophrenia.…”