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. 2015 Apr;168B(3):151-61.
doi: 10.1002/ajmg.b.32298. Epub 2015 Mar 4.

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

Mei-Hua Hall  1 , Chia-Yen Chen, Bruce M Cohen, Kevin M Spencer, Deborah L Levy, Dost Öngür, Jordan W Smoller
Affiliations

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

Mei-Hua Hall et al. Am J Med Genet B Neuropsychiatr Genet. 2015 Apr.

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.

Keywords: bipolar disorders; endophenotypes; event-related potentials; genowide assoication; polygentic risk score; schizophrenia.

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Conflict of interest statement

Conflict of interest: Dr. Ongur reported being on a Scientific Advisory Board for Lilly Inc. in 2013. Drs. Hall, Chen, Cohen, Smoller, and Levy reported no biomedical financial interests or potential conflicts of interest.

Figures

FIG. 1
FIG. 1
Manhattan Plot of GWAS results for sensory gating (P50).
FIG. 2
FIG. 2
Regional plot for Chromosome 14 locus associated with Sensory gating.
FIG. 3
FIG. 3
Regional plot for Chromosome four locus associated with ASSR gamma oscillaton.
FIG. 4
FIG. 4
The variance explained of different phenotypes by polygenic schizophrenia score (PRS-SCZ, left), bipolar score (PRS-BIP, middle), and major depressive disorder (PRS-MDD, right) for different p-cutoff single nucleotide polymorphism sets (box, right); y axis explained variance by the PRS of this phenotype. SCZ schizophrenia; BIP, bipolar disorder; MDD, major depressive disorder. *P < 0.05. PRS-BIP was nominally associated with reduced P3 amplitude at PT < 10−5 and PT < 10−4. Higher genetic risk scores were associated with smaller P3 amplitude. PRS-BIP was also nominally associated with smaller ASSR gamma response. These associations did not remain significant after multiple testing correction.
See this image and copyright information in PMC

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