title: Schizophrenia candidate gene ERBB4: covert routes of vulnerability to psychosis detected at the population level.
abstract: Prior genetic and functional evidence established ERBB4 as a probable schizophrenia susceptibility gene that may confer risk via modulating brain information processing dependent on the integrity of frontotemporal brain circuitry. Utilizing retrospective data drawn from the cross-sectional population-based Athens Study of Psychosis Proneness and Incidence of Schizophrenia (ASPIS) (n = 1127), we attempted to independently replicate and further extend previous findings by examining the effects of ERBB4 gene variants on 3 broad population-based psychosis-related phenotypes: verbal working memory (VWM), trait schizotypy, and stress-induced subclinical psychotic experiences (PE). Three common ERBB4 single nucleotide polymorphisms that were previously associated with schizophrenia and impaired frontotemporal-related information processing (rs7598440, rs839523, and rs707284), their haplotypes, and corresponding diplotypes were tested. VWM performance was significantly associated with rs839523 and rs707284 markers even after correction for multiple testing, thus validating reported findings that have implicated ERBB4 gene variation on working memory. No associations were detected between these ERBB4 variants and trait schizotypy. However, we were able to detect a significant effect of rs7598440 marker on PE expressed under stressful environmental conditions. Combined haplotype analysis of the above 3 markers, identified a "yin-yang" pattern of association, confirmed at the diplotype level. While GGG haplotype homozygotes were associated with "protective" effects on VWM performance and PE, AAA "risk" haplotype carriers were associated with worse VWM performance and simultaneously exhibited significantly elevated PE. This dual, possibly pleiotropic, impact on frontotemporal circuitry and increased sensitivity to psychosocial stress may represent subtle manifestations of ERBB4-related vulnerability to psychosis, expressed at the population level.
authors: University Mental Health Research Institute, Athens, Greece. nikos.stefanis@uwa.edu.au
authors: Nicholas C
authors: NC
authors: Stefanis
authors: Alex
authors: A
authors: Hatzimanolis
authors: Nikolaos
authors: N
authors: Smyrnis
authors: Dimitrios
authors: D
authors: Avramopoulos
authors: Ioannis
authors: I
authors: Evdokimidis
authors: Jim
authors: J
authors: van Os
authors: Costas N
authors: CN
authors: Stefanis
authors: Richard E
authors: RE
authors: Straub
authors: Daniel R
authors: DR
authors: Weinberger
mesh_terms: D000293:Adolescent; D003430:Cross-Sectional Studies; D066246:ErbB Receptors / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008297:Male; D008569:Memory Disorders / Q000235:genetics*; D008570:Memory, Short-Term / Q000502:physiology; D008889:Military Personnel / Q000523:psychology; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011618:Psychotic Disorders / Q000235:genetics*; D066247:Receptor, ErbB-4; D012189:Retrospective Studies; D012559:Schizophrenia / Q000235:genetics*; D012569:Schizotypal Personality Disorder / Q000235:genetics*; D055815:Young Adult
chemical_list: C587689:ERBB4 protein, human; D066246:ErbB Receptors; D066247:Receptor, ErbB-4