title: Effects of neuregulin 3 genotype on human prefrontal cortex physiology.
abstract: The neuregulin 3 gene (NRG3) plays pleiotropic roles in neurodevelopment and is a putative susceptibility locus for schizophrenia. Specifically, the T allele of NRG3 rs10748842 has been associated with illness risk, altered cognitive function, and the expression of a novel splice isoform in prefrontal cortex (PFC), but the neural system effects are unexplored. Here, we report an association between rs10748842 and PFC physiology as measured by functional magnetic resonance imaging of human working memory performance, where a convincing link between increased genetic risk for schizophrenia and increased activation in some PFC areas has been established. In 410 control individuals (195 males, 215 females), we detected a highly significant effect of NRG3 genotype manifesting as an unanticipated increase in ventrolateral PFC activation in nonrisk-associated C allele carriers. An additional analysis including 78 patients with schizophrenia spectrum disorders (64 males, 14 females) and 123 unaffected siblings (53 males, 70 females) revealed a whole-brain significant genotype by group interaction in right dorsolateral PFC (DLPFC), manifesting as a relative activation increase in healthy controls and siblings (C > T/T) and as a hypoactivation in patients (T/T > C). These observed genotype-dependent effects in PFC were not explained by task performance and did not conform to established locales of prefrontal inefficiency linked to genetic risk for schizophrenia. Our data indicate a complex modulation of brain physiology by rs10748842, which does not fit the simple inefficiency model of risk association in DLPFC and suggests that other neurobiological mechanisms are involved.
authors.affiliation: Clinical Brain Disorders Branch, Genes, Cognition, and Psychosis Program, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland 20892, Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, 61859 Mannheim, Germany, Lieber Institute for Brain Development, Johns Hopkins University Medical Campus, Baltimore, Maryland 21205, Departments of Psychiatry, Neurology, and Neuroscience and McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland 21205, and Departments of Psychiatry and Cell and Developmental Biology, University of Colorado, School of Medicine, Aurora, Colorado 80045.
authors.forename: Heike
authors.initials: H
authors.lastname: Tost
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Callicott
authors.forename: Roberta
authors.initials: R
authors.lastname: Rasetti
authors.forename: Radhakrishna
authors.initials: R
authors.lastname: Vakkalanka
authors.forename: Venkata S
authors.initials: VS
authors.lastname: Mattay
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Weinberger
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Law
mesh_terms: D000328:Adult; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D020880:Neuregulins / Q000235:genetics*; D010775:Photic Stimulation / Q000379:methods; D017397:Prefrontal Cortex / Q000502:physiology* / Q000503:physiopathology; D011597:Psychomotor Performance / Q000502:physiology*; D012306:Risk; D012559:Schizophrenia / Q000235:genetics* / Q000503:physiopathology*; D055815:Young Adult
chemical_list: C486357:NRG3 protein, human; D020880:Neuregulins
keywords: ErbB4; NRG3; Neuregulin; genetics; neuroimaging; schizophrenia