RT Journal Article
SR Electronic
T1 Effects of Neuregulin 3 Genotype on Human Prefrontal Cortex Physiology
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 1051
OP 1056
DO 10.1523/JNEUROSCI.3496-13.2014
VO 34
IS 3
A1 Heike Tost
A1 Joseph H. Callicott
A1 Roberta Rasetti
A1 Radhakrishna Vakkalanka
A1 Venkata S. Mattay
A1 Daniel R. Weinberger
A1 Amanda J. Law
YR 2014
UL http://www.jneurosci.org/content/34/3/1051.abstract
AB 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.