Piccolo genotype modulates neural correlates of emotion processing but not executive functioning

S Woudstra,M A Van Buchem,B W Penninx,A Aleman,Z Bochdanovits,E M Opmeer,N J Van Der Wee,L R Demenescu,D J Veltman,F G Zitman,W J Hoogendijk,M-J Van Tol

doi:10.1038/tp.2012.29

Abstract

Major depressive disorder (MDD) is characterized by affective symptoms and cognitive impairments, which have been associated with changes in limbic and prefrontal activity as well as with monoaminergic neurotransmission. A genome-wide association study implicated the polymorphism rs2522833 in the piccolo (PCLO) gene—involved in monoaminergic neurotransmission—as a risk factor for MDD. However, the role of the PCLO risk allele in emotion processing and executive function or its effect on their neural substrate has never been studied. We used functional magnetic resonance imaging (fMRI) to investigate PCLO risk allele carriers vs noncarriers during an emotional face processing task and a visuospatial planning task in 159 current MDD patients and healthy controls. In PCLO risk allele carriers, we found increased activity in the left amygdala during processing of angry and sad faces compared with noncarriers, independent of psychopathological status. During processing of fearful faces, the PCLO risk allele was associated with increased amygdala activation in MDD patients only. During the visuospatial planning task, we found no genotype effect on performance or on BOLD signal in our predefined areas as a function of increasing task load. The PCLO risk allele was found to be specifically associated with altered emotion processing, but not with executive dysfunction. Moreover, the PCLO risk allele appears to modulate amygdala function during fearful facial processing in MDD and may constitute a possible link between genotype and susceptibility for depression via altered processing of fearful stimuli. The current results may therefore aid in better understanding underlying neurobiological mechanisms in MDD.

Highlights

Major depressive disorder (MDD) is a common, multifactorial disorder and is one of the leading causes of years lost due to disability.[1,2] Its core symptoms are affective, manifesting themselves in depressed mood accompanied by low self-esteem and loss of interest in normally enjoyable activities
During the processing of fearful faces, only MDD patients with the piccolo gene (PCLO) risk allele showed increased amygdala activation, whereas no effect of genotype was observed in healthy controls (HC)
MDD patients with the PCLO risk allele performed near-significantly faster than MDD patients with the nonrisk allele, whereas in HC, no significant differences between PCLO genotype were observed during perception of negative emotions

Summary

Introduction

Major depressive disorder (MDD) is a common, multifactorial disorder and is one of the leading causes of years lost due to disability.[1,2] Its core symptoms are affective, manifesting themselves in depressed mood accompanied by low self-esteem and loss of interest in normally enjoyable activities. We conducted a genome-wide association study (GWAS) in MDD using B500 000 singlenucleotide polymorphisms (SNPs), showing one SNP (rs2522833) located at position 82453708 (hapmap genome build 37.1) in the piccolo gene (PCLO) in particular to be of interest in the genetic model for MDD.[16] This association was replicated in some studies,[16,17,18] but not in others.[19,20] The rs2522833 SNP changes the hydrophilic, uncharged amino acid serine to the charged amino acid alanine in the calciumbinding C2A domain of PCLO and may affect protein stability.[21] The PCLO protein is localized at the cytomatrix of the presynaptic active zone and is important in monoaminergic neurotransmission in the brain.[16,22] Recently, Schuhmacher et al.[23] showed that the PCLO SNP rs2522833 is associated with antidepressant treatment response, supporting the involvement of PCLO in MDD. The mechanism through which this PCLO risk allele contributes to MDD is not known, but its primary role in monoaminergic neurotransmission suggests that it may affect activity of brain circuitry involved in emotional information processing and/or executive functioning in MDD.[24]

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