The protocadherin 17 gene affects cognition, personality, amygdala structure and function, synapse development and risk of major mood disorders

Abstract

Major mood disorders, which primarily include bipolar disorder and major depressive disorder, are the leading cause of disability worldwide and pose a major challenge in identifying robust risk genes. Here, we present data from independent large-scale clinical data sets (including 29 557 cases and 32 056 controls) revealing brain expressed protocadherin 17 (PCDH17) as a susceptibility gene for major mood disorders. Single-nucleotide polymorphisms (SNPs) spanning the PCDH17 region are significantly associated with major mood disorders; subjects carrying the risk allele showed impaired cognitive abilities, increased vulnerable personality features, decreased amygdala volume and altered amygdala function as compared with non-carriers. The risk allele predicted higher transcriptional levels of PCDH17 mRNA in postmortem brain samples, which is consistent with increased gene expression in patients with bipolar disorder compared with healthy subjects. Further, overexpression of PCDH17 in primary cortical neurons revealed significantly decreased spine density and abnormal dendritic morphology compared with control groups, which again is consistent with the clinical observations of reduced numbers of dendritic spines in the brains of patients with major mood disorders. Given that synaptic spines are dynamic structures which regulate neuronal plasticity and have crucial roles in myriad brain functions, this study reveals a potential underlying biological mechanism of a novel risk gene for major mood disorders involved in synaptic function and related intermediate phenotypes.

Figure 1

Overview of convergent research strategy and experimental design. The strategy began with clinical genetic association, replication in independent data sets and then meta-analysis of the pooled data. Positive single-nucleotide polymorphism (SNPs) were then tested on biological intermediate phenotypes in human populations and on gene expression in human brain in patients and healthy controls. The latter analyses identified a higher expression of PCDH17 as a risk factor for major mood disorders, which was then characterized the function in cell culture. BPD, bipolar disorder.

Figure 2

Genetic association of PCDH17 with risk for major mood disorders. A physical map of the region is given and depicts known genes within the region. BPD, bipolar disorder; MDD, major depressive disorder.

Figure 3

Effect of the risk SNP rs9537793 on amygdala function. During emotional face-matching task, carriers of the risk allele (G) of rs9537793 exhibited significantly increased allele-dosage-dependent activation in the right amygdala (T=2.74, small-volume family-wise error (few) corrected P-value =0.046). Number of subjects in each group: AA=77, GA=146, GG=74. SNP, single-nucleotide polymorphism.

Figure 4

Risk genotype and diagnosis predict PCDH17 expression. (a) Association of rs9537793 with PCDH17 expression in the 224 postnatal subjects from frontal cortex in BrainCloud data set. (b) Diagnostic analysis of PCDH17 expression in adult samples from frontal cortex. (c) Expression analysis of PCDH17 in iPSCs and neurons derived from BPD patients and healthy controls (each n=3). BPD, bipolar disorder; CON, healthy controls; eQTL, expression quantitative trait loci; MDD, major depressive disorder.

Figure 5

Overexpression of PCDH17 decreases spine density and results in abnormal spine morphology in cultured cortical neurons. Scale bars represent 5 μm. (a) Cultured cortical neurons were transfected at DIV17-18 with EGFP plus mock plasmid or PCDH17-myc and maintained for additional one day. Neuronal morphologies were visualized by EGFP. Representative spines were arrowed in both groups. (b) Quantification of dendritic spine parameters (density, neck length and spine width). (c) Dendritic spines were divided in three different categories depending on their morphology: stubby, thin and mushroom, as indicated in the line drawing on the right. The diagram showed the percentage of total spines belonging to each category in Mock or PCDH17-Myc transfected cortical neurons. Dendritic spines were counted for each condition from four separate cultures. Error bars indicated s.e.m. *P<0.05, **P<0.005, ***P<0.001; Student's two-sided t-test (b) and two-way analysis of variance post hoc Bonferroni test (c).