Gene expression and genetic variation data implicate PCLO in bipolar disorder

Abstract

Background: Genetic variation may contribute to differential gene expression in the brain of individuals with psychiatric disorders. To test this hypothesis, we identified genes that were differentially expressed in individuals with bipolar disorder, along with nearby single nucleotide polymorphisms (SNPs) that were associated with expression of the same genes. We then tested these SNPs for association with bipolar disorder in large case-control samples.

Methods: We used the Stanley Genomics Database to extract gene expression and SNP microarray data from individuals with bipolar disorder (n = 40) and unaffected controls (n = 43). We identified 367 genes that were differentially expressed in the prefrontal cortex of cases vs. controls (fold change > 1.3 and FDR q-value < .05) and 45 nearby SNPs that were associated with expression of those same genes (FDR q-value < .05). We tested these SNPs for association with bipolar disorder in a meta-analysis of genome-wide association studies (GWAS) including 4,936 cases and 6,654 healthy controls.

Results: We identified 45 SNPs that were associated with expression of differentially expressed genes, including HBS1L (15 SNPs), HLA-DPB1 (15 SNPs), AMFR (8 SNPs), PCLO (2 SNPs) and WDR41 (2 SNPs). Of these, one SNP (rs13438494), in an intron of the piccolo (PCLO) gene, was significantly associated with bipolar disorder (FDR adjusted p < .05) in the meta-analysis of GWAS.

Conclusions: These results support the previous findings implicating PCLO in mood disorders and demonstrate the utility of combining gene expression and genetic variation data to improve our understanding of the genetic contribution to bipolar disorder.

Figure 1

A significant association between expression levels of HBS1L and a single nucleotide polymorphism, rs2150681, in brain (false discovery rate q-value < .05). Overall expression levels of HBS1Lare decreased in the prefrontal cortex of bipolar disorder subjects (red) as compared to the unaffected controls (green). Levels of expression in the minor allele (A) were decreased in bipolar disorder subjects (red) as compared to the controls (green), indicating an allelic expression of HBS1L. X axis: genotype; Y axis: gene expression (log 2 scale).

Figure 2

A significant association between expression levels of PCLO and a single nucleotide polymorphism, rs13438494, in brain (false discovery rate q-value < .05). Overall expression levels of PCLO are increased in the prefrontal cortex of bipolar disorder subjects (red) as compared to the unaffected controls (green). X axis: genotype; Y axis: gene expression (log 2 scale).

Figure 3

A quantitative polymerase chain reaction validation of the genes (HBS1L, HLA-DPB1, PCLO, and POLR1D) that are differentially expressed in the prefrontal cortex of bipolar disorder subjects as compared to the unaffected controls. Each gene is shown with fold change and 95% confidence interval (CI) (p < .05).