A cross-species genetic analysis identifies candidate genes for mouse anxiety and human bipolar disorder

David G Ashbrook, Robert W Williams, Lu Lu, Reinmar Hager, David G Ashbrook, Robert W Williams, Lu Lu, Reinmar Hager

Abstract

Bipolar disorder (BD) is a significant neuropsychiatric disorder with a lifetime prevalence of ~1%. To identify genetic variants underlying BD genome-wide association studies (GWAS) have been carried out. While many variants of small effect associated with BD have been identified few have yet been confirmed, partly because of the low power of GWAS due to multiple comparisons being made. Complementary mapping studies using murine models have identified genetic variants for behavioral traits linked to BD, often with high power, but these identified regions often contain too many genes for clear identification of candidate genes. In the current study we have aligned human BD GWAS results and mouse linkage studies to help define and evaluate candidate genes linked to BD, seeking to use the power of the mouse mapping with the precision of GWAS. We use quantitative trait mapping for open field test and elevated zero maze data in the largest mammalian model system, the BXD recombinant inbred mouse population, to identify genomic regions associated with these BD-like phenotypes. We then investigate these regions in whole genome data from the Psychiatric Genomics Consortium's bipolar disorder GWAS to identify candidate genes associated with BD. Finally we establish the biological relevance and pathways of these genes in a comprehensive systems genetics analysis. We identify four genes associated with both mouse anxiety and human BD. While TNR is a novel candidate for BD, we can confirm previously suggested associations with CMYA5, MCTP1, and RXRG. A cross-species, systems genetics analysis shows that MCTP1, RXRG, and TNR coexpress with genes linked to psychiatric disorders and identify the striatum as a potential site of action. CMYA5, MCTP1, RXRG, and TNR are associated with mouse anxiety and human BD. We hypothesize that MCTP1, RXRG, and TNR influence intercellular signaling in the striatum.

Keywords: CMYA5; MCTP1; RXRG; TNR; anxiety; bipolar disorder; cross-species.

Figures

Figure 1
Figure 1
Bipolar disorder traits and analogous mouse phenotypes. On the left, symptoms of the manic and depressive phases of bipolar disorder are shown, as well as behaviors which have been demonstrated to be disrupted in bipolar disorder patients. On the right are mouse phenotypes which are measured by the zero maze and open field test, showing how the human traits link to the mouse traits.
Figure 2
Figure 2
Graphical representation of the research method used, providing a summary of the main findings.
Figure 3
Figure 3
Example QTL maps showing two significant QTL within each of the regions we identified. (A) Chromosome 1, between 155 and 175 Mbp, elevated zero maze traits (GeneNetwork ID 12419, 12361 and 12409; full details in Table 1). (B) Chromosome 13, between 70 and 100 Mbp, open field test traits 11606, 11759, 11607 (Full details in Table 2). This clearly shows that some traits have two peaks, with a non-significant region between, while other traits have significant peaks only at one end or the other of the identified regions. The higher red line indicates the level of genome-wide significance, i.e., a genome-wide corrected p ≤ 0.05, with the blue line showing the significance of the trait at each position. The lower red line indicates the negative additive coefficient, i.e., that C57BL/6J alleles increase trait values, with the scale in green on the left. The colored blocks at the top of the figure show the positions of genes. The orange track at the bottom of each map is the SNP Seismograph track, showing the positions of SNPs within the BXD lines. The location of our four candidate genes are shown, with the width of the line representing the size of the gene.

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