Candidate risk genes for bipolar disorder are highly conserved during evolution and highly interconnected

Abstract

Bipolar disorder (BPD) is a challenging psychiatric disorder characterized by dramatic shifts in mood from mania or hypomania to depressive symptoms that can adversely affect thought processes, social behavior, and work/scholastic performance. [1][2][3] Additional clinical features may include irritability, excessive energy, hyperactivity, disordered thought, and delusions. 2,4,5 The lifetime prevalence rate is in the range 1%-3% of the population for the bipolar spectrum disorders. 1,6,7 Although the full pathogenesis remains unclear, genetic factors contribute substantially to the predisposition for developing symptoms. [8][9][10] Heritability is high and is estimated in the range 60%-85%. 11,12 Nevertheless, environmental factors also contribute to the risk of developing BPD and gene-environment interactions must likewise play a significant role. 13,14 Based on findings that established a genetic basis for BPD, numerous genome-wide association studies (GWAS) have been conducted to identify potential risk alleles. Early GWAS on relatively

Analysis of Major Depression Risk Genes Reveals Evolutionary Conservation, Shared Phenotypes, and Extensive Genetic Interactions

“…The table includes brief gene descriptors, chromosomal locations, associated variants where available, genetic counterparts in C. elegans and zebrafish, and phenotypes derived from the C. elegans database, WormBase (32). We focused on these two species to be comparable to prior research on other psychiatric disorders (30,31), to span a broad evolutionary time-scale and to take advantage of the rich phenotype data available for C. elegans genes. Finally, we noted all of the MDD risk genes that did not have a counterpart in C. elegans (33) and zebrafish (12) by inserting "None" for that species in Supplementary Table 1.…”

“…At an intuitive level, one might imagine that genes causing MDD-a disorder of higher brain function affecting extensive neural networks including the limbic system-would tend to be unique to humans or more prevalent in higher species and absent in simple organisms that lack equivalent brain regions and behavioral complexity. However, based on previous work by our group (30,31), we hypothesized that MDD risk genes would be evolutionarily conserved. As summarized in Figure 1, the MDD risk-gene counterparts are highly conserved (p < 0.01) in C. elegans in comparison to genomic analyses of human genes found in this species.…”

“…The genes were characterized in terms of degree of evolutionary conservation, the phenotypes associated with their genetic counterparts in C. elegans, and gene-gene interactions. Based on previous findings in schizophrenia (30) and bipolar disorder (31), we hypothesized that the MDD risk genes would show an increase in evolutionary conservation and genetic interactions with one another in comparison to randomly-selected genes. As reported here, the MDD risk genes are highly conserved during evolution, involved in essential and pleiotropic processes and are extensively linked in gene interaction networks.…”

New analyses provide supportive evidence for specific genes related to bipolar disorder

“…Altogether this is a very helpful contribution to the literature on the genetics of bipolar disorder, and Franklin and Dwyer 1 are to be commended for their exhaustive work with the genetic databases required to produce these fascinating results.…”

“…Such interactions in the present study are remarkable. The 230 genes implicated in bipolar disorder participated in an average of 22 interactions 1 compared with less than 5 for random gene sets studied for comparison. This is also much more than the interactions of genes implicated in schizophrenia (8 interactions) or genes implicated in rheumatoid arthritis (5.6 interactions).…”