The genetics of bipolar disorder

Abstract

Bipolar disorder is a mood disorder characterized by impairing episodes of mania and depression. Twin studies have established that bipolar disorder is among the most heritable of medical disorders and efforts to identify specific susceptibility genes have intensified over the past two decades. The search for genes influencing bipolar disorder has been complicated by a paucity of animal models, limited understanding of pathogenesis, and the genetic and phenotypic complexity of the syndrome. Linkage studies have implicated several chromosomal regions as harboring relevant genes, but results have been inconsistent. It is now widely accepted that the genetic liability to bipolar disorder reflects the action of many genes of individually small effect, a scenario for which linkage studies are poorly suited. Thus, association studies, which are more powerful for the detection of modest effect loci, have become the focus of gene-finding research. A large number of candidate genes, including biological candidates derived from hypotheses about the pathogenesis of the disorder and positional candidates derived from linkage and cytogenetic studies, have been evaluated. Several of these genes have been associated with the disorder in independent studies (including BDNF, DAOA, DISC1, GRIK4, SLC6A4, and TPH2), but none has been established. The clinical heterogeneity of bipolar disorder and its phenotypic and genetic overlap with other disorders (especially schizophrenia, schizoaffective disorder, and major depressive disorder) has raised questions about the optimal phenotype definition for genetic studies. Nevertheless, genomewide association analysis, which has successfully identified susceptibility genes for a variety of complex disorders, has begun to implicate specific genes for bipolar disorder (DGKH, CACNA1C, ANK3). The polygenicity of the disorder means that very large samples will be needed to detect the modest effect loci that likely contribute to bipolar disorder. Detailed genetic dissection of the disorder may provide novel targets (both pharmacologic and psychosocial) for intervention.

A Genetic Survey of Fluoxetine Action on Synaptic Transmission in Caenorhabditis elegans

“…Intriguingly, a SERT knockout mouse showed reduced brain 5-HT (Bengel et al 1998). Furthermore, an allele of reduced SERT expression is found in patients suffering bipolar disorder and autism (Bartlett et al 2005;Brune et al 2006;Barnett and Smoller 2009). In this study, we identified two distinctive populations of serotonergic neurons in C. elegans: the NSM, ADF, and HSN neurons producing 5-HT and the RIH and AIM neurons absorbing 5-HT from extracellular space but unable to synthesize it.…”

The effect of COMT Val158Met and DRD2 C957T polymorphisms on executive function and the impact of early life stress

“…Indeed, genome‐wide association studies (GWAS) have shown that these disorders are highly polygenic (Barnett & Smoller, 2009; Schizophrenia Working Group of the Psychiatric Genomics, 2014; Shyn et al., 2011) with many genes exerting their influence on numerous neural pathways involved in complex aspects of brain function and likely being impacted upon by environmental events. It has been proposed that individual vulnerability and sensitization to the later development of mental health disorders may partly be regulated through variation in genes encoding proteins that impact on neurotransmitter and hormone systems such as those involved in dopamine, serotonin, and cortisol function (Caspi & Moffitt, 2006; Collip, Myin‐Germeys, & Van Os, 2008; van Winkel, Stefanis, & Myin‐Germeys, 2008; van Winkel, van Nierop, Myin‐Germeys, & van Os, 2013).…”

Kinins and microglial responses in bipolar disorder: a neuroinflammation hypothesis

“…Even though there is no conclusion about genes directly related to the onset and development of the disorder, a group of genes is altered in its expression patterns contributing to some of the phenotypes found in the brain of BD patients. These include serotonin transporter protein (5-HTT), catechol-O-methyltransferase (COMT), D-amino acid oxidase activator (DAOA), brain-derived growth factor (BDNF), among others (McGowan and Kato, 2008;Barnett and Smoller, 2009;Strakowski, 2012). The presence of polymorphisms of those genes has been suggested as the cause for development of BD (Collier et al, 1996;Sklar et al, 2002;Williams et al, 2006).…”