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.Bipolar disorder (BPD) is a common and serious mental disorder characterized by severe mood symptoms, including episodes of mania or hypomania and depression, occurring with a typically cyclical course. Lifetime risk for BPD has typically been reported to be approximately 1%, though recent estimates are as high as 4%. (Kessler et al., 2005). The personal and societal costs of BPD are enormous: even among adequately-treated individuals, relapse is common and the disorder can be profoundly disabling, resulting in serious economic burden (Kessler et al., 2006) Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production pr...

The genetics of bipolar disorder

“…Candidate gene studies have provided tantalizing glimpses into the possible genetic aetiology of BPD but few, if any genes are universally accepted (Smoller and Gardner-Schuster, 2007, Burmeister et al, 2008). Of those genes which have been reasonably well-studied, many are putative candidates because of their central role in neurotransmitter pathways, particularly the dopamine, serotonin and glutamate systems.…”

“…Increased rates of schizophrenia are seen among relatives of people with BPD (Valles et al, 2000, Mortensen et al, 2003), and increased risk for schizoaffective disorder is found among relatives of both schizophrenia and bipolar patients (Kendler and Gardner, 1997, Cardno et al, 2002, Mortensen et al, 2003). Several authors have highlighted regions which have shown linkage to both BPD and schizophrenia, including 6q21–25, 10p14, 13q32–34, 18p11 and 22q11–13 (Berrettini, 2000, Bramon and Sham, 2001, Smoller and Gardner-Schuster, 2007) although it is possible that these shared peaks are due to entirely separate genes, or indeed, just coincidence (Kendler, 2006). Similarly, several candidate genes have been associated with both schizophrenia and bipolar diagnoses (e.g.…”

Alternatively Spliced Genes as Biomarkers for Schizophrenia, Bipolar Disorder and Psychosis: A Blood-Based Spliceome-Profiling Exploratory Study (Supplementry Table)

“…As both disorders are thought to have relatively high heritability (~80%) [3, 4], biomarkers tied to specific candidate genes have often formed the basis for these pursuits. For example, both schizophrenia and bipolar disorder have been the subject of hundreds of candidate-gene association analyses [5–7] and, most recently, a handful of genome-wide association studies [8–14]. Through meta-analysis, our group and others have identified several genetic polymorphisms that influence the risk for one or the other disorder [6, 15–21].…”

Linkage disequilibrium mapping of the chromosome 6q21–22.31 bipolar I disorder susceptibility locus

“…In particular, psychotic BPD and early-onset BPD have been shown to be familial and heritable subtypes that may reflect more genetically homogeneous influences [Smoller and Gardner-Schuster, 2007]. Early-onset BPD was defined as having a first manic or depressive episode before age 18, and psychosis was defined as having had psychotic symptoms or a psychotic diagnosis on any of the STEP-BD instruments that assessed psychosis.…”