The Genetics of Bipolar Disorder
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Molecular Psychiatry (2008) 13, 742–771 & 2008 Nature Publishing Group All rights reserved 1359-4184/08 $30.00 www.nature.com/mp FEATURE REVIEW The genetics of bipolar disorder: genome ‘hot regions,’ genes, new potential candidates and future directions A Serretti and L Mandelli Institute of Psychiatry, University of Bologna, Bologna, Italy Bipolar disorder (BP) is a complex disorder caused by a number of liability genes interacting with the environment. In recent years, a large number of linkage and association studies have been conducted producing an extremely large number of findings often not replicated or partially replicated. Further, results from linkage and association studies are not always easily comparable. Unfortunately, at present a comprehensive coverage of available evidence is still lacking. In the present paper, we summarized results obtained from both linkage and association studies in BP. Further, we indicated new potential interesting genes, located in genome ‘hot regions’ for BP and being expressed in the brain. We reviewed published studies on the subject till December 2007. We precisely localized regions where positive linkage has been found, by the NCBI Map viewer (http://www.ncbi.nlm.nih.gov/mapview/); further, we identified genes located in interesting areas and expressed in the brain, by the Entrez gene, Unigene databases (http://www.ncbi.nlm.nih.gov/entrez/) and Human Protein Reference Database (http://www.hprd.org); these genes could be of interest in future investigations. The review of association studies gave interesting results, as a number of genes seem to be definitively involved in BP, such as SLC6A4, TPH2, DRD4, SLC6A3, DAOA, DTNBP1, NRG1, DISC1 and BDNF. A number of promising genes, which received independent confirmations, and genes that have to be further investigated in BP, have been also systematically listed. In conclusion, the combination of linkage and association approaches provided a number of liability genes. Nevertheless, other approaches are required to disentangle conflicting findings, such as gene interaction analyses, interaction with psychosocial and environmental factors and, finally, endophenotype investigations. Molecular Psychiatry (2008) 13, 742–771; doi:10.1038/mp.2008.29; published online 11 March 2008 Keywords: bipolar disorder; linkage; association studies; gene; polymorphisms Introduction of neurophysiologic alterations associated with the disorder, from animal models and pharmacological Bipolar disorder (BP) is relatively common, with studies, elucidating the mechanisms of action of bipolar-I illness affecting 0.5–1% of the population. psychotropic treatments. An example of this ap- The heritability of BP is high, around 80%;1 never- proach considers the brain-derived neurotrophic theless, finding genes that contribute to the suscepti- factors (BDNFs), which has been investigated in bility to this disorder has proven elusive. This is mood disorders because, on the one hand, animal almost certainly because many genes of small effect studies showed that development of cortical neuronal size (that is, conferring a relative risk of less than two) circuits was related to the expression of brain-BDNF2 contribute to the liability to develop the disorder. and, on the other hand, there was evidence of Strategies for elucidating specific genetic bases for reductions in the volume of the hippocampus in BP include linkage and association methods. In fact, subjects with a history of depression.3 Another two approaches have been mainly employed to example considers the well-known serotonin trans- identify genes to be investigated in BP, as well as in porter gene (SLC6A4), which has been investigated in other complex diseases. First, the so-called ‘func- depressive disorders because its product is the target tional candidate approach,’ based on the selection of of action of serotonin selective reuptake inhibitors, genes that are thought to be involved in the biological the most widely employed antidepressant drugs processes implicated in the disease. Usually, re- currently prescribed for major depression. searchers derive their hypotheses from the knowledge The alternative approach is based on the selection of genes that are located in regions associated with BP Correspondence: Professor A Serretti, Institute of Psychiatry, in linkage studies, the so-called ‘positional candidate University of Bologna, Viale Carlo Pepoli 5, Bologna 40123, Italy. E-mail: [email protected] approach.’ This approach has been employed, for Received 19 August 2007; revised 24 January 2008; accepted 30 example, to select the G30 gene (also called DAOA), January 2008; published online 11 March 2008 as it is located in the 13q33, a region that has been Bipolar disorder genes A Serretti and L Mandelli 743 reported as positively linked to both schizophrenia4 Areas that have been associated with BP are summar- and BP.5 ized in Table 1 and Figure 1. Unfortunately, results from linkage and association Some areas throughout the genome have been studies are not always easily comparable and at repeatedly associated with BP and thus they represent present a comprehensive coverage of available evi- ‘hot regions.’ However, only few of these contain dence is still lacking, despite many efforts of genes that have been investigated in association academic and government institutions. The present studies. These regions are 4p16.1, where wolframin paper reviews current research from linkage and gene (WFS1) and some recently investigated genes, association studies on the molecular bases of BP, such as WD repeat-containing protein 1 (WDR1) and with the aim to point out genomic regions of interest protein phosphatase 2 (PPP2R2C) are located; and promising genes that have to be further investi- 11p15.5, where dopamine receptor D4 (DRD4) and gated, other than summarizing the current state of the tyrosine hydroxylase (TH) are located; 12q24.31, art. Further, we aimed to indicate new potential where nitric oxide synthase 1 (NOS1) is located; interesting genes, located in genome ‘hot regions’ for 18p11.21, where myo-inositol monophosphatase 2 BP and being expressed in the brain. We will discuss (IMPA2) is located; 21q22.2–3, where transient re- the utility to combine linkage, association and other ceptor potential 3 (TRPM3) is located and 22q12.3, approaches, to clarify the genetic mechanisms of BP. where synapsin III (SYN3) is located. Other ‘hot regions’ are 5p15.33, 6q21, 8q24.22, Methods 10q26.2, 13q32.1–3, 17q25.3, 18p11.31, 18q22–23, 20q13.33, Xq26.1. Nevertheless, to our knowledge, We reviewed published studies on linkage and positive findings for genes located within these latter association studies in BP till December 2007, employ- areas have been never reported in association studies. ing the Medline database (http://www.ncbi.nlm.nih. For this purpose, we performed a research for genes gov/) and entering the following key words: BP, located in all these areas (‘Entrez gene’ database), affective disorder, depressive disorder, gene, genetics, which are known to be expressed in the brain association, linkage and chromosome 1 to X. For each (expression profile, ‘Unigene’ database) and known gene/region found positive in BP investigations, we with respect to the biological process they are also searched for other studies investigating the involved in (‘Human Protein Reference Database’). specific gene/region, entering BP/affective disorder/ In Table 2, the reader can find a list of genes select. depressive disorder and gene/region/chromosome. Some of these genes are very close to markers We considered only papers written in English and employed in linkage studies and found positive; in defining BP according to diagnostic and statistical some cases positive markers are located exactly manual of mental disorders (DSM) criteria. Meta- within the gene. analyses and studies combining results of previous A number of other interesting areas have been also investigations were considered as a summary of reported in the literature, and the reader can find a preceding works. In total, 345 studies were selected comprehensive summary in Table 1. (97 linkage studies and 248 association studies––5 including both methodologies). Serotonin-related genes Positive linkage was established when the marker Certainly, one of the most widely investigated genes obtained LOD score of at least 2 or a nominal P-value in BP is serotonin transporter (SLC6A4). This gene is lower than 0.05. Significance in association studies located in 17q11.1–q12, a region found positive in was as well considered with a nominal P-value lower two linkage studies. Positive results have been than 0.05. We precisely localized regions where obtained with respect to a 48 bp promoter polymorph- positive linkage was found by the NCBI Map viewer ism (SERTPR), and four consecutive meta-analyses (http://www.ncbi.nlm.nih.gov/mapview/). Genes lo- confirmed the finding. Though less widely, a VNTR cated in interesting areas and being expressed in the element in the second intron has also been investi- brain, not yet investigated in association studies, were gated, and it was found positive in one meta-analytic identified by the ‘Entrez gene’, ‘Unigene’ databases study, but not in other two. (http://www.ncbi.nlm.nih.gov/sites/entrez), and the Another gene consistently associated with BP, ‘Human Protein Reference Database’ (http:// but not located in a region found in positive www.hprd.org). For this, we entered the specific linkage with BP, is neuronal tryptophan hydroxylase