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 region in ‘Entrez gene,’ we looked at ‘expression (TPH2), which codes for the rate-limiting enzyme profile’ in ‘Unigene’ and classified their product for in the biosynthesis of serotonin in the central molecular class and biological process by the ‘Human nervous system.102 Single nucleotide polymorphisms Protein Reference Database.’ (SNPs) within the gene have been associated with BP in five independent studies, while two studies failed to report associations. Mainly negative Review of linkage studies and new positional results have been instead reported with respect candidate genes to tryptophan hydroxylase 1 (TPH1); however, this Many linkage studies have been performed since the gene seems to be mostly expressed in peripheral 1990s and a huge amount of data has been collected. tissues.103

Molecular Psychiatry Bipolar disorder genes A Serretti and L Mandelli 744 Table 1 Regions reported in linkage studies of BP

Area Marker Position Positive studies (ref.) (no. of Negative studies (ref.) (no. of (Mb) families and ethnicity) families and ethnicity)

Chromosome 1 1p36.33 D1S243 2.1 6(7, Caucasian) 1p36.11 D1S234 25.0 7(75, Caucasian) 1p32.1 D1S220 59.0 7(75, Caucasian) rs2989476 60.8 8(1868 subjects, Caucasian) 1p31.1 D1S224 71.9 9(97, mixed) D1S216 77.4 10(2, Caucasian) 1q23.3 D1S2675 160.4 11(41, Caucasian) 1q31.3 D1S1660 196.8 12(22, Caucasian) 13(41, Caucasian) D1S413 196.8 14(38, Caucasian) 1q32.1 D1S1678 201.7 12(22, Caucasian) D1S1606 200.2 9(97, mixed) 1q42.13 D1S103 228.9 15(10, Caucasian) 1q42.2 D1S251 229.7 6(7, Caucasian) D1S2800 232.5 16(13, Caucasian) 1q44 D1S1609 242.1 17(98 plus 64, Caucasian)

Chromosome 2 2p25.1 rs4027132 11.9 8(1868 subjects, Caucasian) 2p21 D2S1356 43.2 18(16, Azores) 19(97, mixed) D2S391 46.2 20(70, Caucasian) 2p13.2 D2S1394 72.9 21(250, 93% Caucasian) 19(97, mixed) 2q11.2 D2S2972 114.4 22(32, Caucasian) 2q12.1 rs7570682 104.3 8(1868 subjects, Caucasian) 2q14.1 rs1375144 115.6 8(1868 subjects, Caucasian) 2q21.3 D2S369 134.8 7(75, Caucasian) 2q24.1 D2S141 156.5 7(75, Caucasian) 2q24.3 D2S1776 169.3 17(98 plus 64, Caucasian) 2q31.1 D2S326 172.80 7(75, Caucasian) rs12465451 176.6 8(1868 subjects, Caucasian) 2q37.1 D2S427 231.9 19(97, mixed) 2q37.3 D2S125 240.8 23(151, Caucasian) 24(395, Caucasian) rs2953145 241.2 8(1868 subjects, Caucasian)

Chromosome 3 3p23 rs4276227 32.3 8(1868 subjects, Caucasian) 3p21.32 D3S3685 42.4 11(41, Caucasian) 3p14.2 D3S4542 51.0 5(20, Caucasian) D3S1300 60.4 20(70, Caucasian) D3S17766 58.9 5(20 Caucasian) 3q23 D3S1764 140.6 21(250, 93% Caucasian) 25(97, mixed US) 3q25.1 D3S1279 152.5 26(13, Caucasian) 3q26.31 D3S1565 174.9 7(75, Caucasian) 3q27.1 rs683395 184.3 8(1868 subjects, Caucasian) 3q28 D3S2398 190.9 5(20, Caucasian) 3q29 D3S1265 197.0 6(7, Caucasian)

Chromosome 4 4p16.1 D4S394 7.0 27(11, Caucasian) 28(97, mixed US) 29(4, Caucasian) 10(2, Caucasian) D4S2366 6.5 30(1, Turkish) 4p14 D4S405 40.0 24(395, Caucasian) 4q23 D4S1647 99.6 28(97, mixed US) 4q31.21 D4S1625 143.7 31(39, Columbian) 4q31.23 SHGC-106437 150.0 32(52, Caucasian) 4q35.1 D4S2924 186.6 33(1, Caucasian) D4S3335 185.5 34(153, mixed US) 4q35.2 D4S2390 189.9 34(153, mixed US) D4S1652 190.3 35(55, Caucasian)

Molecular Psychiatry Bipolar disorder genes A Serretti and L Mandelli 745 Table 1 Continued

Area Marker Position Positive studies (ref.) (no. of Negative studies (ref.) (no. of (Mb) families and ethnicity) families and ethnicity)

Chromosome 5 5p15.33 D5S417 3.1 5(20, Caucasian) D5S2849 3.4 36(154, mixed US) D5S1492 3.7 25(97, mixed US) 5q23.1 D5S2501 110.0 18(16, Azores) D5S804 125.1 25(97, mixed US) 5q32 D5S436 145.1 20(70, Caucasian) D5S2033 145.9 37(1, Costa Rica) 5q33.1 D5S636 149.8 38(1, Costa Rica) D5S673 151.5 37(1, Costa Rica) 14(38, Caucasian) 5q33.2 D5S410 152.7 20(70, Caucasian) 5q33.3 D5S820 156.0 39(40, Caucasian) 5q35.1 D5S1456 168.9 25(97, mixed US)

Chromosome 6 6p21.1 rs6458307 42.8 8(1868 subjects, Caucasian) 6p23 ATA50C05ZP 25.1 22(32, Caucasian) 6q21 D6S1021 104.7 10(2, Caucasian); 21(250, 93% Caucasian); 39(40, Caucasian); 18(16, Azores); 24(395, Caucasian) Not reported 107.9 40(1067, combined analysis) D6S474 112.9 9(97, mixed); 7(75, Caucasian) Not reported 125.8 41(25, Caucasian) 6q23.3 D6S1009 137.3 10(2, Caucasian); 9(97, mixed)

Chromosome 7 7p21.1 D7S3051 18.2 18(16, Azores) D7S507 17.5 28(97, mixed US); 26(13, Caucasian) 7q22.1 D7S518 101.6 42(10, Caucasian) 7q32.1 D7S635 127.1 42(10, Caucasian) 7q35 D7S2195 143.4 28(97, mixed US) 7q36.1 D7S3070 151.2 22(32, Caucasian)

Chromosome 8 8p23.1 D8S1825 8.0 43(154 schizophrenics with history of mania, Costa Rica) D8S542 10.1 8p21.2 D8S382 26.0 7(75, Caucasian) 8p12 rs2609653 34.2 8(1868 subjects, Caucasian) 8q13.1 D8S1136 82.3 22(32, Caucasian) 8q13.2 D8S2323 70.2 25(97, mixed US); 31(39, Columbia) 8q24.13 D8S514 123.8 7(75 Caucasian); 26(13, Caucasian) 8q24.22 D8S529 134.1 44(65, Caucasian) D8S256 134.5 21(250, 93% Caucasian); 45(153, Caucasian) rs2945733 134.7 46(115 plus 103, Caucasian) rs1870126 135.2 rs1457466 135.2 rs765847 135.2 Not reported 135.4 40(1067, combined analysis) 8q24.23 D8S272 137.8 47(50, Caucasian) 8q24.3 D8S1741 140.7 15(10, Caucasian); 39(40, Caucasian)

Chromosome 9 9p22.3–21.1 Not reported Broad area 48(meta-analysis) 9q21.13 D9S175 77.1 15(10, Caucasian) 9q21.32 D9S264 84.6 47(50, Caucasian) 9q31.1 D9S938 105.0 31(39, Columbian); 39(40, Caucasian) D9S1690 103.1 26(13, Caucasian) 9q31.3 Not reported 115.0 49(58, mixed US) 9q32 rs10982256 114.3 8(1868 subjects, Caucasian)

Molecular Psychiatry Bipolar disorder genes A Serretti and L Mandelli 746 Table 1 Continued

Area Marker Position Positive studies (ref.) (no. of Negative studies (ref.) (no. of (Mb) families and ethnicity) families and ethnicity)

D9S302 116.1 28(97, mixed US) D9S1824 115.9 30(1, Turkish) D9S1776 116.9 26(13, Caucasian)

Chromosome 10 10p12.33 D10S1423 19.4 50(140, mixed US) 10q11.21–22.1 Not reported Broad area 48(meta-analysis) 10q21.2 D10S1225 64.4 31(39, Columbian) D10S589 61.1 14(38, Caucasian) 10q21.3 D10S581 65.5 42(10, Caucasian) 10q22.2 D10S188 75.0 25(97, mixed US) 10q26.12 D10S1757 122.3 7(75, Caucasian) 10q26.2 D10S1223 128.7 5(20, Caucasian) D10S217 129.4 51(75, Caucasian); 10(2, Caucasian) D10S1223 128.0 52(153, Caucasian) D10S186 128.6 9(97, mixed)

Chromosome 11 11p15.5 TH 2.1 53(23, Caucasian); 54(11, Caucasian); 57(2, Caucasian); 58(1 55(23, Caucasian); 56(56, mixed US); Caucasian); 59(1 Caucasian); 52(153, Caucasian) 60(14, Caucasian); 61(1, Caucasian) 11q12.2 D11S4191 59.7 11(41, Caucasian) Not reported 60.0 40(1067, combined analysis) 11q13.2 D11S987 67.6 18(16, Azores)

Chromosome 12 12q13.12 D12S339 47.4 62(2, Caucasian) 12q21.1 rs1526805 75.0 8(1868 subjects, Caucasian) 12q23.1 D12S69 99.0 52(153, Caucasian) 12q24.31 D12S1639 124.9 10(2, Caucasian) D12S342 124.4 6(7, Caucasian) D12S378 123.2 14(38, Caucasian) rs2230912 120.1 63(41, Iranian) 12q24.32 D12S2078 26.5 22(32, Caucasian)

Chromosome 13 13q Not reported 64(Meta-analysis) 13q12.11 D13S175 19.7 7(75, Caucasian) 13q12.3 D13S1 35.9 65(1, Caucasian) D11S1493 32.9 19(97, mixed); 30(1, Turkish) Not reported 42.4 40(1067, combined analysis) 13q13.2 D13S1493 32.9 45(153, Caucasian) 13q14.2 D11S153 47.7 26(13, Caucasian) 13q32.1 D13S793 95.6 19(97, mixed); 36(154, mixed US) 5(20, Caucasian) D13S154 95.0 5(20, Caucasian); 66(52, Caucasian) 13q32.2 D13S1252 97.3 12(22, Caucasian) 13q32.3 D13S779 82.3 67(22, Caucasian); 39(40, Caucasian) D13S225 100.3 5(20, Caucasian); 66(52, Caucasian) 13q33.3 D13S796 106.6 5(20, Caucasian); 66(52, Caucasian)

Chromosome 14 14q24.1 D14S588 69.3 22(32, Caucasian) 14q24.1–32.12 Not reported Broad area 48(meta-analysis) 14q22.2 D14S281 54.1 68(49, Caucasian) 14q22.3 D14S276 54.7 7(75, Caucasian) rs10134944 57.2 8(1868 subjects, Caucasian) 14q32.12 GATA31B 91.0 69(97, mixed US) 14q32.33 rs11622475 103.4 8(1868 subjects, Caucasian)

Chromosome 15 15q22.2 D15S643 57.5 17(98 plus 64, Caucasian)

Molecular Psychiatry Bipolar disorder genes A Serretti and L Mandelli 747 Table 1 Continued

Area Marker Position Positive studies (ref.) (no. of Negative studies (ref.) (no. of (Mb) families and ethnicity) families and ethnicity)

15q26.2 D15S207 94.0 70(16, Caucasian) D15S657 94.5 70(16, Caucasian) 15q26.3 D15S1014 95.8 70(16, Caucasian) D15S212 95.9 70(16, Caucasian) D15S966 96.7 70(16, Caucasian)

Chromosome 16 16p13.3 D16S521 0.03 71(12, Caucasian) Unknown 1.9 72(1, Caucasian) D16S291 2.2 71(12, Caucasian) TTTA028 2.3 22(32, Caucasian) 16p13.2 D16S510 5.7 10(2, Caucasian) D16S423 5.9 71(12, Caucasian) D16S2616 6.3 36(154, mixed US) D16S513 8.2 71(12, Caucasian) 16p13.13 D16D748 12.0 45(153, Caucasian) 16p13.12 D16S2619 13.6 25(97, mixed US) 16p12.1 rs420259 23.5 8(1868 subjects, Caucasian) 16q12.2 rs1344484 51.4 8(1868 subjects, Caucasian) 16q23.1 D16S516 77.6 20(70, Caucasian)

Chromosome 17 17p12 D17S921 14.2 31(39, Columbian); 39(40, Caucasian) D17S799 13.1 73(18, Caucasian) 17p11.2 D17S1857 16.3 74(12, Caribbean) D17S783 21.2 73(18, Caucasian) 17q11.2 D17S925 24.3 14(38, Caucasian) D17S841 24.5 75(48, Caucasian) SLC6A4 27.0 73(18, Caucasian) D17S798 28.3 74(12, Caribbean) 20(70, Caucasian) 17q24.3 Not reported 64.3 40(1067, combined analysis) D17S949 65.9 74(12, Caribbean) 17q25.3 D17S668 77.6 76(22, Cuban) D17S928 77.8 21(250, 93% Caucasian); 74(12, Caribbean)

Chromosome 18 18p11.1–q12.3 Not reported Broad area 48(meta-analysis) 18p11.32 rs12607596 1.7 77(344, Caucasian) rs1893157 2.3 rs11080994 2.9 18p11.31 D18S54 3.6 78(6, Caucasian) rs541039 4.3 77(344, Caucasian) rs551920 4.3 rs9635859 4.7 D18S452 5.9 23(151, Caucasian) rs1940594 5.9 77(344, Caucasian) rs6506386 6.4 18p11.23 rs16952222 7.6 77(344, Caucasian) 18p11.22 rs10853370 9.0 77(344, Caucasian) D18S1150 10.2 12(22, Caucasian) 18p11.21 D18S542 11.4 79(meta-analysis) D18S53 11.4 80(3 pooled samples, mixed) D18S37 13.1 79(meta-analysis) 18q12.1 D18S478 23.4 74(12, Caribbean) Not reported 44.9 40(1067, combined analysis) 18q22.1 D18S477 63.2 38(1, Costa Rica) D18S878 61.5 45(153, Caucasian) 18q22.3 D18S380 71.3 38(1, Costa Rica) D18S541 68.3 11(41, Caucasian) D18S43 68.9 78(6, Caucasian) D18S469 69.4 81(58, mixed US) 82(48, Caucasian)

Molecular Psychiatry Bipolar disorder genes A Serretti and L Mandelli 748 Table 1 Continued

Area Marker Position Positive studies (ref.) (no. of Negative studies (ref.) (no. of (Mb) families and ethnicity) families and ethnicity)

18q23 D18S554 73.1 83(2, Costa Rica); 38(1, Costa Rica) 82(48, Caucasian) D18S70 75.9 28(97, mixed US); 83(2, Costa Rica); 38(1, Costa Rica); 84(57, Caucasian) D18S380 69.9 82(48, Caucasian)

Chromosome 19 19p13.3 D19S216 4.9 26(13, Caucasian) 19p13.12 D19S714 15.5 18(16, Azores) 28(97, mixed US) 19q13.33 D19S907 55.7 42(10, Caucasian)

Chromosome 20 20p13 rs3761218 3.7 8(1868 subjects, Caucasian) 20p12.2 D20S162 9.9 34(153, mixed US) D20S189 11.2 14(38, Caucasian) D20S186 11.4 20(70, Caucasian) 20p12.1 D20S604 12.5 30(1, Turkish) D20S470 17.3 30(1, Turkish) 20q11 Not reported Not reported 49(58, mixed US) 20q11.23 D21S478 36.6 18(16, Azores) 28(97, mixed US); 30(1, Turkish) 20q13.12 D20S836 44.3 30(1, Turkish) D20S119 43.0 14(38, Caucasian) 20q13.13 D20S480 51.5 39(40, Caucasian) 20q13.33 D20S173 58.3 28(97, mixed US); 50(140, mixed US); 30(1, Turkish) Not reported 60.0 41(25, Caucasian)

Chromosome 21 21q21.1 D21S1437 20.6 22(32, Caucasian) 21q22.2 D21S1260 27.9 85(56, Caucasian); 86(40, Caucasian) D21S1255 38.7 12(22, Caucasian) 21q22.13 D21S1252 36.7 87(18, Caucasian); 88(150, mixed US) D21S198 41.3 89(12, Caucasian) 21q22.3 PFKL 44.5 5(20, Caucasian); 90(57, Caucasian); 91(60, Caucasian) 89(57, Caucasian) D21S171 44.8 92(23, Caucasian); 93(1 Caucasian)

Chromosome 22 22q11.1 Not reported 15.0 40(1067, combined analysis) D22S420 16.2 16(13, Caucasian) 22q12.3 Not reported 32.0 64(353, meta-analysis) D22S281 32.6 94(142, Caucasian) D22S277 34.6 95(10, Caucasian) D22S278 34.7 96(79, Arabic) rs8138016 35.0 8(1868 subjects, Caucasian) 22q13.1 D22S283 35.0 97(52, mixed US)

Chromosome X Xp22.11 DXS989 23.0 19(97, mixed) Xp11.3 GATA144D04 44.8 56(56, mixed US) Xq Not reported 98(5, Caucasian) Xq22.3 rs975687 111.0 8(1868 subjects Caucasian) Xq26.1 DXS1047 128.9 99(41, Caucasian); 19(97, mixed) DXS994 130.1 100(1, Caucasian) Xq27–28 Unknown Broad area 101(14, Caucasian) Xq27.1 GATA31E08 140.0 19(97, mixed)

Abbreviation: BP, bipolar disorder. For each region, the positive marker and its location have been reported. In bold, meta-analysis or analyses on pooled samples.

Molecular Psychiatry Bipolar disorder genes A Serretti and L Mandelli 749

Figure 1 Genome areas where linkage with bipolar disorder (BP) has been reported. Bold arrows indicate stronger evidence. Images have been derived from the Idiogram album (Human copyright 1994 David Adler); we acknowledge the Department of Pathology, University of Washington, for allowing the use of figures for publication.

The following serotonin receptors’ genes have been Dopaminergic genes investigated in more than one study: serotonin A second gene widely investigated and consistently receptor 1A (HTR1A), serotonin receptor 2A associated with BP is DRD4, located in a region found (HTR2A), serotonin receptor 2C (HTR2C) and seroto- in positive linkage with BP (11p15.5). In particular, nin 7 receptor (HTR7). HTR1A, after a first negative a VNTR in the third exon was repeatedly reported report, was found associated with BP in two studies associated with BP and a recent meta-analysis con- with respect to a dinucleotide tandem repeats (CAn/ firmed the finding. Another promising dopamine GTn) and a G > A SNP in exon 1. Some evidence, receptor gene is dopamine receptor D1 (DRD1), though contrasting, does also exist for HTR2A, which was initially reported as negative in studies located in the positive region 13q14–q21. Association investigating the promoter –48A/G polymorphism, has been reported for 516C > T, 1438G > A and except for two positive reports following. However, 62428C > T (rs6313) polymorphisms, while mainly other polymorphisms within the gene were investi- negative findings were reported for þ 74C > A, 102T/ gated and while some did not show association with C, 1354C/T (except Ranade et al.104) and His452Tyr BP, two studies on haplotypes reported positive polymorphisms. With respect to HTR2C, two studies results. reported negative association for a cys23-ser23 poly- Dopamine transporter gene (SLC6A3) is a third morphism in exon 4, while a third study found a dopaminergic gene reliably involved in BP. Whereas positive association. Other variants in the 50 regula- first studies investigating the 40 bp VNTR in the tory region of the gene did not give positive results, 30 untranslated region mainly reported negative whereas positive association for the þ 12C > G SNP in findings, positive results were obtained analyzing exon 3 was observed in one study. Finally, three other polymorphisms, such as the À67A/T in Asiatic studies focused on HTR7 and two of these failed to populations, and haplotypes located in the promoter find an association with BP; however, the gene is region and at the end region of the gene. located in the interesting region 10q21–q24, thus Some other dopaminergic genes, found positively further investigation may be required. associated in at least one study, were extensively In conclusion, consistent association has been investigated but studies mainly failed to find them found for SLC6A4 and TPH2. HTR1A, HTR2A and associated with BP. This was the case of dopamine HTR2C seem to be promising candidate genes as well, receptor D3 (DRD3), dopa decarboxylase gene (DDC), while HTR7 mainly gave negative results. Never- involved in the synthesis of both dopamine and theless, further investigation is required. Other serotonin; and TH, located in the hot region 11p15.5 serotoninergic genes of interest, needing additional and involved in the conversion of phenylalanine to investigation, are listed in Tables 3 and 4. dopamine.

Molecular Psychiatry Bipolar disorder genes A Serretti and L Mandelli 750 Table 2 Genes located into regions repeatedly linked with BP; all genes in the list are expressed in the brain

Position Gene symbol Protein’s molecular class Biological process

4p16.1 TBC1D14* GTPase-activating protein Cell communication; signal transduction GPR78 G-protein-coupled receptor DRD5 G-protein-coupled receptor activity HTRA3 Serine protease Protein metabolism MAN2B2 Enzyme: glycosidase Metabolism; energy pathways HMX1 Transcription factor Regulation of nucleobase, nucleoside, nucleotide and nucleic acid metabolism CCDC96 Transcription regulatory protein MGC21874 Transcription regulatory protein KIAA1729 Unclassified

KIAA1327 DNA-binding protein JAKMIP1 Adapter molecule Vesicle-mediated transport; signal complex formation; cytoskeleton organization and biogenesis; regulation of nucleobase, nucleoside, nucleotide and nucleic acid metabolism

6q21 CD164 Adhesion molecule Cell communication; signal transduction CDC2L6 Serine/threonine kinase SESN1 Cell cycle control protein GPR6 G-protein-coupled receptor FYN Tyrosine kinase NR2E1 Nuclear receptor AIM1 Calcium-binding protein Cell communication; regulation of cell proliferation; signal transduction TRAF3IP2 Unclassified Signal transduction SEC63 Transport/cargo protein Transport SNX3 Transport/cargo protein Intracellular signaling cascade; protein transport FIG4 Enzyme: phospholipase Metabolism; energy pathways SMPD2 Enzyme: phosphodiesterase DDO Enzyme: oxidase RTN4IP1 Enzyme: dehydrogenase PPIL6 Enzyme: isomerase QRSL1 Enzyme: amidinotransferase HACE1* Ubiquitin proteasome system protein Protein metabolism MICAL1 Cytoskeletal protein Cell growth and/or maintenance POPDC3 Unclassified LAMA4 Adhesion molecule TUBE1 Cytoskeletal protein CCNC Cell cycle control protein Regulation of cell cycle ATG5 Cytoskeletal protein Apoptosis CD24 Unclassified Immune response FOXO3 Transcription factor Regulation of nucleobase, nucleoside, nucleotide and nucleic acid metabolism CDC40 Transcription regulatory protein HDAC2 Transcription regulatory protein ZBTB24 DNA-binding protein

8q24.22 ST3GAL1* Enzyme: sialyltransferase Metabolism; energy pathways

10q26.2 MMP21 Metallo protease Protein metabolism DHX32 ATPase Metabolism; energy pathways GPR26 G-protein-coupled receptor Cell communication; signal transduction

11p15.5 STIM1 Adhesion molecule Cell communication; signal transduction DUSP8 Dual specificity phosphatase SCT Peptide hormone TSPAN32 Membrane transport protein EPS8L2 Adapter molecule BRSK2 Serine/threonine kinase SIGIRR Unclassified

Molecular Psychiatry Bipolar disorder genes A Serretti and L Mandelli 751 Table 2 Continued

Position Gene symbol Protein’s molecular class Biological process

TOLLIP Adapter molecule LSP1 Calcium-binding protein IGF2 Growth factor CDKN1C Cell cycle control protein IFITM2 Integral membrane protein RASSF7 GTPase-activating protein HRAS GTPase RIC8A Guanine nucleotide exchange factor LRDD Adapter molecule SYT8 Calcium-binding protein TUB Transcription regulatory protein Signal transduction CD151 Cell surface receptor Cell communication; cell motility NUP98 Transport/cargo protein Transport CHRNA10 Extracellular ligand-gated channel KCNQ1 Voltage-gated channel TRPM5 Integral membrane protein BET1L Transport/cargo protein HBG1 Transport/cargo protein HBG2 Transport/cargo protein HBB Transport/cargo protein SLC25A22 Membrane transport protein AP2A2 Transport/cargo protein SLC22A18AS Transport/cargo protein SLC22A18 Membrane transport protein Ion transport CHID1 Transport/cargo protein Transport; cell proliferation; cell activation; cell differentiation CTSD Aspartic protease Protein metabolism PSMD13 Ubiquitin proteasome system protein CARS Enzyme: ligase Metabolism; energy pathways TRIM3 Anchor protein Cell growth and/or maintenance KRTAP5-2 Structural protein CEND1 Integral membrane protein KRTAP5-5 Structural protein PHLDA2 Unclassified Apoptosis IFITM3 Integral membrane protein Immune response NAP1L4 Chaperone Regulation of nucleobase, nucleoside, nucleotide and nucleic acid metabolism RRM1 Cell cycle control protein TRIM21 Ribonucleoprotein RNH1 Translation regulatory protein IRF7 Transcription factor DEAF1 Transcription regulatory protein PNPLA2 Enzyme: hydrolase CD81 Enzyme: oxidase ZNF195 Transcription factor SIRT3 Enzyme: deacetylase Gene silencing

12q24.31 CABP1 Calcium-binding protein Cell communication; signal transduction RHOF GTPase GPR109B G-protein-coupled receptor DIABLO Cell cycle control protein RAB35 GTPase DENR Unclassified ANAPC5 Cell cycle control protein SCARB1 Cell surface receptor GPR81 G-protein-coupled receptor MPHOSPH9 Cell cycle control protein KNTC1 Cell cycle control protein GPR109A G-protein-coupled receptor PITPNM2 Integral membrane protein PXN Cytoskeletal-associated protein Signal transduction TMED2 Transport/cargo protein Transport

Molecular Psychiatry Bipolar disorder genes A Serretti and L Mandelli 752 Table 2 Continued

Position Gene symbol Protein’s molecular class Biological process

VPS33A Transport/cargo protein ORAI1 Ion channel Ion transport VPS37B Transport/cargo protein Protein transport ATP6V0A2 ATPase Metabolism; energy pathways AACS* Enzyme: ligase EIF2B1 Translation regulatory protein Protein metabolism UNQ1887 Protease SFRS9 RNA-binding protein FBXL10 Ubiquitin proteasome system protein RNF10 Ubiquitin proteasome system protein OGFOD2 Enzyme: oxygenase DNAH10 Cytoskeletal protein Cell growth and/or maintenance HIP1R Cytoskeletal-associated protein IL31 Cytokine Immune response RNF34 Ubiquitin proteasome system protein Apoptosis TRIAP1 Protease inhibitor Antiapoptosis; DNA repair SETD8 Enzyme: methyltransferase Regulation of nucleobase, nucleoside, nucleotide and nucleic acid metabolism MLXIP Transcription factor POP5 Ribonuclease ARL6IP4 Unclassified CDK2AP1 Unclassified GTF2H3 Transcription factor LOC338799 Transcription regulatory protein DDX55 RNA helicase DHX37 RNA helicase

13q32.1–3 GPR180 G-protein-coupled receptor Cell communication; signal transduction EBI2 G-protein-coupled receptor TMTC4 Integral membrane protein DOCK9 Guanine nucleotide exchange factor Signal transduction RANBP5* Transport/cargo protein Transport TM9SF2 Integral membrane protein NALCN Voltage-gated channel TGDS Enzyme: hydratase Metabolism; energy pathways UGCGL2 Enzyme: glycosyltransferase HS6ST3 Enzyme: sulphotransferase RNF113B Ubiquitin proteasome system protein Protein metabolism DZIP1 Unclassified Cell growth and/or maintenance FARP1 Guanine nucleotide exchange factor MBNL2 RNA-binding protein Regulation of nucleobase, nucleoside, nucleotide and nucleic acid metabolism

17q25.3 C1QTNF1 Unclassified Cell communication; signal transduction SOCS3 Adapter molecule GALR2 Integral membrane protein RAB40B Unclassified RAC3 GTPase UTS2R G-protein-coupled receptor NPB Ligand ARL16 GTPase Signal transduction GPS1 Unclassified AATK Tyrosine kinase CYGB Transport/cargo protein Transport SYNGR2 Integral membrane protein SLC25A10 Transport/cargo protein SLC26A11 Transport/cargo protein CHMP6 Unclassified SLC25A19 Membrane transport protein FLJ21865 Enzyme: glycosidase Metabolism; energy pathways PGS1 Enzyme: synthase CANT1 Enzyme: hydrolase

Molecular Psychiatry Bipolar disorder genes A Serretti and L Mandelli 753 Table 2 Continued

Position Gene symbol Protein’s molecular class Biological process

SGSH Enzyme: hydrolase PCYT2 Enzyme: nucleotidyltransferase PYCR1 Enzyme: oxidoreductase DCXR Enzyme: oxidoreductase TBCD Chaperone Protein metabolism FN3K Enzyme: transferase THOC4 Chaperone MRPL38 Ribosomal subunit USP36 Ubiquitin proteasome system protein AZI1 Cytoskeletal-associated protein Cell differentiation; cell growth and/or maintenance ARHGDIA Unclassified Cell growth and/or maintenance ANAPC11 Enzyme: ligase Mitosis MAFG Transcription factor Transcription CBX8 Transcription regulatory protein Regulation of nucleobase, nucleoside, nucleotide and nucleic acid metabolism DUS1L* Unclassified CBX4 Transcription regulatory protein CBX2 DNA-binding protein EIF4A3 Unclassified TNRC6C RNA-binding protein SIRT7 Enzyme: deacetylase

18p11.31 MRCL3 Calcium-binding protein Cell communication; signal transduction MRCL2 Cytoskeletal protein Cell growth and/or maintenance LPIN2 Unclassified MYOM1 Structural protein LAMA1 Extracellular matrix protein L3MBTL4* Transcription regulatory protein Transcription; regulation of nucleobase, nucleoside, nucleotide and nucleic acid metabolism

18p11.21 PSMG2 Cell cycle control protein Cell communication; signal transduction SPIRE1 Transport/cargo protein Transport CEP192 Cytoskeletal protein Cell growth and/or maintenance TUBB6 Cytoskeletal protein CIDEA Unclassified Apoptosis ZNF519 DNA-binding protein Regulation of nucleobase, nucleoside, nucleotide and nucleic acid metabolism

18q22–23 PARD6G Adapter molecule Cell communication; signal transduction MC4R G-protein-coupled receptor Signal transduction GALR1 G-protein-coupled receptor ATP9B ATPase Transport TXNDC10 Oxidoreductase Metabolism; energy pathways CYB5A Enzyme: oxidoreductase MBP Structural protein Immune response; neurogenesis CTDP1 Phosphatase Transcription NFATC1 Transcription factor Regulation of nucleobase, nucleoside, nucleotide and nucleic acid metabolism SALL3 DNA-binding protein ZNF407 DNA-binding protein ZNF516 DNA-binding protein

20q13.33 HRH3 G-protein-coupled receptor Cell communication; signal transduction SYCP2 DNA-binding protein RGS19 GTPase-activating protein PRPF6 Adapter molecule OPRL1 G-protein-coupled receptor ADRM1 Adhesion molecule Signal transduction VAPB Membrane transport protein Transport SLCO4A1 Membrane transport protein

Molecular Psychiatry Bipolar disorder genes A Serretti and L Mandelli 754 Table 2 Continued

Position Gene symbol Protein’s molecular class Biological process

ARFGAP1 GTPase-activating protein Protein transport; lipid metabolism PCMTD2 Enzyme: methyltransferase Metabolism; energy pathways DNAJC5 Chaperone Protein metabolism PSMA7 Ubiquitin proteasome system protein DIDO1 Unclassified Apoptosis CABLES2 Unclassified ZNF512B DNA-binding protein Regulation of nucleobase, nucleoside, nucleotide and nucleic acid metabolism GMEB2 Transcription factor MYT1 Transcription factor UCKL1 Enzyme: transferase TAF4* Transcription factor SLC2A4RG Transcription factor SOX18 Transcription factor ZBTB46 Unclassified C20orf20 Transcription regulatory protein

21q22.2–3 DSCAM Adhesion molecule Cell communication; signal transduction PCP4 Unclassified MX1* GTPase MCM3AP Cell cycle control protein SH3BGR Adapter molecule PSMG1 Unclassified RIPK4 Serine/threonine kinase SNF1LK Serine/threonine kinase ITGB2 Adhesion molecule PWP2 Cell cycle control protein PDE9A Enzyme: phosphodiesterase CGMP-mediated signaling KCNJ15 Inward rectifier channel Transport TMEM1 Integral membrane protein SLC19A1 Membrane transport protein SLC37A1 Membrane transport protein PTTG1IP Transport/cargo protein TMPRSS3 Serine protease Ion transport ABCG1 Transport/cargo protein Lipid transport CBR3 Enzyme: oxidoreductase Metabolism; energy pathways NDUFV3 Enzyme: oxidoreductase LSS Enzyme: mutase PDXK Enzyme: phosphotransferase PRMT2 Enzyme: methyltransferase CBS Enzyme: synthase PFKL Enzyme: phosphotransferase SYNJ1 Enzyme: phosphatase Metabolism AGPAT3 Enzyme: acyltransferase PIGP Enzyme: transferase Lipid metabolism CRYAA Heat shock protein Protein metabolism BACE2* Protease SUMO3 Ubiquitin proteasome system protein CSTB Protease inhibitor UBE2G2 Ubiquitin proteasome system protein FTCD Enzyme: methyltransferase Amino acid and derivative metabolism ADARB1 Enzyme: deaminase RNA metabolism B3GALT5 Enzyme: glycosyltransferase Protein modification POFUT2 Enzyme: fucosyltransferase Development MX2 GTPase Immune response ICOSLG Ligand BRWD1 Unclassified Cell growth and/or maintenance DOPEY2 Unclassified COL18A1 Extracellular matrix protein COL6A2 Extracellular matrix protein COL6A1 Extracellular matrix protein PCNT Cytoskeletal protein

Molecular Psychiatry Bipolar disorder genes A Serretti and L Mandelli 755 Table 2 Continued

Position Gene symbol Protein’s molecular class Biological process

PKNOX1 Transcription factor Transcription ETS2 Transcription factor Regulation of nucleobase, nucleoside, nucleotide and nucleic acid metabolism HMGN1 Transcription regulatory protein ERG* Transcription factor ZNF295 Transcription regulatory protein PRDM15 DNA-binding protein DIP2A Transcription regulatory protein HSF2BP Transcription regulatory protein PCBP3 RNA-binding protein RSPH1 DNA-binding protein RUNX1 Transcription factor U2AF1 Ribonucleoprotein

22q12.3 YWHAH Adapter molecule Cell communication; signal transduction DEPDC5 Unclassified LARGE* Enzyme: glycosyltransferase Metabolism; energy pathways APOL6 Transport/cargo protein TMPRSS6 Serine protease Protein metabolism FOXRED2 Enzyme: oxidoreductase TIMP3 Extracellular matrix protein Cell growth and/or maintenance SMTN Cytoskeletal-associated protein

Xq26.1 GPC4 Integral membrane protein Cell communication; signal transduction GPC3 Integral membrane protein HPRT1 Enzyme: ribosyltransferase Metabolism; energy pathways

Abbreviation: BP, bipolar disorder. Official symbols of the genes are reported, according to the Entrez gene database (http://www.ncbi.nlm.nih.gov/sites/entrez). Asterisks indicate genes very close to markers in positive linkage with BP; in some cases the marker is located in the gene region.

In conclusion, studies support the involvement In conclusion, though GABAergic genes did not of dopaminergic genes such as DRD4 and SLC6A3 provide strong evidence in BP; GABRA1 and GA- in BP. DRD1 is another promising candidate, though BRA5 can be considered promising candidate genes. less confirmed. Other dopaminergic genes of Other GABAergic genes of interest, needing further interest and needing further investigation are listed investigation, are listed in Table 4. in Table 4. Acetylcholine-related genes g-Aminobutyric acid-related genes The cholinergic system has been poorly investigated Among g-aminobutyric acid (GABA) pathway’s genes, in BP. However, the cholinergic receptor, neuronal g-aminobutyric acid A receptor, a-1 (GABRA1) gave nicotinic, a polypeptide 7 (CHRNA7), has been promising evidence. After a first negative report, suggested as a promising candidate gene. It encodes GABRA1 was found associated with BP in one study for a nicotinic acetylcholine receptor, previously employing both case–control and family-based asso- associated with the risk to develop schizophrenia.352 ciation studies: in particular, this study reported In BP, two studies reported positive associations in positive findings for the 156T > C SNP. Recently, 12 both Caucasians and Asians, while a third investiga- SNPs within the gene have been analyzed but found tion in a Caucasian population reported a negative negative. finding. Other acetylcholinergic genes of interest, g-Aminobutyric acid A receptor, a-5 (GABRA5) needing further investigation, can be found listed in encodes a GABA-a receptor having a unique benzo- Table 4. diazepine pharmacology.351 Two studies, in both Caucasians and Asians, reported positive associations Glutamate-related genes with BP, analyzing different polymorphisms within This system has also been poorly investigated in BP. the gene. Instead, mainly negative results were However, a gene pertaining to the glutamatergic obtained analyzing g-aminobutyric acid A receptor, pathway has been consistently associated with BP. a-3 (GABRA3), though it is located in an interesting This is the case of D-amino acid oxidase activator region for BP (Xq28). (DAOA), located in a region in positive linkage with

Molecular Psychiatry Bipolar disorder genes A Serretti and L Mandelli 756 Table 3 Genes associated with BP and investigated in at least three independent samples

Region Gene Positive studies Negative studies

Chromosome 1 1p36.23 PER3 97,105 1p36.3 MTHFR 106 107,108 1q23.3* RGS4 109 110–112 1q42.1 DISC1 8,112–115 116

Chromosome 3 3q13.3 DRD3 117–120 3q13.3 GSK3B 121,122 112,123–125

Chromosome 4 4p16.1* WFS1 126,127 128–134

Chromosome 5 5p15.3 SLC6A3 135–140 112,141–145 5q11.2–q13 HTR1A 146,147 148 5q34–35* GABRA1 149 112,150 5q35.1* DRD1 151–153 154–159

Chromosome 6 6p21–22 TNF 160 161,162 6p21.3 DTNBP1 110,163–167 112

Chromosome 7 7p11 DDC 168 168–172

Chromosome 8 8p22–p11* NRG1 173–175 112

Chromosome 10 10q21–q24* HTR7 147 146,176

Chromosome 11 11p15.5* DRD4 177 TH 178 55,133,179–183 11p15.3–p14 TPH1 184 112,146,185–194 11p15.2 ARNTL 97,105 11p13 BDNF 195–204 112,205–211 11q23.1 NCAM1 212,213 11q23.2 DRD2 118,214 119,141,143,144,155,157,215–220

Chromosome 12 12p12 GRIN2B 110,221 12q21.1 TPH2 222–226 112,227,228 12q24.11–24.22 DAO 110,229 230

Chromosome 13 13q14–q21* HTR2A 104,147,231–233 146,231,234–238 13q33.2* DAOA 239,229,230,240,241 242

Chromosome 15 15q11.2–q12 GABRA5 243,244 15q14 CHRNA7 245,246 247

Chromosome 17 17q11.1–q12* SLC6A4 236,248–250 112,251 17q23.3 ACE 252 253–256

Chromosome 18 18p11.21* IMPA2 257,258 112,259 18q21.1 TCF4 260 261,262

Molecular Psychiatry Bipolar disorder genes A Serretti and L Mandelli 757 Table 3 Continued

Region Gene Positive studies Negative studies

Chromosome 20 20q12–q13.1 PLCG1 263,264

Chromosome 21 21q22.3* TRPM2 265,266 267

Chromosome 22 22q11.21 COMT 268–273 111,112,120,133,274–278 22q12.1 XBP1 279 280,281

Chromosome X Xp11.23 MAOA 282–285 286–288 Xq24 HTR2C 147,289 146,290,291 Xq28* GABRA3 292 293,294 SYBL1 295,296

Abbreviation: BP, bipolar disorder. The position of genes and positive and negative studies are reported. Symbols of the gene refer to the OMIM database (http://www.ncbi.nlm.nih.gov/sites/entrez?db = OMIM&itool = toolbar). Asterisks near the position of the gene indicate that the region has been found in positive linkage with BP. In bold, meta-analysis or large studies on pooled sample.

BP (13q33.2). DAOA plays a role in the activation of Other amines’ metabolism-related genes N-methyl-D-aspartate receptors, members of the glu- Monoamine oxidase A (MAOA) is located in the tamate receptor channel superfamily, which are positive region Xp11.3 and is a widely investigated implicated in both schizophrenia and BP.4,239 A gene in BP, because MAOA protein oxidizes neuro- number of SNPs within this gene have been positively transmitters such as serotonin, norepinephrine and associated with BP in six independent studies in dopamine. In the late 1990s, a meta-analysis and one Caucasians. Recently, a large study reported a signi- study on five pooled samples confirmed the associa- ficant association between a polymorphism close to tion between a CA repeat microsatellite in intron 2 DAOA (rs1981272) and BP. and BP, in both Caucasians and Asians. A second N-Methyl-D-aspartate 2B (GRIN2B) encodes for a repeat polymorphism in the promoter of MAOA was N-methyl-D-aspartate receptor and it is another reported associated in BP in one study on five pooled promising gene in BP. It is involved in long-term samples, but one study in Asians did not report a potentiation and in activity-dependent increase in the significant association and two following studies in efficiency of synaptic transmission and it is thought Caucasian were negative for this promoter variant. to underlie certain kinds of memory and learning.353 Recently, the haplotype composed of the CA repeat Recently, two studies investigated this gene in BP, microsatellite and the promoter polymorphism was reporting positive findings, particularly in association found positive in Caucasian BP. with psychotic symptoms. Catechol-O-methyltransferase (COMT) is another Another gene of interest is dystrobrevin-binding promising candidate gene, as it encodes for an protein 1 (DTNBP1), expressed in all principal enzyme that catalyzes the degradation of catechola- neuronal populations of the hippocampus; the pro- mines, including the neurotransmitters dopamine, tein is located in presynaptic axon terminals of the epinephrine and norepinephrine. The gene obtained glutamatergic neurons. A significant reduction of controversial results. The largely investigated 158Val/ dysbindin-1 in the terminal fields of intrinsic gluta- Met polymorphism was found not associated with BP, matergic connections of the hippocampus was ob- except in some studies. However, other polymorph- served in schizophrenic subjects.354 In BP, SNPs isms were investigated and two studies reported within DTNBP1 were found associated with the positive association investigating rs165599; other disease in three Caucasian samples and two Korean polymorphisms (rs2097603, À941T/G) were asso- populations; furthermore, a polymorphism close to ciated with BP as well. the gene (rs742206) has been reported associated with BP in a large study in Caucasians. Signal transduction-related genes Given these first observations, particularly with A gene of interest is IMPA2, located in a region respect to the reliable involvement of DAOA in BP, consistently associated with BP (18p11.21). Myo- other genes of the glutamatergic pathways have to be inositols play a crucial role in the phosphatidylino- taken into account in the investigation of genetics of BP. sitol signaling pathway, which is thought to be

Molecular Psychiatry Bipolar disorder genes A Serretti and L Mandelli 758 Table 4 Genes associated with BP but investigated in less than three studies

Position Gene symbol Positive studies Negative studies

1p36–p35 HTR6 297 298 1p13.3 VAV3 299 1q42–q43* AGT 255 1q43 MTR 300 2p11 TACR1 112 2q14 IL1B 301 2q14.1* DPP10 8 2q14.2 IL1RN 301 2q31* GAD1 302 302 112 2q37.1* NCL 299 3p24.1 RBMS3 299 3q24 PLSCR4 299 3q28* SST 303 4p16–p15.3 SLC2A9 29 4p16.1* PPP2R2C 304 WDR1 29 SORCS2 299 4q13.3 C4orf35 299 UNQ689 299 4q22 PDLIM5 305 4q34–35* FAT 306 GABRB2 112 5q31–q33* HTR4 307 6p21.3 GRM4 110 FKBP5 308 6p21.32 SKIV2L 299 6q23.2 TAAR6 309,310 7q21.1* ABCB1 311 8p21* CHRNA2 246 9q32–34* DFNB31 299 9q34.3 GRIN1 312 313 10p12.2 PIP5K2A 314 315 10q25 SLC18A2 316 11p12 NGL1 299 11p15.3 GALNTL4 299 11q22.3 GRIK4 317 11q23.1–q23.2 HTR3B 318 HTR3A 319 11q24.3 C11orf44 299 12q12–q13* TIMELESS 105 12q24.1–q24.3 CIT 320 12q24.11–12 CUTL2 321 112 12q24.2–q24.31* NOS1 110 322 P2X7 323 12q24.32* LOC387895 (Slynar) 324 13q14.11 DGKH 299 13q33.1 VGCNL1 299 14q21–q22* OTX2 325 14q22.1–q22.2* GCH1 68 112 14q24* MTHFD1 300 14q32.3 AKT1 326 112 14q32.11 CHES1 299 15q13–q14 SLC12A6 327 15q24 CHRNA5 246 CHRNB4 246 16p2 PALB2 8 16p13.3* SSTR5 328 ADCY9 329 A2BP1 299 16p13.2* GRIN2A 330 16q23.2 PLCG2 299

Molecular Psychiatry Bipolar disorder genes A Serretti and L Mandelli 759 Table 4 Continued

Position Gene symbol Positive studies Negative studies

17p13.1 ALOX12B 331 17p13.3 NXN 299 17p12–p11* CHRNB1 246 17q25.1 LLGL2 299 18p11.21* CHMP 1.5 332 18p11.22* NAPG 333 NDUFV2 334 18q11.2 LAMA3 299 AQP4 299 18q12.3 PIK3C3 335 19q12–q13.2 ATP1A3 336 337 20p13 PSMF1 299 21q22.2–q22.3* S100B 338 22q11.2–q13* IL2RB 110 22q11.21 BCR 339 112 PIK4CA 340 TUBA8 110 22q11.22 GNAZ 340 22q11.23–12.1 ADRBK2 341 111 22q12.3* SYN3 342 TOM 343 22q13.1* SYNGR1 344 ADSL 345 22q13.3 GPR24 345 22q13.33 MLC1 346 BRD1 347 Xq28* GPR50 348 349 IL9R 350

Abbreviation: BP, bipolar disorder. The position of genes and positive and negative studies are reported. Symbols of the gene refer to the OMIM database (http://www.ncbi.nlm.nih.gov/sites/entrez?db = OMIM&itool = toolbar). Asterisks near the position of the gene indicate that the region has been found in positive linkage with BP. modified by lithium. Three studies investigated this been poorly investigated. It encodes proteins that gene in BP and two found a positive involvement of accelerate the GTPase activities of G protein SNPs À461C > T and À207T > C in Arabic and Japa- a-subunits, thus driving G proteins into their nese populations. However, one study in Caucasians inactive GDP-bound forms. Nevertheless, preliminary failed to find a positive association between studies failed to find an involvement of this gene À461C > T and BP, and other polymorphisms in BP. ( þ 97G > A, þ 99G > A and rs3786282A > C) as well. Synaptobrevin-like 1 (SYBL1) is located in the Recently, another negative report has been published. pseudoautosomal region Xq28. Synaptobrevin is an Phospholipase C g 1 isoform A (PLCG1) encodes an intrinsic membrane protein of small synaptic vesicles enzyme that mediate the production of second- and may play a role in the molecular events under- messenger molecules. To our knowledge, only two lying neurotransmitter release and vesicle recycling. studies investigated this gene in BP, both focusing on SYBL1 is subjected to X inactivation and it is inactive an intronic dinucleotide repeat polymorphism. The on Y chromosome, thereby maintaining dosage two studies reported small but positive associations compensation. A G-C SNP in intron 5 was reported in lithium responders. associated with BP finding have been replicated in Another gene of interest is transient receptor two independent samples. potential cation channel, subfamily M, member 2 In conclusion, some genes involved in signal (TRPM2), located in a ‘hot region’ (21q22). TRPM2 transduction can be involved in susceptibility for BP proteins are thought to be subunits of capacitative or related features. Further investigation is certainly calcium entry channels, which mediate calcium required and other genes have to be taken into influx into cells.355 A first positive finding was account. Some of them can be found listed in Table 4. soon followed by two independent but contrasting replications. Cell maintenance and/or cell growth-related genes Regulator of G protein signaling 4 (RGS4), though A promising candidate gene in BP is glycogen located in an interesting region (1q23.3), has synthase kinase 3-b gene (GSK3B), involved in energy

Molecular Psychiatry Bipolar disorder genes A Serretti and L Mandelli 760 metabolism, neuronal cell development and body stimulating peptide; it has been extensively investi- pattern formation.356 The mostly investigated T-50C gated but mainly negative results were obtained. polymorphism was at first associated with BP, but Finally, tumor necrosis factor (TNF), which en- then negative reports were published. Nevertheless, codes multifunctional proinflammatory cytokine, has an increased frequency in BP of a duplication in copy been poorly investigated, but preliminary findings number variation, probably affecting 30-coding ele- mainly failed to find an involvement of this gene ments, has been reported recently. in BP. BDNF is located in 11p13, not far from a marker In conclusion, genes involved in cell growth and associated with BP (D11S987 18). This gene seems to maintenance may play an important role in the be consistently associated with BP. BDNF codes for a development of BP. In fact, three important genes, prosurvival factor induced by cortical neurons that is BDNF, NRG1 and DISC1 showed consistent associa- necessary for survival of striatal neurons in the tion with the disorder. brain.357 A G > A SNP at nucleotide 196 results in a val66-to-met change in the 50 pro-region of the human Transcription factor-related genes BDNF protein. This polymorphism has been asso- Only two genes related to transcription have been ciated with BP in nine independent studies in found positive in at least one study, but they both Caucasians. Nevertheless, six other studies reported then received negative replications. These genes are negative findings, and a recent meta-analysis failed to transcription factor 4 (TCF4), encoding proteins that support an involvement of this polymorphism in BP. bind to a motif of the glucocorticoid response element Other studies, investigating a microsatellite located (GRE) and X-box binding protein 1 (XBP1), encoding a approximately 1.0 kb upstream of the translation protein that is thought to act as a transcription factor initiation site (BDNF-LCPR), reported positive asso- by recognizing the X2 promoter element of some class ciation in three independent samples. Recently, a II major histocompatibility complex genes (HLA). polymorphism (rs4923460) in the BDNF opposite Nevertheless, this pathway needs more attention strand (BDNFOS), has been found positive in a large and the reader can find possibly interesting genes Caucasian BP sample. To summarize, eleven studies listed in Table 4. confirmed the association between BDNF and BP, particularly in Caucasians. Circadian rhythm-related genes Another gene reliably involved in BP is neuregulin Period homolog 3 (PER3), located in a region linked 1 gene (NRG1), previously found positive in schizo- with BP (1p36.33), is involved in the regulation of phrenia.358 The gene is expressed predominantly in circadian rhythms in physiology and behavior362 and early embryogenesis;359 its product promotes the it has been shown to be a promising candidate gene proliferation and survival of the oligodendrocyte, for susceptibility of BP. To our knowledge, only two and the myelinating cell of the central nervous studies investigated this gene in association with BP system.360,361 A number of SNPs within NRG1 were and both reported positive findings. found associated with BP in three different studies. Another promising gene is aryl hydrocarbon recep- Recently, a large study in Caucasians reported a tor nuclear translocator-like (ARNTL), which encodes positive association between a polymorphism closed the protein Arntl that dimerizes with the circadian to NRG1 (rs1487152) and BP, though another recent locomotor output cycles kaput (Clock) protein. Clock- paper did not find any association. Arntl heterodimers appear to drive the PER transcrip- Again, a gene consistently associated with BP is tional oscillations.363 In BP, two studies reported disrupted in schizophrenia 1 (DISC1), located in positive association with some SNPs within the gene. 1q42.1, close to a region found in positive linkage with BP (1q42.2). DISC1 encodes an 854-amino-acid Genes needing further investigation protein, which interact with a variety of cytoskeletal The present review also aimed to give some sugges- proteins, some of these associated with cortical tions for future research. In fact, there are a number of development. After a first negative report, a number genes that will need attention: genes that gave of SNPs within the gene have been associated with BP preliminary controversial results and genes that have in four independent studies. been found positive but need replication in indepen- Cell adhesion molecule, neural, 1 (NCAM1) is a dent samples. These genes are summarized in Table 4, promising candidate in BP. It encodes a protein that is where their symbol, according to OMIM (http://www. important in brain cell development and in adhesion, ncbi.nlm.nih.gov/entrez/query.fcgi?db = OMIM), their cell signaling and neuroplasticity in the adult brain. position and references, are reported. Furthermore, in Polymorphisms within the gene have been associated Table 2, a lot of genes that were never investigated can with BP in a Japanese sample and, recently, in a be found for further studies. Caucasian one. Angiotensin I-converting enzyme isoform 1 (ACE) Summary seems to be less consistently involved in BP. It plays Some genes have been consistently associated with an important role in blood pressure regulation and BP, while other showed promising results. What is electrolyte balance by hydrolyzing angiotensin I into particularly interesting is the fact that genes we found angiotensin II, a potent vasopressor, and aldosterone- reliably involved in BP pertain to different pathways:

Molecular Psychiatry Bipolar disorder genes A Serretti and L Mandelli 761 serotonin (SLC6A4 and TPH2), dopamine (DRD4 and morphisms to be examined across a whole region of SLC6A3), glutamate (DAOA and DTNBP1), cell interest; nevertheless, the researcher has to be aware growth and/or maintenance pathways (NRG1, DISC1 of the high risk of false positives when analyzing a and BDNF), supporting the idea that BP is a complex large number of polymorphisms. The traditional disorder, involving different biological processes, stringent significance cutoff may not be appropriate probably interacting with each other. There is less for low-risk conferring variants. evidence with respect to genes pertaining to GABA, Furthermore, as already underlined by Hayden and acetylcholine, signal transduction pathways, tran- Nurnberger,365 different approaches will probably be scription factors and circadian rhythms. Neverthe- necessary to clarify the genetic mechanisms of BP and less, these last pathways have been much less findings may prove more robust through increased investigated than those providing consistent results, use of designs that incorporate the complex nature of thus further attention needs to be paid to these BP. We agree with Hayden that future study should biological systems as well. take into account interactive effects among genes, because BP is a complex disease, likely to result from Discussion the effect of multiple genes interacting with each other. Again, evidence suggest that environmental The present paper reviewed current research from factors play a significant role in the development366 linkage and association studies on BP, with the aim to and course of the illness,367 thus future studies are point out genomic regions of interest and promising required to take into account individual psychosocial genes that have to be further investigated, other variables that may interact with liability genes than summarizing the current state of the art. In fact, for BP. We also agree with Hayden on the fact that in the recent years, a large number of linkage genetic research on BP would also benefit from the and association studies have been conducted, produ- investigation of endophenotypes associated with cing an extremely large number of findings. Never- the disease. This is of particular benefit when theless, results from linkage and association studies controversial results are obtained in different studies, are not always easily comparable and at present a leading to the idea that a particular gene may be comprehensive coverage of available evidence is still involved in some aspect related to the disorder, but lacking. not to the disorder per se.368 In fact, gene variants may In this review, we at first outlined a number of ‘hot exert a broad effect on plural aspects of human regions,’ as indicated by linkage studies on families. behavior, in both its normal and pathological expres- In some of these areas, interesting genes are actually sions. An example of this broad effect is the variant located that have been investigated in association within the serotonin transporter gene (SERTPR), studies. However, many other genes are located in which affect a number of features, such as neuro- these regions and they have never been investigated. anatomy, personality, way to react to stressors, social To provide the reader a preliminary map of future adjustment, anxiety and depressive symptoms, potential candidate genes, we searched for genes response to pharmacological treatments and many known to be expressed in the brain and located in other features.369 these interesting areas. This is a common strategy In conclusion, in the present review we summar- when searching for ‘positional candidate genes’; ized findings derived from linkage and association nevertheless, a review of them, though preliminary, studies on BP, with the aim to point out genomic limited to some areas and to known brain-expressed regions of interest and promising genes that have to be genes, does not exist. further investigated. The different nature of systems Second, we reviewed the literature for functional involved makes it difficult to hypothesize at present a and positional candidate genes investigated in case– unitary pathophysiology pathway. Because of the control and family-based association studies. We complex nature of BP, different approaches will found a number of genes consistently associated with probably be necessary to clarify the genetic mechan- BP, such as SLC6A4, TPH2, DRD4, SLC6A3, DAOA, isms of BP. DTNBP1, NRG1, DISC1 and BDNF. Other genes are particularly promising, such as DRD1, HTR1A, HTR2A, HTR2C, COMT, MAOA, GABRA1, GABRA5 References and others. Further research is needed regarding these 1 McGuffin P, Rijsdijk F, Andrew M, Sham P, Katz R, Cardno A. The genes; much more with respect to other genes less heritability of bipolar affective disorder and the genetic relation- investigated or that never received independent ship to unipolar depression. Arch Gen Psychiatry 2003; 60: 497– replications. Overall, it is our advise that future 502. 2 Huntley GW, Benson DL, Jones EG, Isackson PJ. Developmental studies should investigate a panel of SNPs, possibly expression of brain derived neurotrophic factor mRNA by covering the entire length of the gene, to cover as neurons of fetal and adult monkey prefrontal cortex. Brain Res much as possible all variations potentially affecting Dev Brain Res 1992; 70: 53–63. the expression of the gene or the nature of its product 3 Sheline YI, Wang PW, Gado MH, Csernansky JG, Vannier MW. (functional variations). We presented a similar ap- Hippocampal atrophy in recurrent major depression. Proc Natl 364 Acad Sci USA 1996; 93: 3908–3913. proach for HTR1A. High-throughout genotyping 4 Chumakov I, Blumenfeld M, Guerassimenko O, Cavarec L, Palicio M, and microarray-based technologies allow many poly- Abderrahim H et al. Genetic and physiological data implicating the

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