Abstract
Depression is common in patients with schizophrenia and it is well established from family studies that rates of depression are increased among relatives of probands with schizophrenia, making it likely that the phenotypes described under the categories of affective and non-affective psychoses share some genetic risk factors. Family linkage studies have identified several chromosomal regions likely to contain risk genes for schizophrenia and bipolar disorder, suggesting common susceptibility loci. Candidate gene association studies have provided further evidence to suggest that some genes including two of the most studied candidates, Disrupted in Schizophrenia 1 (DISC1) and Neuregulin 1 (NRG1) may be involved in both types of psychosis. We have recently identified another strong candidate for a role in both schizophrenia and affective disorders,GRIK4 a glutamate receptor mapped to chromosome 11q23 [Glutamate Receptor, Ionotropic, Kainate, type 4]. This gene is disrupted by a translocation breakpoint in a patient with schizophrenia, and case control studies show significant association ofGRIK4 with both schizophrenia and bipolar disorder. Identifying genes implicated in the psychoses may eventually provide the basis for classification based on biology rather than symptoms, and suggest novel treatment strategies for these complex brain disorders.
Similar content being viewed by others
References
Bakker SC, ML Hoogendoorn, JP Selten, W Verduijn, PL Pearson, RJ Sinke and RS Kahn (2004) Neuregulin 1: genetic support for schizophrenia subtypes.Mol. Psychiatry 9, 1061–1063.
Berrettini W (2004) Bipolar disorder and schizophrenia: convergent molecular data.Neuromolecular Med. 5, 109–117.
Blackwood DH, DM St Clair, WJ Muir and JC Duffy (1991) Auditory P300 and eye tracking dysfunction in schizophrenic pedigrees.Arch. Gen. Psychiatry 48, 899–909.
Blackwood DH, A Fordyce, MT Walker, DM St Clair, DJ Porteous and WJ Muir (2001) Schizophrenia and affective disorders - cosegregation with a translocation at chromosome 1q42 that directly disrupts brain-expressed genes: clinical and P300 findings in a family.Am. J. Hum. Genet. 69, 428–433.
Blouin JL, B A Dombroski, SK Nath, VK Lasseter, PS Wolyniec, G Nestadt, M Thornquist, G Ullrich, J McGrath, L Kasch, M Lamacz, MG Thomas, C Gehrig, U Radhakrishna, SE Snyder, KG Balk, K Neufeld, KL Swartz, N DeMarchi, {GN} Papadimitriou, DG Dikeos, CN Stefanis, A Chakravarti, B Childs, DE Housman, HH Kazazian, S Antonarakis and AE Pulver (1998) Schizophrenia susceptibility loci on chromosomes 13q32 and 8p21.Nat. Genet. 20, 70–73.
Brzustowicz LM, WG Honer, EW Chow, D Little, J Hogan, K Hodgkinson and AS Bassett (1999) Linkage of familial schizophrenia to chromosome 13q32.Am. J. Hum. Genet. 65, 1096–1103.
Burdick KE, CA Hodgkinson, PR Szeszko, T Lencz JM Ekholm, JM Kane, D Goldman and AK Malhotra (2005)DISC1 and neurocognitive function in schizophrenia.Neuroreport 16, 1399–1402.
Callicott JH, RE Straub, L Pezawas, MF Egan, VS Mattay AR Hariri, BA Verchinski, A Meyer-Lindenberg, R Balkissoon, B Kolachana, TE Goldberg and DR Weinberger (2005) Variation inDISC1 affects hippocampal structure and function and increases risk for schizophrenia.Proc. Natl. Acad. Sci. USA 102, 8627–8632.
Cannon TD, W Hennah, TG van Erp, PM Thompson, J Lonnqvist, M Huttunen, T Gasperoni, A Tuulio-Henriksson, T Pirkola, AW Toga, J Kaprio, J Mazziotta and L Peltonen (2005) Association ofDISC1/TRAX haplotypes with schizophrenia, reduced prefrontal gray matter, and impaired short- and long-term memory.Arch. Gen. Psychiatry 62, 1205–1213.
Chesler EJ, L Lu, S Shou, Y Qu, J Gu, J Wang, HC Hsu, JD Mountz, NE Baldwin, MA Langston, DW Threadgill, KF Manly and RW Williams (2005) Complex trait analysis of gene expression uncovers polygenic and pleiotropic networks that modulate nervous system function.Nat. Genet. 37, 233–242.
Corvin AP, DW Morris, K McGhee, S Schwaiger, P Scully, J Quinn, D Meagher, DS Clair, JL Waddington and M Gill (2004) Confirmation and refinement of an ‘at-risk’ haplotype for schizophrenia suggests the EST cluster, Hs.97362, as a potential susceptibility gene at the neuregulin-1 locus.Mol. Psychiatry 9, 208–213.
Curtis D, G Kalsi, J Brynjolfsson, M McInnis, J O’Neill, C Smyth, E Moloney, P Murphy, A McQuillin, H Petursson and H Gurling (2003) Genome scan of pedigrees multiply affected with bipolar disorder provides further support for the presence of a susceptibility locus on chromosome 12q23-q24, and suggests the presence of additional loci on 1p and 1q.Psychiatr. Genet. 13, 77–84.
Detera-Wadleigh SD, JA Badner, WH Berrettini, T Yoshikawa, LR Goldin, G Turner, DY Rollins, T Moses, AR Sanders, JD Karkera, LE Esterling, J Zeng, TN Ferraro, JJ Guroff D Kazuba, ME Maxwell, JI Nurnberger JI Jr and ES Gershon (1999) A high-density genome scan detects evidence for a bipolar-disorder susceptibility locus on 13q32 and other potential loci on 1q32 and 18p11.2.Proc. Natl. Acad. Sci. USA 96, 5604–5609.
Ekelund J, I Hovatta, A Parker, T Paunio, T Varilo, R Martin, J Suhonen, P Ellonen, G Chan, JS Sinsheimer, E Sobel, H Juvonen, R Arajarvi, T Partonen, J Suvisaari, J Lonnqvist, J Meyer and L Peltonen (2001) Chromosome 1 loci in Finnish schizophrenia families.Hum. Mol. Genet. 10, 1611–1617.
Ekelund J, W Hennah, T Hiekkalinna, A Parker, J Meyer, J Lonnqvist andL Peltonen (2004) Replication of 1q42 linkage in Finnish schizophrenia pedigrees.Mol. Psychiatry 9, 1037–1041.
Fallin MD, VK Lasseter, D Avramopoulos, KK Nicodemus, PS Wolyniec, JA McGrath, G Steel, G Nestadt, KY Liang RL Huganir, D Valle and AE Pulver (2005) Bipolar I disorder and schizophrenia: a 440-single-nucleotide polymorphism screen of 64 candidate genes among Ashkenazi Jewish case-parent trios.Am. J. Hum. Genet. 77, 918–936.
Gasperoni TL, J Ekelund, M Huttunen, CG Palmer, A Tuulio-Henriksson, J Lonnqvist, J Kaprio, L Peltonen and TD Cannon (2003) Genetic linkage and association between chromosome 1q and working memory function in schizophrenia.Am. J. Med. Genet. B Neuropsychiatr. Genet. 116, 8–16.
Gejman PV, M Martinez, Q Cao, E Friedman, WH Berrettini, LR Goldin, P Koroulakis, C Ames, MA Lerman and ES Gershon (1993) Linkage analysis of fifty-seven microsatellite loci to bipolar disorder.Neuropsychopharmacology 9, 31–40.
Green EK, R Raybould, S Macgregor, K Gordon-Smith, J Heron, S Hyde, D Grozeva, M Hamshere, N Williams, MJ Owen, MC O’Donovan, L Jones, I Jones, G Kirov and N Craddock (2005) Operation of the schizophrenia susceptibility gene, neuregulin 1, across traditional diagnostic boundaries to increase risk for bipolar disorder.Arch. Gen. Psychiatry 62, 642–648.
Gurling HM, G Kalsi, J Brynjolfson, T Sigmundsson R Sherrington, BS Mankoo, T Read, P Murphy, E Blaveri, A McQuillin, H Petursson and D Curtis (2001) Genomewide genetic linkage analysis confirms the presence of susceptibility loci for schizophrenia, on chromosomes 1q32.2, 5q33.2, and 8p21-22 and provides support for linkage to schizophrenia, on chromosomes 11q23.3-24 and 20q12.1-11.23.Am. J. Hum. Genet. 68, 661–673.
Hall D, JA Gogos and M Karayiorgou (2004) The contribution of three strong candidate schizophrenia susceptibility genes in demographically distinct populations.Genes Brain Behav. 3, 240–248.
Hamshere ML, P Bennett, N Williams, R Segurado, A Cardno, N Norton, D Lambert, H Williams, G Kirov, A Corvin P Holmans, L Jones, I Jones, M Gill, MC O’Donovan MJ Owen and N Craddock (2005) Genomewide linkage scan in schizoaffective disorder: significant evidence for linkage at 1q42 close toDISC1, and suggestive evidence at 22q11 and 19p13.Arch. Gen. Psychiatry 62, 1081–1088.
Harrison PJ and DR Weinberger (2005) Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence.Mol. Psychiatry 10, 40–68; image 5.
Hennah W, T Varilo, M Kestila, T Paunio, R Arajarvi, J Haukka, A Parker, R Martin, S Levitzky, T Partonen, J Meyer, J Lonnqvist, L Peltonen and J Ekelund (2003) Haplotype transmission analysis provides evidence of association forDISC1 to schizophrenia and suggests sex-dependent effects.Hum. Mol. Genet. 12, 3151–3159.
Hennah W, A Tuulio-Henriksson, T Paunio, J Ekelund T Varilo, T Partonen, TD Cannon, J Lonnqvist and L Peltonen (2005) A haplotype within theDISC1 gene is associated with visual memory functions in families with a high density of schizophrenia.Mol. Psychiatry 10, 1097–1103.
Hodgkinson CA, D Goldman, J Jaeger, S Persaud, JM Kane, RH Lipsky and AK Malhotra (2004) Disrupted in schizophrenia 1 (DISC1): association with schizophrenia, schizoaffective disorder, and bipolar disorder.Am. J. Hum. Genet. 75, 862–872.
Hwu HG, CM Liu, CS Fann, WC Ou-Yang and SF Lee (2003) Linkage of schizophrenia with chromosome 1q loci in Taiwanese families.Mol. Psychiatry 8, 445–452.
Kaufmann CA, B Suarez, D Malaspina, J Pepple, D Svrakic, PD Markel, J Meyer, CT Zambuto, K Schmitt, TC Matise, JM Harkavy Friedman, C Hampe, H Lee, D Shore, D Wynne, SV Faraone, MT Tsuang and CR Cloninger (1998) NIMH Genetics Initiative Millenium Schizophrenia Consortium: linkage analysis of African-American pedigrees.Am. J. Med. Genet. 81, 282–289.
Kendler KS, CJ MacLean, FA O’Neill, J Burke, B Murphy, F Duke, R Shinkwin, SM Easter, BT Webb, J Zhang, D Walsh and RE Straub (1996) Evidence for a schizophrenia vulnerability locus on chromosome 8p in the Irish Study of High-Density Schizophrenia Families.Am. J. Psychiatry 153, 1534–1540.
LaBuda MC, M Maldonado, D Marshall, K Otten and DS Gerhard (1996) A follow-up report of a genome search for affective disorder predisposition loci in the Old Order Amish.Am. J. Hum. Genet. 59, 1343–1362.
Lewis CM, DF Levinson, LH Wise, LE DeLisi, RE Straub I Hovatta, NM Williams, SG Schwab, AE Pulver, SV Faraone, LM Brzustowicz, CA Kaufmann, DL Garver, HM Gurling, E Lindholm, H Coon, HW Moises, W Byerley, SH Shaw, A Mesen, R Sherrington, FA O’Neill, D Walsh, KS Kendler, J Ekelund, T Paunio, J Lonnqvist, L Peltonen, MC O’Donovan, MJ Owen, DB Wildenauer, W Maier, G Nestadt, JL Blouin, SE Antonarakis, BJ Mowry, JM Silverman, RR Crowe, CR Cloninger, MT Tsuang, D Malaspina, JM Harkavy-Friedman, DM Svrakic, AS Bassett, J Holcomb, G Kalsi, A McQuillin, J Brynjolfson, T Sigmundsson, H Petursson, E Jazin, T Zoega and T Helgason (2003) Genome scan meta-analysis of schizophrenia and bipolar disorder, part II: Schizophrenia.Am. J. Hum. Genet. 73, 34–48.
Li T, H Stefansson, E Gudfinnsson, G Cai, X Liu, RM Murray, V Steinthorsdottir, D Januel, VG Gudnadottir, H Petursson, A Ingason, JR Gulcher, K Stefansson and DA Collier (2004) Identification of a novel neuregulin 1 at-risk haplotype in Han schizophrenia Chinese patients, but no association with the Icelandic/Scottish risk haplotype.Mol. Psychiatry 9, 698–704.
Liu CM, HG Hwu, CS Fann, CY Lin, YL Liu, WC Ou-Yang and SF Lee (2005) Linkage evidence of schizophrenia to loci near neuregulin 1 gene on chromosome 8p21 in Taiwanese families.Am. J. Med. Genet. B Neuropsychiatr. Genet. 134, 79–83.
Macgregor S, PM Visscher SA Knott, P Thomson, DJ Porteous, JK Millar, RS Devon, D Blackwood and WJ Muir (2004) A genome scan and follow-up study identify a bipolar disorder susceptibility locus on chromosome 1q42.Mol. Psychiatry 9, 1083–1090.
Maier W, D Lichtermann, P Franke, R Heun, P Falkai and M Rietschel (2002) The dichotomy of schizophrenia and affective disorders in extended pedigrees.Schizophr. Res. 57, 259–266.
McGuffin P, MJ Owen and II Gottesman (2002)Psychiatric Genetics and Genomics (Oxford University Press:(Oxford and New York), pp 247–266.
McInnis MG, DM Dick, VL Willour, D Avramopoulos, DF MacKinnon, SG Simpson, JB Potash, HJ Edenberg, ES Bowman, FJ McMahon, C Smiley, JL Chellis, Y Huo, T Diggs, ET Meyer, M Miller, AT Matteini, NL Rau, JR DePaulo, ES Gershon, JA Badner, JP Rice, AM Goate, SD Detera-Wadleigh, JI Nurnberger, T Reich, PP Zandi and TM Foroud (2003) Genome-wide scan and conditional analysis in bipolar disorder: evidence for genomic interaction in the National Institute of Mental Health genetics initiative bipolar pedigrees.Biol. Psychiatry 54,1265–1273.
Millar JK, JC Wilson-Annan, S Anderson, S Christie, MS Taylor, CA Semple, RS Devon, DM Clair, WJ Muir, DH Blackwood and DJ Porteous (2000) Disruption of two novel genes by a translocation co-segregating with schizophrenia.Hum. Mol. Genet. 9, 1415–123.
Ophoff RA, MA Escamilla, SK Service, M Spesny, DB Meshi, W Poon, J Molina, E Fournier, A Gallegos, C Mathews, T Neylan, SL Batki, E Roche, M Ramirez, S Silva, MC De Mille, P Dong, PE Leon, VI Reus, LA Sandkuijl and NB Freimer (2002) Genomewide linkage disequilibrium mapping of severe bipolar disorder in a population isolate.Am. J. Hum. Genet. 71, 565–574.
Park N, SH Juo, R Cheng, J Liu, JE Loth, B Lilliston, J Nee, A Grunn, K Kanyas, B Lerer, J Endicott, TC Gilliam and M Baron (2004) Linkage analysis of psychosis in bipolar pedigrees suggests novel putative loci for bipolar disorder and shared susceptibility with schizophrenia.Mol. Psychiatry 9, 1091–1099.
Petryshen TL, FA Middleton, A Kirby, KA Aldinger, S Purcell, AR Tahl, CP Morley, L McGann, KL Gentile, GN Rockwell, HM Medeiros, C Carvalho A Macedo, A Dourado, J Valente, CP Ferreira, NJ Patterson, MH Azevedo, MJ Daly, CN Pato, MT Pato and P Sklar (2005) Support for involvement of neuregulin 1 in schizophrenia pathophysiology.Mol. Psychiatry 10, 366–374, 328.
Pickard BS, JK Millar, DJ Porteous, WJ Muir and DH Blackwood (2005) Cytogenetics and gene discovery in psychiatric disorders.Pharmacogenomics J. 5, 81–88.
Pulver AE, VK Lasseter, L Kasch, P Wolyniec, G Nestadt JL Blouin, M Kimberland, R Babb, S Vourlis, H Chenet al. (1995) Schizophrenia: a genome scan targets chromosomes 3p and 8p as potential sites of susceptibility genes.Am. J. Med. Genet. 60, 252–260.
Pulver AE, J Mulle, G Nestadt, KL Swartz, JL Blouin B Dombroski, KY Liang, DE Housman, HH Kazazian, SE Antonarakis, VK Lasseter, PS Wolyniec, MH Thornquist and JA McGrath (2000) Genetic heterogeneity in schizophrenia: stratification of genome scan data using co-segregating related phenotypes.Mol. Psychiatry 5, 650–653.
Sachs NA, A Sawa, SE Holmes, CA Ross, LE DeLisi and RL Margolis (2005) A frameshift mutation in Disrupted in Schizophrenia 1 in an American family with schizophrenia and schizoaffective disorder.Mol. Psychiatry 10, 758–764.
Shaw SH, M Kelly, AB Smith, G Shields, PJ Hopkins, J Loftus, SH Laval, A Vita, M De Hert, LR Cardon, TJ Crow, R Sherrington and LE DeLisi (1998) A genome-wide search for schizophrenia susceptibility genes.Am. J. Med. Genet. 81, 364–376.
Shibata H, T Aramaki, M Sakai, H Ninomiya, N Tashiro, N Iwata, N Ozaki and Y Fukumaki (2006) Association study of polymorphisms in the GluR7, KA1 and KA2 kainate receptor genes (GRIK3, GRIK4, GRIK5) with schizophrenia.Psychiatry Res. 141, 39–51.
Stefansson H, E Sigurdsson, V Steinthorsdottir, S Bjornsdottir, T Sigmundsson, S Ghosh, J Brynjolfsson, S Gunnarsdottir, O Ivarsson, TT Chou, O Hjaltason, B Birgisdottir, H Jonsson, VG Gudnadottir, E Gudmundsdottir, A Bjornsson, B Ingvarsson, A Ingason, S Sigfusson, H Hardardottir, RP Harvey, D Lai, M Zhou, D Brunner, V Mutel, A Gonzalo, G Lemke, J Sainz, G Johannesson, T Andresson, D Gudbjartsson, A Manolescu, ML Frigge, ME Gurney, A Kong, JR Gulcher, H Petursson and K Stefansson (2002) Neuregulin 1 and susceptibility to schizophrenia.Am. J. Hum. Genet. 71, 877–892.
Stefansson H, J Sarginson, A Kong, P Yates, V Steinthorsdottir, E Gudfinnsson, S Gunnarsdottir, N Walker, H Petursson, C Crombie, A Ingason, JR Gulcher, K Stefansson and D St Clair (2003) Association of neuregulin 1 with schizophrenia confirmed in a Scottish population.Am. J. Hum. Genet. 72, 83–87.
Takahashi S, SV Faraone, J Lasky-Su and MT Tsuang (2005) Genome-wide scan of homogeneous subtypes of NIMH genetics initiative schizophrenia families.Psychiatry Res. 133, 111–122.
Tang JX, WY Chen, G He, J Zhou, NF Gu, GY Feng and L He (2004) Polymorphisms within 5′ end of the neuregulin 1 gene are genetically associated with schizophrenia in the Chinese population.Mol. Psychiatry 9, 11–12.
Thomson PA, SE Harris, JM Starr, LJ Whalley, DJ Porteous and IJ Deary (2005a) Association between genotype at an exonic SNP inDISC1 and normal cognitive aging.Neurosci. Lett. 389, 41–45.
Thomson PA, NR Wray, JK Millar, KL Evans, SL Hellard, A Condie, WJ Muir, DH Blackwood and DJ Porteous (2005b) Association between the TRAX/DISC locus and both bipolar disorder and schizophrenia in the Scottish population.Mol. Psychiatry 10, 657–668, 616.
Wildenauer DB, G Schwab, W Maier and SD Detera-Wadleigh (1999) Do schizophrenia and affective disorder share susceptibility genes?Schizophr. Res. 39, 107–111; discussion 160.
Yang JZ, TM Si, Y Ruan, YS Ling, YH Han, XL Wang, M Zhou, HY Zhang, QM Kong, C Liu, DR Zhang, YQ Yu, SZ Liu, GZ Ju, L Shu, DL Ma and D Zhang (2003) Association study of neuregulin 1 gene with schizophrenia.Mol. Psychiatry 8, 706–709.
Zhang F, J Sarginson, C Crombie, N Walker, D Stclair and D Shaw (2006) Genetic association between schizophrenia and theDISC1 gene in the Scottish population.Am. J. Med. Genet. B Neuropsychiatr. Genet. 141 (2), 155–159.
Zhang X, M Tochigi, J Ohashi, K Maeda, T Kato, Y Okazaki, N Kato, K Tokunaga, A Sawa and T Sasaki (2005) Association study of theDISC1/TRAX locus with schizophrenia in a Japanese population.Schizophr. Res. 79, 175–180.
Zhao X, Y Shi, J Tang, R Tang, L Yu, N Gu, G Feng, S Zhu, H Liu, Y Xing, S Zhao, H Sang, Y Guan, D St Clair and L He (2004) A case control and family based association study of the neuregulin1 gene and schizophrenia.J. Med. Genet. 41, 31–34.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Blackwood, D.H.R., Pickard, B.J., Thomson, P.A. et al. Are some genetic risk factors common to schizophrenia, bipolar disorder and depression? evidence fromDISC1, GRIK4 andNRG1 . neurotox res 11, 73–83 (2007). https://doi.org/10.1007/BF03033484
Received:
Revised:
Issue Date:
DOI: https://doi.org/10.1007/BF03033484