Abstract
Genetic vulnerability to psychiatric illness extends across major psychiatric illness. Neuregulin 1 (NRG1) is a large gene on chromosome 8p, that has been identified as a susceptibility factor in bipolar disorder and schizophrenia. In particular, a core at risk haplotype has received considerable attention for a putative role in the pathophysiology of the major psychoses (schizophrenia and bipolar disorder). This core haplotype can be represented by three markers 478B14-848, 420M9-1395, and SNP8NRG221533. We genotyped 312 families with bipolar probands, and 120 families with schizophrenia probands. Association of the core haplotype was tested for with age-at-onset and with three phenotypes: major psychosis, schizophrenia, and bipolar disorder. Neither age of onset (P = 0.893) nor the major psychosis phenotype (P = 0.374) was associated with the core haplotype in the overall sample. Ours was the first study to investigate the NRG1 core haplotype with age of onset of major psychoses, and despite our preliminary negative findings, this area deserves further investigation.
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Axelson D, Birmaher B, Strober M, Gill MK, Valeri S, Chiappetta L, Ryan N, Leonard H, Hunt J, Iyengar S, Bridge J, Keller M (2006) Phenomenology of children and adolescents with bipolar spectrum disorders. Arch Gen Psychiatry 63:1139–1148
Berrettini W (2004) Bipolar disorder and schizophrenia. Neuromolecular Med 5:109–117
Birmaher B, Axelson D, Strober M, Gill MK, Valeri S, Chiappetta L, Ryan N, Leonard H, Hunt J, Iyengar S, Keller M (2006) Clinical course of children and adolescents with bipolar spectrum disorders. Arch Gen Psychiatry 63:175–183
Cardno AG, Thomas K, McGuffin P (2002) Clinical variables and genetic loading for schizophrenia: analysis of published Danish adoption study data. Schizophr Bull 28:393–400
Cassidy F, Roche S, Claffey E, McKeon P (2006) First family-based test for association of neuregulin with bipolar affective disorder. Mol Psychiatry 11:706–707
Dorado P, Penas-Lledo EM, Llerena A (2007) CYP2D6 polymorphism: implications for antipsychotic drug response, schizophrenia and personality traits. Pharmacogenomics 8:1597–1608
Georgieva L, Dimitrova A, Ivanov D, Nikolov I, Williams NM, Grozeva D, Zaharieva I, Toncheva D, Owen MJ, Kirov G, O’Donovan MC (2008) Support for neuregulin 1 as a susceptibility gene for bipolar disorder and schizophrenia. Biol Psychiatry 64:419–427
Green EK, Raybould R, Macgregor S, Gordon-Smith K, Heron J, Hyde S, Grozeva D, Hamshere M, Williams N, Owen MJ, O’Donovan MC, Jones L, Jones I, Kirov G, Craddock N (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
Hahn CG, Wang HY, Cho DS, Talbot K, Gur RE, Berrettini WH, Bakshi K, Kamins J, Borgmann-Winter KE, Siegel SJ, Gallop RJ, Arnold SE (2006) Altered neuregulin 1-erbB4 signaling contributes to NMDA receptor hypofunction in schizophrenia. Nat Med 12:824–828
Horvath S, Xu X, Laird NM (2001) The family based association test method: strategies for studying general genotype–phenotype associations. Eur J Hum Genet 9:301–306
Horvath S, Xu X, Lake SL, Silverman EK, Weiss ST, Laird NM (2004) Family-based tests for associating haplotypes with general phenotype data: application to asthma genetics. Genet Epidemiol 26:61–69
Lange C, DeMeo DL, Laird NM (2002) Power and design considerations for a general class of family-based association tests: quantitative traits. Am J Hum Genet 71:1330–1341
Lange C, DeMeo D, Silverman EK, Weiss ST, Laird NM (2004) PBAT: tools for family-based association studies. Am J Hum Genet 74:367–369
Li T, Stefansson H, Gudfinnsson E, Cai G, Liu X, Murray RM, Steinthorsdottir V, Januel D, Gudnadottir VG, Petursson H, Ingason A, Gulcher JR, Stefansson K, Collier DA (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
Li D, Collier DA, He L (2006) Meta-analysis shows strong positive association of the neuregulin 1 (NRG1) gene with schizophrenia. Hum Mol Genet 15:1995–2002
Lin PI, Vance JM, Pericak-Vance MA, Martin ER (2007) No gene is an island: the flip-flop phenomenon. Am J Hum Genet 80:531–538
Mokliatchouk O, Blacker D, Rabinowitz D (2001) Association tests for traits with variable age at onset. Hum Hered 51(1–2):46–53
Moskvina V, O’Donovan MC (2007) Detailed analysis of the relative power of direct and indirect association studies and the implications for their interpretation. Hum Hered 64:63–73
Newberg AR, Catapano LA, Zarate CA, Manji HK (2008) Neurobiology of bipolar disorder. Expert Rev Neurother 8:93–110
Ozaki M, Sasner M, Yano R, Lu HS, Buonanno A (1997) Neuregulin-[beta] induces expression of an NMDA-receptor subunit. Nature 390:691–694
Perlis RH, Purcell S, Fagerness J, Kirby A, Petryshen TL, Fan J, Sklar P (2008) Family-based association study of lithium-related and other candidate genes in bipolar disorder. Arch Gen Psychiatry 65:53–61
Petryshen TL, Middleton FA, Kirby A, Aldinger KA, Purcell S, Tahl AR, Morley CP, McGann L, Gentile KL, Rockwell GN, Medeiros HM, Carvalho C, Macedo A, Dourado A, Valente J, Ferreira CP, Patterson NJ, Azevedo MH, Daly MJ, Pato CN, Pato MT, Sklar P (2004) Support for involvement of neuregulin 1 in schizophrenia pathophysiology. Mol Psychiatry 10:366–374
Stefansson H, Sigurdsson E, Steinthorsdottir V, Bjornsdottir S, Sigmundsson T, Ghosh S, Brynjolfsson J, Gunnarsdottir S, Ivarsson O, Chou TT, Hjaltason O, Birgisdottir B, Jonsson H, Gudnadottir VG, Gudmundsdottir E, Bjornsson A, Ingvarsson B, Ingason A, Sigfusson S, Hardardottir H, Harvey RP, Lai D, Zhou M, Brunner D, Mutel V, Gonzalo A, Lemke G, Sainz J, Johannesson G, Andresson T, Gudbjartsson D, Manolescu A, Frigge ML, Gurney ME, Kong A, Gulcher JR, Petursson H, Stefansson K (2002) Neuregulin 1 and susceptibility to schizophrenia. Am J Hum Genet 71:877–892
Stefansson H, Sarginson J, Kong A, Yates P, Steinthorsdottir V, Gudfinnsson E, Gunnarsdottir S, Walker N, Petursson H, Crombie C, Ingason A, Gulcher JR, Stefansson K, St Clair D (2003) Association of neuregulin 1 with schizophrenia confirmed in a Scottish population. Am J Hum Genet 72:83–87
Thomson PA, Christoforou A, Morris SW, Adie E, Pickard BS, Porteous DJ, Muir WJ, Blackwood DH, Evans KL (2007) Association of Neuregulin 1 with schizophrenia and bipolar disorder in a second cohort from the Scottish population. Mol Psychiatry 12:94–104
Walss-Bass C, Raventos H, Montero AP, Armas R, Dassori A, Contreras S, Liu W, Medina R, Levinson DF, Pereira M, Leach RJ, Almasy L, Escamilla MA (2006) Association analyses of the neuregulin 1 gene with schizophrenia and manic psychosis in a Hispanic population. Acta Psychiatr Scand 113:314–321
Wan C, Yang Y, Feng G, Gu N, Liu H, Zhu S, He L, Wang L (2005) Polymorphisms of myelin-associated glycoprotein gene are associated with schizophrenia in the Chinese Han population. Neurosci Lett 388:126–131
Williams NM, Preece A, Spurlock G, Norton N, Williams HJ, Zammit S, O’Donovan MC, Owen MJ (2003) Support for genetic variation in neuregulin 1 and susceptibility to schizophrenia. Mol Psychiatry 8:485–487
Yang YF, Qin W, Shugart YY, He G, Liu XM, Zhou J, Zhao XZ, Chen Q, La YJ, Xu YF, Li XW, Gu NF, Feng GY, Song H, Wang P, He L (2005) Possible association of the MAG locus with schizophrenia in a Chinese Han cohort of family trios. Schizophr Res 75:11–19
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The authors would like to thank the Canadian Institutes of Health Research and the National Alliance for Research on Schizophrenia and Depression for funding support.
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Voineskos, D., De Luca, V., MacGregor, S. et al. Neuregulin 1 and age of onset in the major psychoses. J Neural Transm 116, 479–486 (2009). https://doi.org/10.1007/s00702-008-0182-9
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DOI: https://doi.org/10.1007/s00702-008-0182-9