Abstract
Neuregulin-1 (NRG-1) is a putative susceptibility gene for schizophrenia but the neurocognitive processes that may involve NRG-1 in schizophrenia are unknown. Deficits in antisaccade (AS) and smooth pursuit eye movements (SPEM) are promising endophenotypes, which may be associated with brain dysfunctions underlying the pathophysiology of schizophrenia. The aim of this study was to investigate the associations of NRG-1 genotypes with AS and SPEM in schizophrenia patients and healthy controls. Patients (N = 113) and controls (N = 106) were genotyped for two NRG-1 single nucleotide polymorphisms (SNPs); SNP8NRG222662, a surrogate marker for the originally described Icelandic NRG-1 risk haplotype, and SNP8NRG243177, which has recently been associated with individual differences in brain function. Subjects underwent infrared oculographic assessment of AS and SPEM. The study replicates previous findings of impaired AS and SPEM performance in schizophrenia patients (all P < 0.005; all d = 0.5–1.5). SNP8NRG243177 risk allele carriers had marginally increased variability of AS spatial error (P = 0.050, d = 0.3), but there were no significant genotype effects on other eye movement variables and no significant diagnosis-by-genotype interactions. Generally, risk allele carriers (G allele for SNP8NRG222662 and T allele for SNP8NRG243177) had numerically worse performance than non-carriers on most AS and SPEM variables. The results do not suggest that NRG-1 genotype significantly affects AS and SPEM task performance. However, the power of the sample to identify small effects is limited and the possibility of a type II error must be kept in mind. Larger samples may be needed to reliably investigate such gene effects on oculomotor endophenotypes.
Similar content being viewed by others
References
Arolt V, Lencer R, Nolte A, Muller-Myhsok B, Purmann S, Schurmann M, Leutelt J, Pinnow M, Schwinger E (1996) Eye tracking dysfunction is a putative phenotypic susceptibility marker of schizophrenia and maps to a locus on chromosome 6p in families with multiple occurrence of the disease. Am J Med Genet 67:564–579
Arolt V, Lencer R, Purmann S, Schurmann M, Muller-Myhsok B, Krecker K, Schwinger E (1999) Testing for linkage of eye tracking dysfunction and schizophrenia to markers on chromosomes 6, 8, 9, 20, and 22 in families multiply affected with schizophrenia. Am J Med Genet 88:603–606
Bakker SC, Hoogendoorn ML, Selten JP, Verduijn W, Pearson PL, Sinke RJ, Kahn RS (2004) Neuregulin 1: genetic support for schizophrenia subtypes. Mol Psychiatry 9:1061–1063
Braff DL, Freedman R, Schork NJ, Gottesman II (2007) Deconstructing schizophrenia: an overview of the use of endophenotypes in order to understand a complex disorder. Schizophr Bull 33:21–32
Calkins ME, Iacono WG, Curtis CE (2003) Smooth pursuit and antisaccade performance evidence trait stability in schizophrenia patients and their relatives. Int J Psychophysiol 49:139–146
Calkins ME, Iacono WG, Ones DS (2008) Eye movement dysfunction in first-degree relatives of patients with schizophrenia: a meta-analytic evaluation of candidate endophenotypes. Brain Cogn 68:436–461
Clementz BA, McDowell JE, Zisook S (1994) Saccadic system functioning among schizophrenia patients and their first-degree biological relatives. J Abnorm Psychol 103:277–287
Corvin AP, Morris DW, McGhee K, Schwaiger S, Scully P, Quinn J, Meagher D, Clair DS, Waddington JL, Gill M (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
Duan J, Martinez M, Sanders AR, Hou C, Krasner AJ, Schwartz DB, Gejman PV (2005) Neuregulin 1 (NRG1) and schizophrenia: analysis of a US family sample and the evidence in the balance. Psychol Med 35:1599–1610
Einarsson KR, Magnusdottir BB, Sigurdsson E, Petursson H, Sigmundsson T (2004) The deficit syndrome of schizophrenia and neuregulin-1. Schizophr Res 67:53
Ettinger U, Kumari V, Collier DA, Powell J, Luzi S, Michel TM, Zedomi O, Williams SC (2008) Catechol-O-methyltransferase (COMT) val158met genotype is associated with BOLD response as a function of task characteristic. Neuropsychopharmacology 33:3046–3057
Ettinger U, Kumari V, Crawford TJ, Davis RE, Sharma T, Corr PJ (2003) Reliability of smooth pursuit, fixation, and saccadic eye movements. Psychophysiology 40:620–628
Fukui N, Muratake T, Kaneko N, Amagane H, Someya T (2006) Supportive evidence for neuregulin 1 as a susceptibility gene for schizophrenia in a Japanese population. Neurosci Lett 396:117–120
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
Go RC, Perry RT, Wiener H, Bassett SS, Blacker D, Devlin B, Sweet RA (2005) Neuregulin-1 polymorphism in late onset Alzheimer’s disease families with psychoses. Am J Med Genet B Neuropsychiatr Genet 139B:28–32
Gottesman II, Gould TD (2003) The endophenotype concept in psychiatry: etymology and strategic intentions. Am J Psychiatry 160:636–645
Hakonarson H, Gulcher JR, Stefansson K (2003) deCODE genetics, Inc. Pharmacogenomics 4:209–215
Hall D, Gogos JA, Karayiorgou M (2004) The contribution of three strong candidate schizophrenia susceptibility genes in demographically distinct populations. Genes Brain Behav 3:240–248
Hall J, Whalley HC, Job DE, Baig BJ, McIntosh AM, Evans KL, Thomson PA, Porteous DJ, Cunningham-Owens DG, Johnstone EC, Lawrie SM (2006) A neuregulin 1 variant associated with abnormal cortical function and psychotic symptoms. Nat Neurosci 9:1477–1478
Hancock ML, Canetta SE, Role LW, Talmage DA (2008) Presynaptic type III neuregulin1-ErbB signaling targets {alpha}7 nicotinic acetylcholine receptors to axons. J Cell Biol 181:511–521
Haraldsson HM, Ettinger U, Magnusdottir BB, Sigmundsson T, Sigurdsson E, Ingason A, Petursson H (2008) Catechol-O-methyltransferase val158met polymorphism and antisaccade eye movements in schizophrenia. Schizophr Bull
Haraldsson HM, Ettinger U, Magnusdottir BB, Sigmundsson T, Sigurdsson E, Ingason A, Petursson H (in press) COMT val158met genotype and smooth pursuit eye movements in schizophrenia. Psychiatry Res
Haraldsson HM, Ettinger U, Magnusdottir BB, Sigmundsson T, Sigurdsson E, Petursson H (2008) Eye movement deficits in schizophrenia: investigation of a genetically homogenous Icelandic sample. Eur Arch Psychiatry Clin Neurosci 258:373–383
Hariri AR, Weinberger DR (2003) Functional neuroimaging of genetic variation in serotonergic neurotransmission. Genes Brain Behav 2:341–349
Heinz A, Smolka MN (2006) The effects of catechol O-methyltransferase genotype on brain activation elicited by affective stimuli and cognitive tasks. Rev Neurosci 17:359–367
Helgason A, Yngvadottir B, Hrafnkelsson B, Gulcher J, Stefansson K (2005) An Icelandic example of the impact of population structure on association studies. Nat Genet 37:90–95
Holzman PS, Proctor LR, Levy DL, Yasillo NJ, Meltzer HY, Hurt SW (1974) Eye-tracking dysfunctions in schizophrenic patients and their relatives. Arch Gen Psychiatry 31:143–151
Ingason A, Soeby K, Timm S, Wang AG, Jakobsen KD, Fink-Jensen A, Hemmingsen R, Berg Rasmussen H, Werge T (2006) No significant association of the 5′ end of neuregulin 1 and schizophrenia in a large Danish sample. Schizophr Res 83:1–5
Iwata N, Suzuki T, Ikeda M, Kitajima T, Yamanouchi Y, Inada T, Ozaki N (2004) No association with the neuregulin 1 haplotype to Japanese schizophrenia. Mol Psychiatry 9:126–127
Katsanis J, Taylor J, Iacono WG, Hammer MA (2000) Heritability of different measures of smooth pursuit eye tracking dysfunction: a study of normal twins. Psychophysiology 37:724–730
Kay SR, Fiszbein A, Opler LA (1987) The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull 13:261–276
Keri S, Kiss I, Seres I, Kelemen O (2009) A polymorphism of the neuregulin 1 gene (SNP8NRG243177/rs6994992) affects reactivity to expressed emotion in schizophrenia. Am J Med Genet B Neuropsychiatr Genet 150B(3):418–420
Kim JW, Lee YS, Cho EY, Jang YL, Park DY, Choi KS, Jeun HO, Cho SH, Jang SY, Hong KS (2006) Linkage and association of schizophrenia with genetic variations in the locus of neuregulin 1 in Korean population. Am J Med Genet B Neuropsychiatr Genet 141B:281–286
Krug A, Markov V, Eggermann T, Krach S, Zerres K, Stocker T, Shah NJ, Schneider F, Nothen MM, Treutlein J, Rietschel M, Kircher T (2008) Genetic variation in the schizophrenia-risk gene neuregulin1 correlates with differences in frontal brain activation in a working memory task in healthy individuals. Neuroimage 42:1569–1576
Law AJ, Lipska BK, Weickert CS, Hyde TM, Straub RE, Hashimoto R, Harrison PJ, Kleinman JE, Weinberger DR (2006) Neuregulin 1 transcripts are differentially expressed in schizophrenia and regulated by 5′ SNPs associated with the disease. Proc Natl Acad Sci USA 103:6747–6752
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
Malone SM, Iacono WG (2002) Error rate on the antisaccade task: heritability and developmental change in performance among preadolescent and late-adolescent female twin youth. Psychophysiology 39:664–673
Mathew SV, Law AJ, Lipska BK, Davila-Garcia MI, Zamora ED, Mitkus SN, Vakkalanka R, Straub RE, Weinberger DR, Kleinman JE, Hyde TM (2007) Alpha7 nicotinic acetylcholine receptor mRNA expression and binding in postmortem human brain are associated with genetic variation in neuregulin 1. Hum Mol Genet 16:2921–2932
Matthysse S, Holzman PS, Gusella JF, Levy DL, Harte CB, Jorgensen A, Moller L, Parnas J (2004) Linkage of eye movement dysfunction to chromosome 6p in schizophrenia: additional evidence. Am J Med Genet B Neuropsychiatr Genet 128B:30–36
McIntosh AM, Moorhead TW, Job D, Lymer GK, Munoz Maniega S, McKirdy J, Sussmann JE, Baig BJ, Bastin ME, Porteous D, Evans KL, Johnstone EC, Lawrie SM, Hall J (2008) The effects of a neuregulin 1 variant on white matter density and integrity. Mol Psychiatry 13:1054–1059
Mill J, Tang T, Kaminsky Z, Khare T, Yazdanpanah S, Bouchard L, Jia P, Assadzadeh A, Flanagan J, Schumacher A, Wang SC, Petronis A (2008) Epigenomic profiling reveals DNA-methylation changes associated with major psychosis. Am J Hum Genet 82:696–711
Myles-Worsley M, Coon H, McDowell J, Brenner C, Hoff M, Lind B, Bennett P, Freedman R, Clementz B, Byerley W (1999) Linkage of a composite inhibitory phenotype to a chromosome 22q locus in eight Utah families. Am J Med Genet 88:544–550
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 (2005) Support for involvement of neuregulin 1 in schizophrenia pathophysiology. Mol Psychiatry 10:366–374, 328
Riley B, Kendler KS (2006) Molecular genetic studies of schizophrenia. Eur J Hum Genet 14:669–680
Rosa A, Gardner M, Cuesta MJ, Peralta V, Fatjo-Vilas M, Miret S, Navarro ME, Comas D, Fananas L (2007) Family-based association study of neuregulin-1 gene and psychosis in a Spanish sample. Am J Med Genet B Neuropsychiatr Genet 144B:954–957
Rybakowski JK, Borkowska A, Czerski PM, Dmitrzak-Weglarz M, Hauser J (2003) The study of cytosolic phospholipase A2 gene polymorphism in schizophrenia using eye movement disturbances as an endophenotypic marker. Neuropsychobiology 47:115–119
Rybakowski JK, Borkowska A, Czerski PM, Hauser J (2001) Dopamine D3 receptor (DRD3) gene polymorphism is associated with the intensity of eye movement disturbances in schizophrenic patients and healthy subjects. Mol Psychiatry 6:718–724
Rybakowski JK, Borkowska A, Czerski PM, Hauser J (2002) Eye movement disturbances in schizophrenia and a polymorphism of catechol-O-methyltransferase gene. Psychiatry Res 113:49–57
Sheehan DV, Lecrubier Y, Sheehan KH, Amorim P, Janavs J, Weiller E, Hergueta T, Baker R, Dunbar GC (1998) The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry 59(Suppl 20):22–33 quiz 34–57
Shih RA, Belmonte PL, Zandi PP (2004) A review of the evidence from family, twin and adoption studies for a genetic contribution to adult psychiatric disorders. Int Rev Psychiatry 16:260–283
Spitzer R, Endicott J (1977) The schedule for affective disorders and schizophrenia lifetime version. New York State Psychiatric Institute, New York
Spitzer RL, Endicott J, Robins E (1978) Research diagnostic criteria: rationale and reliability. Arch Gen Psychiatry 35:773–782
Stefanis NC, Trikalinos TA, Avramopoulos D, Smyrnis N, Evdokimidis I, Ntzani EE, Hatzimanolis A, Ioannidis JP, Stefanis CN (2008) Association of RGS4 variants with schizotypy and cognitive endophenotypes at the population level. Behav Brain Funct 4:46
Stefanis NC, Trikalinos TA, Avramopoulos D, Smyrnis N, Evdokimidis I, Ntzani EE, Ioannidis JP, Stefanis CN (2007) Impact of schizophrenia candidate genes on schizotypy and cognitive endophenotypes at the population level. Biol Psychiatry 62:784–792
Stefanis NC, Van Os J, Avramopoulos D, Smyrnis N, Evdokimidis I, Hantoumi I, Stefanis CN (2004) Variation in catechol-o-methyltransferase val158 met genotype associated with schizotypy but not cognition: a population study in 543 young men. Biol Psychiatry 56:510–515
Stefansson H, Rujescu D, Cichon S, Pietilainen OP, Ingason A, Steinberg S, Fossdal R, Sigurdsson E, Sigmundsson T, Buizer-Voskamp JE, Hansen T, Jakobsen KD, Muglia P, Francks C, Matthews PM, Gylfason A, Halldorsson BV, Gudbjartsson D, Thorgeirsson TE, Sigurdsson A, Jonasdottir A, Bjornsson A, Mattiasdottir S, Blondal T, Haraldsson M, Magnusdottir BB, Giegling I, Moller HJ, Hartmann A, Shianna KV, Ge D, Need AC, Crombie C, Fraser G, Walker N, Lonnqvist J, Suvisaari J, Tuulio-Henriksson A, Paunio T, Toulopoulou T, Bramon E, Di Forti M, Murray R, Ruggeri M, Vassos E, Tosato S, Walshe M, Li T, Vasilescu C, Muhleisen TW, Wang AG, Ullum H, Djurovic S, Melle I, Olesen J, Kiemeney LA, Franke B, Sabatti C, Freimer NB, Gulcher JR, Thorsteinsdottir U, Kong A, Andreassen OA, Ophoff RA, Georgi A, Rietschel M, Werge T, Petursson H, Goldstein DB, Nothen MM, Peltonen L, Collier DA, St Clair D, Stefansson K, Kahn RS, Linszen DH, van Os J, Wiersma D, Bruggeman R, Cahn W, de Haan L, Krabbendam L, Myin-Germeys I (2008) Large recurrent microdeletions associated with schizophrenia. Nature 455:232–236
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
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
Tang JX, Chen WY, He G, Zhou J, Gu NF, Feng GY, He L (2004) Polymorphisms within 5′ end of the Neuregulin 1 gene are genetically associated with schizophrenia in the Chinese population. Mol Psychiatry 9:11–12
Thaker GK, Wonodi I, Avila MT, Hong LE, Stine OC (2004) Catechol O-methyltransferase polymorphism and eye tracking in schizophrenia: a preliminary report. Am J Psychiatry 161:2320–2322
Thiselton DL, Webb BT, Neale BM, Ribble RC, O’Neill FA, Walsh D, Riley BP, Kendler KS (2004) No evidence for linkage or association of neuregulin-1 (NRG1) with disease in the Irish study of high-density schizophrenia families (ISHDSF). Mol Psychiatry 9:777–783 image 729
Trillenberg P, Lencer R, Heide W (2004) Eye movements and psychiatric disease. Curr Opin Neurol 17:43–47
Ungerleider LG, Courtney SM, Haxby JV (1998) A neural system for human visual working memory. Proc Natl Acad Sci USA 95:883–890
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
Wonodi I, Hong LE, Stine OC, Mitchell BC, Elliott A, Roberts RC, Conley RR, McMahon RP, Thaker GK (2009) Dopamine transporter polymorphism modulates oculomotor function and DAT1 mRNA expression in schizophrenia. Am J Med Genet B Neuropsychiatr Genet 150B(2):282–289
Yang JZ, Si TM, Ruan Y, Ling YS, Han YH, Wang XL, Zhou M, Zhang HY, Kong QM, Liu C, Zhang DR, Yu YQ, Liu SZ, Ju GZ, Shu L, Ma DL, Zhang D (2003) Association study of neuregulin 1 gene with schizophrenia. Mol Psychiatry 8:706–709
Zhao X, Shi Y, Tang J, Tang R, Yu L, Gu N, Feng G, Zhu S, Liu H, Xing Y, Zhao S, Sang H, Guan Y, St Clair D, He L (2004) A case control and family based association study of the neuregulin1 gene and schizophrenia. J Med Genet 41:31–34
Acknowledgments
The authors would like to thank the doctors and nurses at the Landspitali-University Hospital Division of Psychiatry for their assistance with subject recruitment. Funding for this study was provided by the Icelandic Research Fund (060461021), a European Union Research Grant (37761) and by the Wyeth Foundation for Psychiatric Research. Dr. Ettinger is funded by grant ET 31/2-1 (Deutsche Forschungsgemeinschaft). All funding sources had no further role in study design, in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the article for publication.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Haraldsson, H.M., Ettinger, U., Magnusdottir, B.B. et al. Neuregulin-1 genotypes and eye movements in schizophrenia. Eur Arch Psychiatry Clin Neurosci 260, 77–85 (2010). https://doi.org/10.1007/s00406-009-0032-2
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00406-009-0032-2