Abstract
In this study, we report a genome scan for psychiatric disease susceptibility loci in 13 Scottish families. We follow up one of the linkage peaks on chromosome 1q in a substantially larger sample of 22 families affected by schizophrenia (SCZ) or bipolar affective disorder (BPAD). To minimise the effect of genetic heterogeneity, we collected mainly large extended families (average family size >18). The families collected were Scottish, carried no chromosomal abnormalities and were unrelated to the large family previously reported as segregating a balanced (1 : 11) translocation with major psychiatric disease. In the genome scan, we found linkage peaks with logarithm of odds (LOD) scores >1.5 on chromosomes 1q (BPAD), 3p (SCZ), 8p (SCZ), 8q (BPAD), 9q (BPAD) and 19q (SCZ). In the follow-up sample, we obtained most evidence for linkage to 1q42 in bipolar families, with a maximum (parametric) LOD of 2.63 at D1S103. Multipoint variance components linkage gave a maximum LOD of 2.77 (overall maximum LOD 2.47 after correction for multiple tests), 12 cM from the previously identified SCZ susceptibility locus DISC1. Interestingly, there was negligible evidence for linkage to 1q42 in the SCZ families. These results, together with results from a number of other recent studies, stress the importance of the 1q42 region in susceptibility to both BPAD and SCZ.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Owen MJ, Williams NM, O'Donovan MC . The molecular genetics of schizophrenia: findings promise new insights. Mol Psychiatr 2004; 9: 14–27.
Brzustowicz LM, Hodgkinson KA, Chow EWC, Honer WG, Bassett AS . Location of a major susceptibility locus for familiar schizophrenia on chromosome 1q21-q22. Science 2000; 288: 678–682.
Gurling HMD, Kalsi G, Brynjolfson J, Sigmundsson T, Sherrington R, Mankoo BS et al. 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 2001; 68: 661–673.
Rosa A, Fananas L, Cuesta MJ, Peralta V, Sham P . 1q21–q22 locus is associated with susceptibility to the reality–distortion syndrome of schizophrenia spectrum disorders. Am J Med Genet 2002; 114: 516–518.
Lewis CM, Levinson DF, Wise LH, DeLisi LE, Straub RE, Hovatta I et al. Genome scan meta-analysis of schizophrenia and bipolar disorder, part II: Schizophrenia. Am J Hum Genet 2003; 73: 34–48.
Stclair D, Blackwood D, Muir W, Carothers A, Walker M, Spowart G et al. Association within a family of a balanced autosomal translocation with major mental-illness. Lancet 1990; 336: 13–16.
Blackwood DHR, Fordyce A, Walker MT, St Clair DM, Porteous DJ, Muir WJ . 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 2001; 69: 428–433.
Millar JK, Wilson-Annan JC, Anderson S, Christie S, Taylor MS, Semple CAM et al. Disruption of two novel genes by a translocation co-segregating with schizophrenia. Hum Mol Genet 2000; 9: 1415–1423.
Hovatta I, Varilo T, Suvisaari J, Terwilliger JD, Ollikainen V, Arajarvi R et al. A genomewide screen for schizophrenia genes in an isolated Finnish subpopulation, suggesting multiple susceptibility loci. Am J Hum Genet 1999; 65: 1114–1124.
Ekelund J, Hovatta I, Parker A, Paunio T, Varilo T, Martin R et al. Chromosome 1 loci in Finnish schizophrenia families. Hum Mol Genet 2001; 10: 1611–1617.
Hwu HG, Liu CM, Fann CJ, Ou-Yang WC, Lee SC . Linkage of schizophrenia with chromosome 1q loci in Taiwanese families. Mol Psychiatr 2003; 8: 445–452.
Detera-Wadleigh SD, Badner JA, Berrettini WH, Yoshikawa T, Goldin LR, Turner G et al. A high-density genome scan detects evidence for a bipolardisorder susceptibility locus on 13q32 and other potential loci on 1q32 and 18p11.2. Proc Natl Acad Sci USA 1999; 96: 5604–5609.
McInnis MG, Lan TH, Willour VL, McMahon FJ, Simpson SG, Addington AM et al. Genome-wide scan of bipolar disorder in 65 pedigrees: supportative evidence for linkage at 8q24, 18q22, 4q32, 2p12, and 13q12. Mol Psychiatr 2003; 8: 288–298.
Curtis D, Kalsi G, Brynjolfsson J, McInnis M, O'Neill J, Smyth C et al. 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 2003; 13: 77–84.
Gejman PV, Martinez M, Cao QH, Friedman E, Berrettini WH, Goldin LR et al. Linkage analysis of 57 microsatellite loci to bipolar disorder. Neuropsychopharmacology 1993; 9: 31–40.
LaBuda MC, Maldonado M, Marshall D, Otten K, Gerhard DS . A follow-up report of a genome search for affective disorder predisposition loci in the old order Amish. Am J Hum Genet 1996; 59: 1343–1362.
Wildenauer DB, Schwab SG, Maier W, Detera-Wadleigh SD . Do schizophrenia and affective disorder share susceptibility genes? Schizophr Res 1999; 39: 107–111.
Berrettini WH . Are schizophrenic and bipolar disorders related? A review of family and molecular studies. Biol Psychiatry 2000; 48: 531–538.
Levinson DF, Holmans PA, Laurent C, Riley B, Pulver AE, Gejman PV et al. No major schizophrenia locus detected on chromosome 1q in a large multicenter sample. Science 2002; 296: 739–741.
Macgregor S, Visscher PM, Knott S, Porteous D, Muir W, Millar K et al. Is schizophrenia linked to chromosome 1q? Science 2002; 298: 2277a.
Bassett AS, Chow EWC, Vieland VJ, Brzustowicz L . Is schizophrenia linked to chromosome 1q? Science 2002; 298: 2277a.
Levinson DF, Holmans PA, Laurent C, Mallet J, Riley B, Kendler KS et al. Is schizophrenia linked to chromosome 1q? Resp Sci 2002; 298: 2277a.
Devon RS, Anderson S, Teague PW, Burgess P, Kipari TM, Semple CA et al. Identification of polymorphisms within Disrupted in Schizophrenia 1 and Disrupted in Schizophrenia 2, and an investigation of their association with schizophrenia and bipolar affective disorder. Psychiatr Genet 2001; 11: 71–78.
Abecasis GR, Cherny SS, Cookson WO, Cardon LR . Merlin-rapid analysis of dense genetic maps using sparse gene flow trees. Nat Genet 2002; 30: 97–101.
Almasy L, Blangero J . Multipoint quantitative-trait linkage analysis in general pedigrees. Am J Hum Genet 1998; 62: 1198–1211.
Cottingham RW, Idury RM, Schaffer AA . Faster sequential genetic-linkage computations. Am J Hum Genet 1993; 53: 252–263.
Sham P . Statistics in Human Genetics. Arnold: London, UK, 1998.
Goring HHH, Terwilliger JD . Linkage analysis in the presence of errors I: complex-valued recombination fractions and complex phenotypes. Am J Hum Genet 2000; 66: 1095–1106.
Allison DB, Neale MC, Zannolli R, Schork NJ, Amos CI, Blangero J . Testing the robustness of the likelihood-ratio test in a variance-component quantitative-trait loci-mapping procedure. Am J Hum Genet 1999; 65: 531–544.
Lander E, Kruglyak L . Genetic dissection of complex traits—guidelines for interpreting and reporting linkage results. Nat Genet 1995; 11: 241–247.
Williams JT, Blangero J . Power of variance component linkage analysis to detect quantitative trait loci. Ann Hum Genet 1999; 63: 545–563.
Goring HHH, Terwilliger JD . Linkage analysis in the presence of errors IV: joint pseudomarker analysis of linkage and/or linkage disequilibrium on a mixture of pedigrees and singletons when the mode of inheritance cannot be accurately specified. Am J Hum Genet 2000; 66: 1310–1327.
Dempster E, Lerner I . Heritability of threshold characters. Genetics 1950; 35: 212–236.
Segurado R, Detera-Wadleigh SD, Levinson DF, Lewis CM, Gill M, Nurnberg JI et al. Genome scan meta-analysis of schizophrenia and bipolar disorder, part III: Bipolar disorder. Am J Hum Genet 2003; 73: 49–62.
Gilmour AR, Gogel BJ, Cullis BR, Welham SJ, Thompson R . ASREML User Guide Release 1.0. VSN International Ltd: Hemel Hempstead, HP1 1ES, UK, 2002.
Lynch M, Walsh B . Genetics and Analysis of Quantitative Traits. Sineaur Associates: Sunderland, USA, 1998.
Blouin JL, Dombroski BA, Nath SK, Lasseter VK, Wolyniec PS, Nestadt G et al. Schizophrenia susceptibility loci on chromosomes 13q32 and 8p21. Nat Genet 1998; 20: 70–73.
Stefansson H, Sigurdsson E, Steinthorsdottir V, Bjornsdottir S, Sigmundsson T, Ghosh S et al. Neuregulin 1 and susceptibility to schizophrenia. Am J Hum Genet 2002; 71: 877–892.
Acknowledgements
Financial support was provided by the Medical Research Council (UK), The Biotechnology and Biological Sciences Research Council (UK), The Chief Scientist Office of the Scottish Executive, the Royal Society and Akzo-Nobel (Organon). We are indebted to all the other participants in the European Science Foundation Program on Molecular Neurobiology of Mental Illnesses for being the initial stimulus to these studies.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Macgregor, S., Visscher, P., Knott, S. et al. A genome scan and follow-up study identify a bipolar disorder susceptibility locus on chromosome 1q42. Mol Psychiatry 9, 1083–1090 (2004). https://doi.org/10.1038/sj.mp.4001544
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.mp.4001544
Keywords
This article is cited by
-
Role of disrupted in schizophrenia 1 (DISC1) in stress-induced prefrontal cognitive dysfunction
Translational Psychiatry (2013)
-
Comprehensive behavioral analysis of ENU-induced Disc1-Q31L and -L100P mutant mice
BMC Research Notes (2012)
-
Gender-specific association of TSNAX/DISC1 locus for schizophrenia and bipolar affective disorder in South Indian population
Journal of Human Genetics (2012)
-
Genome-wide linkage analysis of 972 bipolar pedigrees using single-nucleotide polymorphisms
Molecular Psychiatry (2012)
-
Impact of DISC1 variation on neuroanatomical and neurocognitive phenotypes
Molecular Psychiatry (2011)