Abstract
Bipolar disorder (BPD) is a common disorder characterized by episodes of mania, hypomania and depression. The genetic background of BPD remains undefined, although several putative loci predisposing to BPD have been identified. We have earlier reported significant evidence of linkage for BPD to chromosome Xq24–q27.1 in an extended pedigree from the late settlement region of the genetically isolated population of Finland. Further, we established a distinct chromosomal haplotype covering a 19 cM region on Xq24–q27.1 co-segregating with the disorder. Here, we have further analyzed this X-chromosomal region using a denser marker map and monitored X-chromosomal haplotypes in a study sample of 41 Finnish bipolar families. Only a fraction of the families provided any evidence of linkage to this region, suggesting that a relatively rare gene predisposing to BPD is enriched in this linked pedigree. The genome-wide scan for BPD predisposing loci in this large pedigree indicated that this particular X-chromosomal region provides the best evidence of linkage genome-wide, suggesting an X-chromosomal gene with a major role for the genetic predisposition of BPD in this family.
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References
Goodwin FK, Jamison KR . Manic-Depressive Illness Oxford University Press: New York 1990
Straub RE, Lehner T, Luo Y, Loth JE, Shao W, Sharpe L et al. A possible vulnerability locus for bipolar affective disorder on chromosome 21q22.3 Nat Genet 1994 8: 291–296
Blackwood DH, He L, Morris SW, McLean A, Whitton C, Thomson M et al. A locus for bipolar affective disorder on chromosome 4p Nat Genet 1996 12: 427–430
McInnes LA, Escamilla MA, Service SK, Reus VI, Leon P, Silva S et al. A complete genome screen for genes predisposing to severe bipolar disorder in two Costa Rican pedigrees Proc Natl Acad Sci 1996 93: 13060–13065
Rice JP, Goate A, Williams JT, Bierut L, Dorr D, Wu W et al. Initial genome scan of the NIMH genetics initiative bipolar pedigrees: chromosomes 1, 6, 8, 10, and 12 Am J Med Genet 1997 74: 247–253
Ginns EI, St Jean P, Philibert RA, Galdzicka M, Damschroder-Williams P et al. A genome-wide search for chromosomal loci linked to mental health wellness in relatives at high risk for bipolar affective disorder among the Old Order Amish Proc Natl Acad Sci 1998 95: 15531–15536
Morissette J, Villeneuve A, Bordeleau L, Rochette D, Laberge C, Gagne B et al. Genome-wide search for linkage of bipolar affective disorders in a very large pedigree derived from a homogeneous population in Quebec points to a locus of major effect on chromosome 12q23–q24 Am J Med Gen 1999 88: 567–587
Peltonen L, Palotie A, Lange K . Use of population isolates for mapping complex traits Nat Rev Genet 2000 1: 182–190
Kuokkanen S, Sundvall M, Terwilliger JD, Tienari PJ, Wikstrom J, Holmdahl R et al. A putative vulnerability locus to multiple sclerosis maps to 5p14–p12 in a region syntenic to the murine locus Eae2 Nat Genet 1996 13: 477–480
Pajukanta P, Nuotio I, Terwilliger JD, Porkka KV, Ylitalo K, Pihlajamaki J et al. Linkage of familial combined hyperlipidaemia to chromosome 1q21–q23 Nat Genet 1998 18: 369–373
Mahtani MM, Widen E, Lehto M, Thomas J, McCarthy M, Brayer J et al. Mapping of a gene for type 2 diabetes associated with an insulin secretion defect by a genome scan in Finnish families Nat Genet 1996 14: 90–94
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
Pekkarinen P, Terwilliger J, Bredbacka PE, Lonnqvist J, Peltonen L . Evidence of a predisposing locus to bipolar disorder on Xq24–q27.1 in an extended Finnish pedigree Genome Res 1995 5: 105–115
Kuoppasalmi KLJ, Pylkkanen K, Huttunen M . Classification of mental disorders in Finland: a comparison of the Finnish classification of mental disorders 1987 with DSM-III-R Psychiatria Fennica 1989 20: 65–81
Kessing LV . Validity of diagnoses and other clinical register data in patients with affective disorder Eur Psychiatry 1998 13: 392–398
Kieseppä T, Partonen T, Kaprio J, Lönnqvist J . Accurancy of register- and record-based bipolar I disorder diagnoses in Finland; a study of twins Acta Neuropsychiatrica 2000 13: 106–109
Vandenplas S, Wiid I, Grobler-Rabie A, Brebner K, Ricketts M, Wallis G et al. Blot hybridisation analysis of genomic DNA J Med Genet 1984 21: 164–172
Cox DR, Burmeister M, Price ER, Kim S, Myers RM . Radiation hybrid mapping: a somatic cell genetic method for constructing high-resolution maps of mammalian chromosomes Science 1990 250: 245–250
Gyapay G, Schmitt K, Fizames C, Jones H, Vega-Czarny N, Spillett D et al. A radiation hybrid map of the human genome Hum Mol Genet 1996 5: 339–346
Terwilliger JD, Goring HH . Gene mapping in the 20th and 21st centuries: statistical methods, data analysis, and experimental design Hum Biol 2000 72: 63–132
Ott J . Analysis of Human Genetic Linkage, rev edn John Hopkins University Press: Baltimore 1991 p 223
Terwilliger JD, Ott J . A haplotype-based ‘haplotype relative risk’ approach to detecting allelic associations Hum Hered 1992 42: 337–346
Spielman RS, McGinnis RE, Ewens WJ . Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM) Am J Hum Genet 1993 52: 506–516
Kruglyak L, Daly MJ, Reeve-Daly MP, Lander ES . Parametric and nonparametric linkage analysis: a unified multipoint approach Am J Hum Genet 1996 58: 1347–1363
Ott J . Computer-simulation methods in human linkage analysis Proc Natl Acad Sci 1989 86: 4175–4178
Lander E, Kruglyak L . Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results Nat Genet 1995 11: 241–247
Blackwood DH, He L, Morris SW, McLean A, Whitton C, Thomson M et al. A locus for bipolar affective disorder on chromosome 4p Nat Genet 1996 12: 427–430
Ewald H, Degn B, Mors O, Kruse TA . Significant linkage between bipolar affective disorder and chromosome 12q24 Psychiatr Genet 1998 8: 131–140
Craddock N, Owen M, Burge S, Kurian B, Thomas P, McGuffin P . Familial cosegregation of major affective disorder and Darier's disease (keratosis follicularis) Br J Psychiatry 1994 164: 355–358
Freimer NB, Reus VI, Escamilla M, Spesny M, Smith L, Service S et al. An approach to investigating linkage for bipolar disorder using large Costa Rican pedigrees Am J Med Genet 1996 67: 254–263
Blackwood D, Muir W . Molecular genetics and the epidemiology of bipolar disorder Ann Med 2001 33: 242–247
Craddock N, Owen M . Christmas disease and major affective disorder Br J Psychiatry 1992 160: 715
Reich T, Clayton PJ, Winokur G . Family history studies: V. The genetics of mania Am J Psychiatry 1969 125: 1358–1369
Lucotte G, Landoulsi A, Berriche S, David F, Babron MC . Manic depressive illness is linked to factor IX in a French pedigree Ann Genet 1992 35: 93–95
Gill M, Castle D, Duggan C . Cosegregation of Christmas disease and major affective disorder in a pedigree Br J Psychiatry 1992 160: 112–114
Jeffries FM, Reiss AL, Brown WT, Meyers DA, Glicksman AC, Bandyopadhyay S . Bipolar spectrum disorder and fragile X syndrome: a family study Biol Psychiatry 1993 33: 213–216
Baron M . X-linkage and manic-depressive illness: a reassessment Soc Biol 1991 38: 179–188
Liu J, Aita VM, Wang Z, Knowles JA, Terwilliger J, Matis TC et al. Progress in a genome-wide search for genetic factors for bipolar disorder Am J Med Genet 1997 74: 590 (abstract)
Stine OC, McMahon FJ, Chen L, Xu J, Meyers DA, MacKinnon DF et al. Initial genome screen for bipolar disorder in the NIMH genetics initiative pedigrees: chromosomes 2, 11, 13, 14, and X Am J Med Genet 1997 74: 263–269
Gecz J, Barnett S, Liu J, Hollway G, Donnelly A, Eyre H et al. Characterization of the human glutamate receptor subunit 3 gene (GRIA3), a candidate for bipolar disorder and nonspecific X-linked mental retardation Genomics 1999 62: 356–368
Saito T, Parsia S, Papolos DF, Lachman HM . Analysis of the pseudoautosomal X-linked gene SYBL1 in bipolar affective disorder: description of a new candidate allele for psychiatric disorders Am J Med Genet 2000 96: 317–323
Acknowledgements
We are very grateful to the participation of the members of the families involved in the study. We also want to thank Mari Sipila for the excellent technical assistance. In addition, the contribution of Drs Jesper Ekelund, Iiris Hovatta, Tero Hiekkalinna, Per-Erik Bredbacka, Lea Muhonen and Jari Seppälä have been invaluable.
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Ekholm, J., Pekkarinen, P., Pajukanta, P. et al. Bipolar disorder susceptibility region on Xq24–q27.1 in Finnish families. Mol Psychiatry 7, 453–459 (2002). https://doi.org/10.1038/sj.mp.4001104
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DOI: https://doi.org/10.1038/sj.mp.4001104
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