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The Wellcome trust UK–Irish bipolar affective disorder sibling-pair genome screen: first stage report

Abstract

We have completed the first stage of a two-stage genome wide screen designed to identify chromosomal regions that may harbour susceptibility genes for bipolar affective disorder. The first stage screening sample included 509 subjects from 151 nuclear families recruited within the United Kingdom and Republic of Ireland. This sample contained 154 narrowly defined affected sibling pairs (DSM-IV BPI) and 258 broadly defined affected sibling pairs (DSM-IV BPI, SABP, BPII, BPNOS or MDD(R)), approximately two thirds of all families contained at least one other additional typed individual. All individuals were genotyped using 398 highly polymorphic microsatellite markers from Applied Biosystems's Linkage Mapping Set Version 2. The average inter-marker distance was 9.6?cM and the mean heterozygosity was 0.78. Analysis of these data using non-parametric linkage methods (MAPMAKER/SIBS) found no evidence for loci of major effect and no regions reached genome-wide significance for either suggestive or significant linkage. We identified 19 points across the genome where the MLS exceeded a value set for follow up in our second stage screen (MLS≥0.74 (equivalent to a nominal pointwise significance of 5%) under the narrowest diagnostic model). These points were on chromosomes 2, 3, 4, 6, 7, 9, 10, 12, 17, 18 & X. Some of these points overlapped with previous linkage reports both within bipolar affective disorder and other psychiatric illnesses. Under the narrowest diagnostic model, the single most significant multipoint linkage was on chromosome 18 at marker D18S452 (MLS=1.54). Overall the highest MLS was 1.70 on chromosome 2 at marker D2S125, under the broadest diagnostic model.

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References

  1. Goodwin FK, Jamison KR . Manic-depressive Illness Oxford University Press: New York 1990

    Google Scholar 

  2. Weissman MM, Bland RC, Canino GJ, Faravelli C, Greenwald S, Hwu HG et al. Cross-national epidemiology of major depression and bipolar disorder J Am Med Assoc 1996 276: 293–299

    Article  CAS  Google Scholar 

  3. Kraeplin E . Manic-depressive Insanity and Paranoia Ayer Publishing: Salem, NH 1921

    Book  Google Scholar 

  4. Craddock N, Jones I . Genetics of bipolar disorder J Med Genet 1999 36: 585–594

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Craddock N, Khodel V, Van Eerdewegh P, Reich T . Mathematical limits of multilocus models—the genetic transmission of bipolar disorder Am J Hum Genet 1995 57: 690–702

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Craddock N, Van Eerdewegh P, Reich T . Single major locus models for bipolar disorder are implausible Am J Med Genet 1997 74: 18

    Article  CAS  PubMed  Google Scholar 

  7. Blackwood DHR, He L, Morris SW, McLean A, Whitton C, Thomson M et al. A locus for bipolar affective disorder on chromosome 4p Nature Genet 1996 12: 427–430

    Article  CAS  PubMed  Google Scholar 

  8. Nurnberger JI, DePaulo JR, Gershon ES, Reich T, Blehar MC, Edenberg HJ et al. Genomic survey of bipolar illness in the NIMH genetics initiative pedigrees: a preliminary report Am J Med Genet 1997 74: 227–237

    Article  Google Scholar 

  9. Asherson P, Mant R, Williams N, Cardno A, Jones L, Murphy K et al. A study of chromosome 4p markers and dopamine D5 receptor gene in schizophrenia and bipolar disorder Mol Psychiatry 1998 3: 310–320

    Article  CAS  PubMed  Google Scholar 

  10. Ewald H, Degn B, Mors O, Kruse TA . Support for the possible locus on chromosome 4p16 for bipolar affective disorder Mol Psychiatry 1998 3: 442–448

    Article  CAS  PubMed  Google Scholar 

  11. Kennedy JL, Basile VS, Macciardi FM . Chromosome 4 Workshop Summary: Sixth World Congress on Psychiatric Genetics, Bonn, Germany, October 6–10, 1998 Am J Med Genet 1999 88: 224–228

    Article  CAS  PubMed  Google Scholar 

  12. Adams LJ, Mitchell PB, Fielder SL, Rosso A, Donald JA, Schofield PR . A susceptibility locus for bipolar affective disorder on chromosome 4q35 Am J Hum Genet 1998 62: 1084–1091

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. McInnis MG, McMahon FJ, MacKinnon DF, Breschel TS, Simpson SG, DePaulo JR . Supportive evidence for a bipolar susceptibility gene on chromosome 4q35 Am J Med Genet 1998 81: 540

    Google Scholar 

  14. Craddock N, Dawson E, Burge S, Parfitt L, Mant R, Roberts Q et al. The gene for Dariers-Disease maps to chromosome 12q23-Q24.1 Hum Mol Genet 1993 2: 2214–2214

    Article  Google Scholar 

  15. Craddock N, Owen M, Burge S, Kurian B, Thomas P, McGuffin P . Familial cosegregation of major affective disorder and Dariers-Disease (Keratosis-Follicularis) Br J Psychiatry 1994 164: 355–358

    Article  CAS  PubMed  Google Scholar 

  16. Dawson E, Parfitt E, Roberts Q, Daniels J, Lim L, Sham P et al. Linkage studies of bipolar disorder in the region of the Dariers-Disease gene on chromosome 12q23–24.1 Am J Med Genet 1995 60: 94–102

    Article  CAS  PubMed  Google Scholar 

  17. 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 Genet 1999 88: 567–587

    Article  CAS  PubMed  Google Scholar 

  18. Berrettini WH, Ferraro TN, Goldin LR, Weeks DE, Detera-Wadleigh S, Nurnberger JI et al. Chromosome-18 DNA markers and manic-depressive illness—evidence for a susceptibility gene Proc Natl Acad Sci USA 1994 91: 5918–5921

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Stine OC, Xu JF, Koskela R, McMahon FJ, Gschwend M, Friddle C et al. Evidence for linkage of bipolar disorder to chromosome-18 with a parent-of-origin effect Am J Hum Genet 1995 57: 1384–1394

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Freimer NB, Reus VI, Escamilla MA, McInnes LA, Spesny M, Leon P et al. Genetic mapping using haplotype, association and linkage methods suggests a locus for severe bipolar disorder (BPI) at 18q22–q23 Nature Genet 1996 12: 436–441

    Article  CAS  PubMed  Google Scholar 

  21. Gershon ES, Badner JA, Detera-Wadleigh SD, Ferraro TN, Berrettini WH . Maternal inheritance and chromosome 18 allele sharing in unilineal bipolar illness pedigrees Am J Med Genet 1996 67: 202–207

    Article  CAS  PubMed  Google Scholar 

  22. 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 USA 1996 93: 13060–13065

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Berrettini WH, Ferraro TN, Goldin LR, Detera-Wadleigh SD, Choi H, Muniec D et al. A linkage study of bipolar illness Arch Gen Psych 1997 54: 27–35

    Article  CAS  Google Scholar 

  24. McMahon FJ, Hopkins PJ, Xu JF, McInnis MG, Shaw S, Cardon L et al. Linkage of bipolar affective disorder to chromosome 18 markers in a new pedigree series Am J Hum Genet 1997 61: 1397–1404

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Detera-Wadleigh SD, Badner JA, Berrettini WH, Yoshikawa T, Goldin LR, Turner G et al. 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 1999 96: 5604–5609

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Nothen MM, Cichon S, Rohleder H, Hemmer S, Franzek E, Fritze J et al. Evaluation of linkage of bipolar affective disorder to chromosome 18 in a sample of 57 German families Mol Psychiatry 1999 4: 76–84

    Article  CAS  PubMed  Google Scholar 

  27. Lander ES, Schork NJ . Genetic dissection of complex traits Science 1994 265: 2037–2048

    Article  CAS  PubMed  Google Scholar 

  28. Craddock N, Owen MJ . Modern molecular-genetic approaches to psychiatric disease Br Med Bullet 1996 52: 434–452

    Article  CAS  Google Scholar 

  29. Risch N, Merikangas K . The future of genetic studies of complex human diseases Science 1996 273: 1516–1517

    Article  CAS  PubMed  Google Scholar 

  30. Holmans P, Craddock N . Efficient strategies for genome scanning using maximum-likelihood affected-sib-pair analysis Am J Hum Genet 1997 60: 657–666

    CAS  PubMed  PubMed Central  Google Scholar 

  31. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders American Psychiatric Press: Washington, DC 1994

  32. Wing JK, Babor T, Brugha T, Burke J, Cooper JE, Giel R et al. SCAN—Schedules for Clinical Assessment in Neuropsychiatry Arch Gen Psychiatry 1990 47: 589–593

    Article  CAS  PubMed  Google Scholar 

  33. Cohen J . Weighted kappa: nominal scale agreement with provision for scaled disagreement or partial credit Psychol Bull 1968 70: 213–220

    Article  CAS  PubMed  Google Scholar 

  34. Brownstein MJ, Carpten JD, Smith JR . Modulation of non-templated nucleotide addition by taq DNA polymerase: primer modifications that facilitate genotyping Biotechniques 1996 20: 1004–1008

    Article  CAS  PubMed  Google Scholar 

  35. Bennett P, Mulcahy T, Owen MJ, Craddock N, Gill M . The Wellcome Trust UK–Irish bipolar sib-pair study: Chromosome 21 Am J Med Genet 1998 81: 541

    Google Scholar 

  36. Fenton I, Sandkuijl LA . MEGABASE/PKD: a genetic database for polycystic kidney disease Contrib Nephrol 1992 97: 118–127

    Article  CAS  PubMed  Google Scholar 

  37. O'Connell JR, Weeks DE . PedCheck: a program for identification of genotype incompatibilities in linkage analysis Am J Hum Genet 1998 63: 259–266

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Göring HH, Ott J . Relationship estimation in affected sib pair analysis of late-onset diseases Eur J Hum Genet 1997 5: 69–77

    PubMed  Google Scholar 

  39. Kruglyak L, Lander ES . Complete multipoint sib-pair analysis of qualitative and quantitative traits Am J Hum Genet 1995 57: 439–454

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Holmans P, Clayton D . Efficiency of typing unaffected relatives in an affected-sib-pair linkage study with single-locus and multiple tightly linked markers Am J Hum Genet 1995 57: 1221–1232

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 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

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Williams NM, Rees MI, Holmans P, Norton N, Cardno AG, Jones LA et al. A two-stage genome scan for schizophrenia susceptibility genes in 196 affected sibling pairs Hum Mol Genet 1999 8: 1729–1739

    Article  CAS  PubMed  Google Scholar 

  43. Nyholt DR . All LODs are not created equal Am J Hum Genet 2000 67: 282–288

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Lander E, Kruglyak L . Genetic dissection of complex traits—guidelines for interpreting and reporting linkage results Nature Genet 1995 11: 241–247

    Article  CAS  PubMed  Google Scholar 

  45. Keller MP, Seifried BA, Rabin BA, Chance PF . Mapping of the kinesin-related gene ATSV to chromosome 2q37 Hum Genet 1999 104: 254–256

    Article  CAS  PubMed  Google Scholar 

  46. Ekelund J, Lichtermann D, Hovatta L, Ellonen P, Suvisaari J, Terwilliger JD et al. Genome-wide scan for schizophrenia in the Finnish population: evidence for a locus on chromosome 7q22 Hum Mol Genet 2000 9: 1049–1057

    Article  CAS  PubMed  Google Scholar 

  47. Long JC, Knowler WC, Hanson RL, Robin RW, Urbanek M, Moore E et al. Evidence for genetic linkage to alcohol dependence on chromosomes 4 and 11 from an autosome-wide scan in an American Indian population Am J Med Genet 1998 81: 216–221

    Article  CAS  PubMed  Google Scholar 

  48. Reich T, Edenberg HJ, Goate A, Williams JT, Rice JP, Van Eerdewegh P et al. Genome-wide search for genes affecting the risk for alcohol dependence Am J Med Genet 1998 81: 207–215

    Article  CAS  PubMed  Google Scholar 

  49. Moises HW, Yang L, Kristbjarnarson H, Wiese C, Byerley W, Macciardi F et al. An international 2-stage genome-wide search for schizophrenia susceptibility genes Nature Genet 1995 11: 321–324

    Article  CAS  PubMed  Google Scholar 

  50. Straub RE, Maclean CJ, Oneill FA, Burke J, Murphy B, Duke F et al. A potential vulnerability locus for schizophrenia on chromosome 6p24–22—Evidence for genetic-heterogeneity Nature Genet 1995 11: 287–293

    Article  CAS  PubMed  Google Scholar 

  51. Schwab SG, Albus M, Hallmayer J, Honig S, Borrmann M, Lichtermann D et al. Evaluation of a susceptibility gene for schizophrenia on chromosome 6p by multipoint affected sib-pair linkage analysis Nature Genet 1995 11: 325–327

    Article  CAS  PubMed  Google Scholar 

  52. Sanders AR, Cao Q, Martinez M, Zhang J, Badner JA, Cravchik A et al. Suggestive evidence for a schizophrenia susceptibility locus on chromosome 6q and replication in an independent series of pedigrees Am J Med Genet 1997 74: 667–668

    Google Scholar 

  53. Schwab SG, Eckstein GN, Albus M, Hallmayer J, Lerer B, Maier W et al. Further evaluation of the region 6p22,23 containing a potential susceptibility gene for schizophrenia Am J Med Genet 1997 74: 668–668

    Google Scholar 

  54. Blouin JL, Dombroski BA, Nath SK, Lasseter VK, Wolyniec PS, Nestadt G et al. Schizophrenia susceptibility loci on chromosomes 13q32 and 8p21 Nature Genet 1998 20: 70–73

    Article  CAS  PubMed  Google Scholar 

  55. Faraone SV, Matise T, Svrakic D, Pepple J, Malaspina D, Suarez B et al. Genome scan of European-American schizophrenia pedigrees: results of the NIMH Genetics Initiative and Millennium Consortium Am J Med Genet 1998 81: 290–295

    Article  CAS  PubMed  Google Scholar 

  56. Foroud T, Castellucio PF, Koller DL, Edenberg HJ, Goate A, Detera-Wadleigh S et al. Genome wide scan of affected relative pairs using the NIMH genetics initiative bipolar affective disorder pedigrees Am J Med Genet 1998 81: 462–462

    Google Scholar 

  57. Schwab SG, Hallmayer J, Albus M, Lerer B, Hanses C, Kanyas K et al. Further evidence for a susceptibility locus on chromosome 10p14–p11 in 72 families with schizophrenia by nonparametric linkage analysis Am J Med Genet 1998 81: 302–307

    Article  CAS  PubMed  Google Scholar 

  58. Straub RE, MacLean CJ, Martin RB, Ma YL, Myakishev MV, Harris-Kerr C et al. A schizophrenia locus may be located in region 10p15–p11 Am J Med Genet 1998 81: 296–301

    Article  CAS  PubMed  Google Scholar 

  59. Paterson AD, Petronis A . Transmission ratio distortion in females on chromosome 10p11–p15 Am J Med Genet 1999 88: 657–661

    Article  CAS  PubMed  Google Scholar 

  60. Craddock N, McGuffin P, Owen M . Dariers-Disease cosegregating with affective-disorder Br J Psychiatry 1994 165: 272–272

    Article  CAS  PubMed  Google Scholar 

  61. Ewald H, Degn B, Mors O, Krause TA . Significant linkage between bipolar affective disorder and chromosome 12q24 Am J Med Genet 1998 81: 540

    Google Scholar 

  62. Arranz MJ, Lin MW, Powell J, Kerwin R, Collier D . 5HT(2a) receptor T102C polymorphism and schizophrenia Lancet 1996 347: 1831–1832

    CAS  PubMed  Google Scholar 

  63. Gutierrez B, Fananas L, Arranz MJ, Valles V, Guillamat R, Vanos J et al. Allelic association analysis of the 5-HT2C receptor gene in bipolar affective disorder Neurosci Lett 1996 212: 65–67

    Article  CAS  PubMed  Google Scholar 

  64. Ogilvie AD, Battersby S, Bubb VJ, Fink G, Harmar AJ, Goodwin GM et al. Polymorphism in serotonin transporter gene associated with susceptibility to major depression Lancet 1996 347: 731–733

    Article  CAS  PubMed  Google Scholar 

  65. Rees M, Norton N, Jones I, McCandless F, Scourfield J, Holmans P et al. Association studies of bipolar disorder at the human serotonin transporter gene (hSERT; 5HTT) Mol Psychiatry 1997 2: 398–402

    Article  CAS  PubMed  Google Scholar 

  66. Ewald H, Flint T, Degn B, Mors O, Kruse TA . A functional variant of the serotonin transporter gene in families with bipolar affective disorder J Affect Dis 1998 48: 135–144

    Article  CAS  PubMed  Google Scholar 

  67. Kirov G, Rees M, Jones I, McCandless F, Owen MJ, Craddock N . Bipolar disorder and the serotonin transporter gene: a family- based association study Psychol Med 1999 29: 1249–1254

    Article  CAS  PubMed  Google Scholar 

  68. Coyle N, Jones I, Roberson E, Lendon C, Craddock N . Variation at the serotonin transporter gene influences susceptibility to bipolar affective puerperal psychosis Lancet 2000 356: 1490–1491

    Article  CAS  PubMed  Google Scholar 

  69. Schwab SG, Hallmayer J, Lerer B, Albus M, Borrmann M, Honig S et al. Support for a chromosome 18p locus conferring susceptibility to functional psychoses in families with schizophrenia, by association and linkage analysis Am J Hum Genet 1998 63: 1139–1152

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Maier W, Hallmayer J, Zill P, Bondy B, Lichtermann D, Ackenheil M et al. Linkage analysis between pericentromeric markers on chromosome 18 and bipolar disorder: a replication test Psych Res 1995 59: 7–15

    Article  CAS  Google Scholar 

  71. Debruyn A, Souery D, Mendelbaum K, Mendlewicz J, VanBroeckhoven C . Linkage analysis of families with bipolar illness and chromosome 18 markers Biol Psychiatry 1996 39: 679–688

    Article  CAS  Google Scholar 

  72. Lin JP, Bale SJ . Parental transmission and D18S37 allele sharing in bipolar affective disorder Genet Epidemiol 1997 14: 665–668

    Article  CAS  PubMed  Google Scholar 

  73. DeLisi LE, Lofthouse R, Lehner T, Morganti C, Vita A, Shields G et al. Failure to find a chromosome 18 pericentric linkage in families with schizophrenia Am J Med Genet 1995 60: 532–534

    Article  CAS  PubMed  Google Scholar 

  74. Claes S, Raeymaekers P, VandenBroeck M, Diependaele S, Debruyn A, Verheyen G et al. A chromosome 18 genetic linkage study in three large Belgian pedigrees with bipolar disorder J Affect Dis 1997 43: 195–205

    Article  CAS  PubMed  Google Scholar 

  75. Kalsi G, Smyth C, Brynjolfsson J, Sherrington RS, Oneill J, Curtis D et al. Linkage analysis of manic depression (bipolar affective disorder) in Icelandic and British kindreds using markers on the short arm of chromosome 18 Hum Hered 1997 47: 268–278

    Article  CAS  PubMed  Google Scholar 

  76. Knowles JA, Rao PA, CoxMatise T, Loth JE, deJesus GM, Levine L et al. No evidence for significant linkage between bipolar affective disorder and chromosome 18 pericentromeric markers in a large series of multiplex extended pedigrees Am J Hum Genet 1998 62: 916–924

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Bowen T, Kirov G, Gill M, Spurlock G, Vallada HP, Murray RM et al. Linkage studies of bipolar disorder with chromosome 18 markers Am J Med Genet 1999 88: 503–509

    Article  CAS  PubMed  Google Scholar 

  78. Norton N, Williams NM, Rees MI, Holmans P, Fenton I, Cardno AC et al. An affected sib pair study for schizophrenia on the X chromosome Am J Med Genet 1998 81: 529–529

    Google Scholar 

  79. Paterson AD, DeLisi L, Faraone SV, Gejman PV, Goossens D, Hovatta I et al. Sixth World Congress of Psychiatric Genetics X Chromosome Workshop Am J Med Genet 1999 88: 279–286

    Article  CAS  PubMed  Google Scholar 

  80. Naumova AK, Leppert M, Barker DF, Morgan K, Sapienza C . Parental origin-dependent, male offspring-specific transmission-ratio distortion at loci on the human X chromosome Am J Hum Genet 1998 62: 1493–1499

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

Nick Craddock was a Wellcome Trust Senior Research Fellow in Clinical Sciences, Ian Jones is a Wellcome Trust Research Training Fellow and George Kirov is a Wellcome Trust Career Development Fellow. The work was supported by grants from the Wellcome Trust. We thank Iain Fenton for continued support of the Megabase software package. We are also grateful to all the clinicians who helped in recruitment. Finally, and most importantly, we are indebted to the families who made this study possible through their enthusiastic and generous participation.

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Bennett, P., Segurado, R., Jones, I. et al. The Wellcome trust UK–Irish bipolar affective disorder sibling-pair genome screen: first stage report. Mol Psychiatry 7, 189–200 (2002). https://doi.org/10.1038/sj.mp.4000957

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