[en] Several independent studies and meta-analyses aimed at identifying genomic regions linked to bipolar disorder (BP) have failed to find clear and consistent evidence of linkage regions. Our hypothesis is that combining the original genotype data provides benefits of increased power and control over sources of heterogeneity that outweigh the difficulty and potential pitfalls of the implementation. We conducted a combined analysis using the original genotype data from 11 BP genomewide linkage scans comprising 5,179 individuals from 1,067 families. Heterogeneity among studies was minimized in our analyses by using uniform methods of analysis and a common, standardized marker map and was assessed using novel methods developed for meta-analysis of genome scans. To date, this collaboration is the largest and most comprehensive analysis of linkage samples involving a psychiatric disorder. We demonstrate that combining original genome-scan data is a powerful approach for the elucidation of linkage regions underlying complex disease. Our results establish genomewide significant linkage to BP on chromosomes 6q and 8q, which provides solid information to guide future gene-finding efforts that rely on fine-mapping and association approaches.
Disciplines :
Genetics & genetic processes
Author, co-author :
McQueen, M. B.
Devlin, B.
Faraone, S. V.
Nimgaonkar, V. L.
Sklar, P.
Smoller, J. W.
Abou Jamra, R.
Albus, M.
Bacanu, S. A.
Baron, M.
Barrett, T. B.
Berrettini, W.
Blacker, D.
Byerley, W.
Cichon, S.
Coryell, W.
Craddock, N.
Daly, M. J.
Depaulo, J. R.
Edenberg, H. J.
Foroud, T.
Gill, M.
Gilliam, T. C.
Hamshere, M.
Jones, I.
Jones, L.
Juo, S. H.
Kelsoe, J. R.
Lambert, D.
Lange, C.
Lerer, B.
Liu, J.
Maier, W.
Mackinnon, J. D.
McInnis, M. G.
McMahon, F. J.
Murphy, D. L.
Nothen, M. M.
Nurnberger, J. I.
Pato, C. N.
Pato, M. T.
Potash, J. B.
Propping, P.
Pulver, A. E.
Rice, J. P.
Rietschel, M.
Scheftner, W.
Schumacher, J.
Segurado, R.
Van Steen, Kristel ; Université de Liège - ULiège > Dép. d'électric., électron. et informat. (Inst.Montefiore) > Bioinformatique
Abecasis GR, Cherny SS, Cookson WO, Cardon LR (2001) GRR: graphical representation of relationship errors. Bioinformatics 17:742-743
- (2002) MERLIN-rapid analysis of dense genetic maps using sparse gene flow trees. Nat Genet 30:97-101
APA (1994) Diagnostic and statistical manual of mental disorders, 4th ed. The American Psychiatric Association, Washington, DC
Bacanu (2005) Robust estimation of critical values for genome scans to detect linkage. Genet Epidemiol 28:24-3 2
Badenhop RF, Moses MJ, Scimone A, Mitchell PB, Ewen-White KR, Rosso A, Donald JA, Adams LJ, Schofield PR (2002) A genome screen of 13 bipolar affective disorder pedigrees provides evidence for susceptibility loci on chromosome 3 as well as chromosomes 9, 13 and 19. Mol Psychiatry 7:851-859
Badner JA, Gershon ES (2002) Meta-analysis of whole-genome linkage scans of bipolar disorder and schizophrenia. Mol Psychiatry 7:405-411
Baron M (2002) Manic-depression genes and the new millennium: poised for discovery. Mol Psychiatry 7:342-358
Bennett P, Segurado R, Jones I, Bort S, McCandless F, Lambert D, Heron J, Comerford C, Middle F, Corvin A, Pelios G, Kirov G, Larsen B, Mulcahy T, Williams N, O'Connell R, O'Mahony E, Payne A, Owen M, Holmans P, Craddock N, Gill M (2002) The Wellcome Trust UK-Irish bipolar affective disorder sibling-pair genome screen: first stage report. Mol Psychiatry 7:189-200
Blackwood DH, He L, Morris SW, McLean A, Whitton C, Thomson M, Walker MT, Woodburn K, Sharp CM, Wright AF, Shibasaki Y, St. Clair DM, Porteous DJ, Muir WJ (1996) A locus for bipolar affective disorder on chromosome 4p. Nat Genet 12:427-430
Cichon S, Schumacher J, Muller DJ, Hurter M, Windemuth C, Strauch K, Hemmer S, et al (2001) A genome screen for genes predisposing to bipolar affective disorder detects a new susceptibility locus on 8q. Hum Mol Genet 10:2933-2944
Coon H, Jensen S, Hoff M, Holik J, Plaetke R, Reimherr F, Wender P, Leppert M, Byerley W (1993) A genome-wide search for genes predisposing to manic-depression, assuming autosomal dominant inheritance. Am J Hum Genet 52:1234-1249
Curtis D, Kalsi G, Brynjolfsson J, Mclnnis M, O'Neill J, Smyth C, Moloney E, Murphy P, McQuillin A, Petursson H, Curling H (2003) 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 13:77-84
Detera-Wadleigh SD, Badner JA, Berrettini WH, Yoshikawa T, Goldin LR, Turner G, Rollins DY, Moses T, Sanders AR, Karkera JD, Esterling LE, Zeng J, Ferraro TN, Guroff JJ, Kazuba D, Maxwell ME, Nurnberger JI Jr, Gershon ES (1999) 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 96:5604-5609
Dick DM, Foroud T, Edenberg HJ, Miller M, Bowman E, Rau NL, DePaulo JR, McInnis M, Gershon E, McMahon F, Rice JP, Beirut LJ, Reich T, Nurnberger J Jr (2002) Apparent replication of suggestive linkage on chromosome 16 in the NIMH Genetics Initiative bipolar pedigrees. Am J Med Genet 114:407-412
Dick DM, Foroud T, Flury L, Bowman ES, Miller MJ, Rau NL, Moe PR, et al (2003) Genomewide linkage analyses of bipolar disorder: a new sample of 250 pedigrees from the National Institute of Mental Health Genetics Initiative. Am J Hum Genet 73:107-114
Dizier MH, Quesneville H, Prum B, Selinger-Leneman H, Clerget-Darupoux F (2000) The triangle test statistic (TTS): a test of genetic homogeneity using departure from the triangle constraints in IBD distribution among affected sib-pairs. Ann Hum Genet 64:433-442
Ekholm JM, Kieseppa T, Hiekkalinna T, Partonen T, Paunio T, Perola M, Ekelund J, Lonnqvist J, Pekkarinen-Ijas P, Peltonen L (2003) Evidence of susceptibility loci on 4q32 and 16p12 for bipolar disorder. Hum Mol Genet 12:1907-1915
Elston RC, Song D, Iyengar SK (2005) Mathematical assumptions versus biological reality: myths in affected sib pair linkage analysis. Am J Hum Genet 76:152-156
Ewald H, Flint T, Kruse TA Mors O (2002) A genome-wide scan shows significant linkage between bipolar disorder and chromosome 12q24.3 and suggestive linkage to chromosomes 1p22-21, 4p16, 6q14-22, 10q26 and 16p13.3. Mol Psychiatry 7:734-744
Fallin MD, Lasseter VK, Wolyneic PS, McGrath JA, Nestadt G, Valle D, Liang K-Y, Pulver AE (2004) Genomewide linkage scan for bipolar-disorder susceptibility loci among Ashkenazi Jewish families. Am J Hum Genet 75:204-219
Friddle C, Koskela R, Ranade K, Hebert J, Cargill M, Clark CD, McInnis M, Simpson S, McMahon F, Stine OC, Meyers D, Xu J, MacKinnon D, Swift-Scanlan T, Jamison K, Folstein S, DaIy M, Kruglyak L, Marr T, DePaulo JR, Botstein D (2000) Full-genome scan for linkage in 50 families segregating the bipolar affective disease phenotype. Am J Hum Genet 66:205-215
Garner C, McInnes LA, Service SK, Spesny M, Fournier E, Leon P, Freimer NB (2001) Linkage analysis of a complex pedigree with severe bipolar disorder, using a Markov chain Monte Carlo method. Am J Hum Genet 68:1061-1064
Gu C, Province M, Todorov A, Rao DC (1998) Meta-analysis methodology for combining non-parametric sibpair linkage results: genetic homogeneity and identical markers. Genet Epidemiol 15:609-626
Holmans P (1993) Asymptotic properties of affected-sib-pair linkage analysis. Am J Hum Genet 52:362-374
Kelsoe JR, Spence MA, Loetscher E, Foguet M, Sadovnick AD, Remick RA, Flodman P, Khristich J, Mroczkowski-Parker Z, Brown JL, Masser D, Ungerleider S, Rapaport MH, Wishart WL, Luebbert H (2001) A genome survey indicates a possible susceptibility locus for bipolar disorder on chromosome 22. Proc Natl Acad Sci USA 98:585-590
Kessler RC, McGonagle KA, Zhao S, Nelson CB, Hughes M, Eshleman S, Wittchen HU, Kendler KS (1994) Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the United States: results from the National Comorbidity Survey. Arch Gen Psychiatry 51:8-19
Kong A, Cox NJ (1997) Allele-sharing models: LOD scores and accurate linkage tests. Am J Hum Genet 61:1179-1188
Kong X, Murphy T, Raj T, He C, White PS, Matise C (2004) A combined linkage-physical map of the human genome. Am J Hum Genet 75:1143-1148
Kruglyak L, Daly MJ, Reeve-Daly MP, Lander ES (1996) Parametric and nonparametric linkage analysis: a unified multipoint approach. Am J Hum Genet 58:1347-1363
Laird N, Horvath S, Xu X (2000) Implementing a unified approach to family based tests of association. Genetic Epidemiol Suppl 19: S36-S42
Laird NM, Mosteller F (1990) Some statistical methods for combining experimental results. Int J Technol Assess Health Care 6:5-30
Lambert D, Middle F, Hamshere ML, Segurado R, Raybould R, Corvin A, Green E, O'Mahony E, Nikolov I, Mulcahy T, Haque S, Bort S, Bennett P, Norton N, Owen MJ, Kirov G, Lendon C, Jones L, Jones I, Holmans P, Gill M, Craddock N (2005) Stage 2 of the Wellcome Trust UK-Irish bipolar affective disorder sibling-pair genome screen: evidence for linkage on chromosomes 6q16-q21, 4q12-q21, 9p21, 10p14-p12 and 18q22. Mol Psychiatry (http://www.nature.com/ mp/journal/vaop/ ncurrent/abs/4001684a.html) (electronically published May 17, 2005; accessed August 2, 2005)
Lander E, Kruglyak L (1995) Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nat Genet 11:241-247
Levinson DF, Levinson MD, Segurado R, Lewis CM (2003) Genome scan meta-analysis of schizophrenia and bipolar disorder, part I: methods and power analysis. Am J Hum Genet 73:17-33
Liu J, Juo SH, Dewan A, Grunn A, Tong X, Brito M, Park N, Loth JE, Kanyas K, Lerer B, Endicott J, Penchaszadeh G, Knowles JA, Ott J, Gilliam TC, Baron M (2003) Evidence for a putative bipolar disorder locus on 2p13-16 and other potential loci on 4q31, 7q34, 8q13, 9q31, 10q21-24, 13q32, 14a21 and 17q11-12. Mol Psychiatry 8:333-342
McInnes LA, Escamilla MA, Service SK, Reus VI, Leon P, Silva S, Rojas E, Spesny M, Baharloo S, Blankenship K, Peterson A, Tyler D, Shimayoshi N, Tobey C, Batki S, Vinogradov S, Meza L, Gallegos A, Fournier E, Smith LB, Barondes SH, Sandkuijl LA, Freimer NB (1996) A complete genome screen for genes predisposing to severe bipolar disorder in two Costa Rican pedigrees. Proc Natl Acad Sci USA 93:13060-13065
McInnis MG, Dick DM, Willour VL, Avramopoulos D, MacKinnon DF, Simpson SG, Potash JB, et al (2003a) Genomewide scan and conditional analysis in bipolar disorder: evidence for genomic interaction in the National Institute of Mental Health Genetics Initiative bipolar pedigrees. Biol Psychiatry 54:1265-1273
McInnis MG, Lan TH, Willour VL, McMahon FJ, Simpson SG, Addington AM, MacKinnon DF, Potash JB, Mahoney AT, Chellis J, Huo Y, Swift-Scanlan T, Chen H, Koskela R, Stine OC, Jamison KR, Holmans R, Folstein SE, Ranade K, Friddle C, Botstein D, Marr T, Beaty TH, Zandi P, DePaulo JR (2003b) Genome-wide scan of bipolar disorder in 65 pedigrees: supportive evidence for linkage at 8q24, 18q22, 4q32, 2p12 and 13q12. Mol Psychiatry 8:288-298
Middleton FA, Pato MT, Gentile KL, Morley CP, Zhao X, Eisener AF, Brown A, Petryshen TL, Kirby AN, Medeiros H, Carvalho C, Macedo A, Dourado A, Coelho I, Valente J, Soares MJ, Ferreira CP, Lei M, Azevedo MH, Kennedy JL, Daly MJ, Sklar P, Pato CN (2004) Genomewide linkage analysis of bipolar disorder by use of a high-density single-nucleotide-polymorphism (SNP) genotyping assay: a comparison with microsatellite marker assays and finding of significant linkage to chromosome 6q22. Am J Hum Genet 74: 886-897
Morissette J, Villeneuve A, Bordeleau L, Rochette D, Laberge C, Gagne B, Laprise C, Bouchard G, Plante M, Gobeil L, Shink E, Weissenbach J, Barden N (1999) 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 88:567-587
NIMH Genetics Initiative Bipolar Group (1997) Genomic survey of bipolar illness in the NIMH Genetics Initiative Pedigrees: a preliminary report. NIMH Genetics Initiative Bipolar Group. Am J Med Genet 74:227-237
NIMH Genetics Workgroup (1999) Report of the NIMH's Genetics Workgroup: genetics and mental disorders. Biol Psychiatry 45:559-602
Park N, Juo SH, Cheng R, Liu J, Loth JE, Lilliston B, Nee J, Grunn A, Kanyas K, Lerer B, Endicott J, Gilliam TC, Baron M (2004) Linkage analysis of psychosis in bipolar pedigrees suggests novel putative loci for bipolar disorder and shared susceptibility loci with schizophrenia. Mol Psychiatry 9:1091-1099
Pato CN, Pato MT, Kirby A, Petryshen TL, Medeiros H, Carvalho C, Macedo A, Dourado A, Coelho I, Valente J, Scares MJ, Ferreira CP, Lei M, Verner A, Hudson TJ, Morley CP, Kennedy JL, Azevedo MH, Daly MJ, Sklar P (2004) Genomewide scan in Portuguese Island families implicates multiple loci in bipolar disorder: fine mapping adds support on chromosomes 6 and 11. Am J Med Genet B Neuropsychiatr Genet 127:30-34
Radhakrishna U, Senol S, Herken H, Gucuyener K, Gehrig C, Blouin JL, Akarsu NA, Antonarakis SE (2001) An apparently dominant bipolar affective disorder (BPAD) locus on chromosome 20p11.2-q11.2 in a large Turkish pedigree. Eur J Hum Genet 9:39-44
Schulze TG, Buervenich S, Badner JA, Steele CJM, Detra-Wadleigh SD, Dick D, Foroud T, Cox NJ, MacKinnon DF, Potash JB, Berrettini WH, Byerley W, Coryell W, DePaulo JR, Gershon ES, Kelsoe JR, McInnis MG, Murphy DL, Reich T, Scheftner W, Nurnberger JI, McMahon FJ (2004) Loci on chromosomes 6q and 6p interact to increase susceptibility to bipolar affective disorder in the National Institute of Mental Health Genetics Initiative pedigrees. Biol Psychiatry 56: 18-23
Segurado R, Detera-Wadleigh SD, Levinson DF, Lewis CM, Gill M, Nurnberger JI Jr, Craddock N, et al (2003) Genome scan meta-analysis of schizophrenia and bipolar disorder, part III: bipolar disorder. Am J Hum Genet 73:49-62
Simpson SG, McMahon FJ, McInnis MG, MacKinnon DF, Edwin D, Folstein SE, DePaulo JR (2002) Diagnostic reliability of bipolar II disorder. Arch Gen Psychiatry 59:736-740
Smoller JW, Finn CT (2003) Family, twin, and adoption studies of bipolar disorder. Am J Med Genet C Semin Med Genet 123:48-58
Tsuang MT, Faraone SV (2000) The genetic epidemiology of bipolar disorder. In: Marneros A, Angst J (eds) Bipolar disorders: 100 years after manic-depressive insanity. Kluwer Academic, Zurich, pp 231-242
Turecki G, Grof P, Grof E, D'Souza V, Lebuis L, Marineau C, Cavazzoni R, Duffy A, Retard C, Zvolsky P, Robertson C, Brewer C, Hudson TJ, Rouleau GA, Aida M (2001) Mapping susceptibility genes for bipolar disorder: a pharmacogenetic approach based on excellent response to lithium. Mol Psychiatry 6:570-578
Venken T, Claes S, Sluijs S, Paterson D, van Duijn C, Adolfsson R, Del-Favero J, Van Broekhoven C (2005) Genomewide scan for affective disorder susceptibility loci in families of a northern Swedish isolated population. Am J Hum Genet 76:237-248
Weissman M, Bruce M, Leaf PJ, Florio LP, Holzer C (1991) Psychiatric disorders in America. In: Robins L, Regier D (eds) Affective disorders. Free Press, New York, pp 53-1
Weissman MM, Bland RC, Canino GJ, Faravelli C, Greenwald S, Hwu HG, Joyce PR, Karam EG, Lee CK, Lellouch J, Lepine JP, Newman SC, Rubio-Stipec M, Wells JE, Wickramaratne PJ, Wittchen H, Yeh EK (1996) Cross-national epidemiology of major depression and bipolar disorder. JAMA 276:293-299
Whittemore AS, Halpern J (1994) A class of tests for linkage using affected pedigree members. Biometrics 50:118-127
Willour VL, Zandi PP, Huo Y, Diggs TL, Chellis JL, MacKinnon DF, Simpson SG, McMahon FJ, Potash JB, Gershon ES, Reich T, Foroud T, Nurnberger JI Jr, DePaulo JR Jr, McInnis MG (2003) Genome scan of the fifty-six bipolar pedigrees from the NIMH genetics initiative replication sample: chromosomes 4, 7, 9, 1 8, 20 and 21. Am J Med Genet B Neuropsychiatr Genet 121:21-27
Wise LH, Lanchbury JS, Lewis CM (1999) Metaanalysis of genome searches. Ann Hum Genet 63:263-272
Zandi PP, Willour VL, Huo Y, Chellis J, Potash JB, MacKinnon DF, Simpson SG, McMahon FJ, Gershon E, Reich T, Foroud T, Nurnberger J Jr, DePaulo JR Jr, McInnish MG (2003) Genome scan of a second wave of NIMH Genetics Initiative bipolar pedigrees: chromosomes 2, 11, 13, 14 and X. Am J Med Genet B Neuropsychiatr Genet 119:69-76