Abstract
Our previous results pointed to a putative gene for susceptibility to bipolar affective disorder located on the chromosomal region 12q23–q24 that segregated in the Saguenay-Lac-St-Jean population of Quebec. We report here results from a second genome-wide scan based on the analysis of 380 polymorphic microsatellite markers. For the purpose of this analysis, an additional 18 families were recruited from the Saguenay-Lac-St-Jean region and pooled to our previous sample to improve its statistical power, giving a total of 394 sampled individuals. This work confirms the presence of a susceptibility locus for affective disorder on chromosome 12q24 with parametric LOD score value of 3.35 at D12S378 when pedigrees were broken into nuclear families and analysed under a recessive segregation model. This result was supported by neighbouring markers and by a LOD score value of 5.05 at D12S378 under model-free analysis. Other regions of lower interest were indicated on chromosomes 2, 5, 7, 9, 10, 17 and 20.
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References
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 4th edn. American Psychiatric Association: Washington, 1994.
Craddock N, Jones I . Genetics of bipolar disorder. J Med Genet 1999; 36: 585–594.
Suarez BK, Hampe CL, Van Eerdewegh P . Problems of replicating linkage claims in psychiatry. In: Gershon ES, Cloninger CR (eds). Genetic Approaches to Mental Disorders. American Psychiatric Press: Washington, DC, 1994 pp 23–46.
Kruglyak L, Lander ES . High-resolution genetic map** of complex traits. Am J Hum Genet 1995; 56: 1212–1223.
Roberts SB, MacLean CJ, Neale MC, Eaves LJ, Kendler KS . Replication of linkage studies of complex traits: an examination of variation in location estimates. Am J Hum Genet 1999; 65: 876–884.
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 . Support for the possible locus on chromosome 4p16 for bipolar affective disorder. Mol Psychiatry 1998; 3: 442–448.
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.
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.
Als TD, Dahl HA, Flint TJ, Wang AG, Vang M, Mors O et al. Possible evidence for a common risk locus for bipolar affective disorder and schizophrenia on chromosome 4p16 in patients from the Faroe Islands. Mol Psychiatry 2004; 9: 93–98.
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.
Dawson E, Parfitt E, Roberts Q, Daniels J, Lim L, Sham P et al. Linkage studies of bipolar disorder in the region of the Darier's disease gene on chromosome 12q23–24.1. Am J Med Genet 1995; 60: 94–102.
Ewald H, Degn B, Mors O, Kruse TA . Significant linkage between bipolar affective disorder and chromosome 12q24. Psychiatr Genet 1998; 8: 131–140.
Ewald H, Flint T, Kruse TA, Mors O . 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 2002; 7: 734–744.
Ewald H, Kruse TA, Mors O . Genome wide scan using homozygosity map** and linkage analyses of a single pedigree with affective disorder suggests oligogenic inheritance. Am J Med Genet 2003; 120B: 63–71.
Morissette J, Villeneuve A, Bordeleau L, Rochette D, Laberge C, Gagné 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.
Degn B, Lundorf MD, Wang A, Vang M, Mors O, Kruse TA et al. Further evidence for a bipolar risk gene on chromosome 12q24 suggested by investigation of haplotype sharing and allelic association in patients from the Faroe Islands. Mol Psychiatry 2001; 6: 450–455.
Abkevich V, Camp NJ, Hensel CH, Neff CD, Russell DL, Hughes DC et al. Predisposition locus for major depression at chromosome 12q22–12q23.2. Am J Hum Genet 2003; 73: 1271–1281.
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.
Ekholm JM, Kieseppa T, Hiekkalinna T, Partonen T, Paunio T, Perola M et al. Evidence of susceptibility loci on 4q32 and 16p12 for bipolar disorder. Hum Mol Genet 2003; 12: 1907–1915.
Shaw SH, Mroczkowski-Parker Z, Shekhtman T, Alexander M, Remick RA, Sadovnick AD et al. Linkage of a bipolar disorder susceptibility locus to human chromosome 13q32 in a new pedigree series. Mol Psychiatry 2003; 8: 558–564.
Liu C, Badner JA, Christian SL, Guroff JJ, Detera-Wadleigh SD, Gershon ES . Fine map** supports previous linkage evidence for a bipolar disorder susceptibility locus on 13q32. Am J Med Genet 2001; 105: 375–380.
Liu J, Juo SH, Dewan A, Grunn A, Tong X, Brito M et al. Evidence for a putative bipolar disorder locus on 2p13–16 and other potential loci on 4q31, 7q34, 8q13, 9q31, 10q21–24, 13q32, 14q21 and 17q11–12. Mol Psychiatry 2003; 8: 333–342.
Hattori E, Liu C, Badner JA, Bonner TI, Christian SL, Maheshwari M et al. Polymorphisms at the G72/G30 gene locus, on 13q33, are associated with bipolar disorder in two independent pedigree series. Am J Hum Genet 2003; 72: 1131–1140.
Berrettini WH, Ferraro TN, Goldin LR, Weeks DE, Detera-Wadleigh S, Nurnberger Jr 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.
Stine OC, Xu J, 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.
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.
Freimer NB, Reus VI, Escamilla MA, McInnis LA, Spesny M, Leon P et al. Genetic map** using haplotype, association and linkage methods suggests a locus for severe bipolar disorder (BPI) at 18q22–q23. Nat Genet 1996; 12: 436–441.
McMahon FJ, Hopkins PJ, Xu J, 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.
Escamilla MA, McInnis LA, Spesny M, Reus VI, Service SK, Shimayoshi N et al. Assessing the feasibility of linkage disequilibrium methods for map** complex traits: an initial screen for bipolar disorder loci on chromosome 18. Am J Hum Genet 1999; 64: 1670–1678.
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.
Detera-Wadleigh SD, Badner JA, Goldin LR, Berrettini WH, Sanders AR, Rollins DY et al. Affected-sib-pair analyses reveal support of prior evidence for a susceptibility locus for bipolar disorder, on 21q. Am J Hum Genet 1996; 58: 1279–1285.
Detera-Wadleigh SD, Badner JA, Yoshikawa T, Sanders AR, Goldin LR, Turner G et al. Initial genome scan of the NIMH genetics initiative bipolar pedigrees: chromosomes 4, 7, 9, 18, 19, 20, and 21q. Am J Med Genet 1997; 74: 254–262.
Smyth C, Kalsi G, Curtis D, Brynjolfsson J, O'Neill J, Rifkin L et al. Two-locus admixture linkage analysis of bipolar and unipolar affective disorder supports the presence of susceptibility loci on chromosomes 11p15 and 21q22. Genomics 1997; 39: 271–278.
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.
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.
Escamilla MA . Population isolates: their special value for locating genes for bipolar disorder. Bipolar Disord 2001; 3: 299–317.
Shink E, Morissette J, Barden N . Genetic heterogeneity in a very large bipolar affective disorder pedigree from Quebec. Am J Med Genet 2003; 119B: 65–68.
Spitzer RL, Williams JBW, Gibbon M . Structured Clinical Interview for DSM-III-R. Biometrics Research, New York State Psychiatric Institute: New York, 1987.
Hall J, LeDuc C, Watson A, Roter A . An approach to high-throughput genoty**. Genome Res 1996; 6: 781–790.
O'Connell JR, Weeks DE . PedCheck: a program for identification of genotype incompatibilities in linkage analysis. Am J Hum Genet 1998; 63: 259–266.
Cottingham RW, Idury RM, Schaeffer AA . Faster sequential genetic linkage computations. Am J Hum Genet 1993; 53: 252–263.
Schaffer AA, Gupta SK, Shriram K, Cottingham RW . Avoiding recomputation in linkage analysis. Hum Hered 1994; 44: 225–237.
O'Connell JR, Weeks DE . The VITESSE algorithm for rapid exact multilocus linkage analysis via genotype set-recording and fuzzy inheritance. Nat Genet 1995; 11: 402–408.
Terwilliger J, Ott J . Handbook of Human Genetic Linkage. The Johns Hopkins University Press: Baltimore and London, 1994.
Durner M, Greenberg DA, Hodge SE . Inter- and intrafamilial heterogeneity: effective sampling strategies and comparison of analysis methods. Am J Hum Genet 1992; 51: 859–870.
Durner M, Vieland VJ, Greenberg DA . Further evidence for the increased power of LOD scores compared with nonparametric methods. Am J Hum Genet 1999; 64: 281–289.
Hauser ER, Boehnke M, Guo SW, Risch N . Affected-sib-pair interval map** and exclusion for complex genetic traits: sampling considerations. Genet Epidemiol 1996; 13: 117–137.
Weeks DE, Ott J, Lathrop GM . SLINK: a general simulation program for linkage analysis. Am J Hum Genet 1990; 47: A204.
Lander ES, Kruglyak L . Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nat Genet 1995; 11: 241–247.
Terwilliger JD, Shannon WD, Lathrop GM, Nolan JP, Goldin LR, Chase GA et al. True and false positive peaks in genomewide scans: applications of length-biased sampling to linkage map**. Am J Hum Genet 1997; 61: 430–438.
Knapp M . Discriminating between true and false-positive peaks in a genomewide linkage scan, by use of the peak length. Am J Hum Genet 1998; 62: 1561–1562.
Monk S, Sakuntabhai A, Carter SA, Bryce SD, Cox R, Harrington L et al. Refined genetic map** of the darier locus to a 1-cM region of chromosome 12q24.1, and construction of a complete, high-resolution P1 artificial chromosome/bacterial artificial chromosome contig of the critical region. Am J Hum Genet 1998; 62: 890–903.
Sakuntabhai A, Ruiz-Perez V, Carter S, Jacobsen N, Burge S, Monk S et al. Mutations in ATP2A2, encoding a Ca2+ pump, cause Darier disease. Nat Genet 1999; 21: 271–277.
Jacobsen NJ, Franks EK, Elvidge G, Jones I, McCandless F, O'Donovan MC et al. Exclusion of the Darier's disease gene, ATP2A2, as a common susceptibility gene for bipolar disorder. Mol Psychiatry 2001; 6: 92–97.
Dawson E, Gill M, Curtis D, Castle D, Hunt N, Murray R et al. Genetic association between alleles of pancreatic phospholipase A2 gene and bipolar affective disorder. Psychiatr Genet 1995; 5: 177–180.
Jacobsen N, Daniels J, Moorhead S, Harrison D, Feldman E, McGuffin P et al. Association study of bipolar disorder at the phospholipase A2 gene (PLA2A) in the Darier's disease (DAR) region of chromosome 12q23–q24.1. Psychiatr Genet 1996; 6: 195–199.
Harvey M, Shink E, Tremblay M, Gagné B, Raymond C, Labbé M et al. Support for the involvement of the TPH2 gene in affective disorders. Mol Psychiatry 2004, July 20 [E-pub ahead of print]. DOI number PMID: 15263906.
Zill P, Baghai TC, Zwanzger P, Schule C, Eser D, Rupprecht R et al. SNP and haplotype analysis of a novel tryptophan hydroxylase isoform (TPH2) gene provide evidence for association with major depression. Mol Psychiatry 2004, May 4 [E-pub ahead of print]. DOI number PMID: 15124006.
Andrew M, Owen MJ . Hyperekplexia: abnormal startle response due to glycine receptor mutations. Br J Psychiatry 1997; 170: 106–108.
Edenberg HJ, Foroud T, Conneally PM, Sorbel JJ, Carr K, Crose C et al. Initial genomic scan of the NIMH genetics initiative bipolar pedigrees: chromosomes 3, 5, 15, 16, 17, and 22. Am J Med Genet 1997; 74: 238–246.
Garner C, McInnes LA, Service SK, Spesny M, Fournier E, Leon P et al. Linkage analysis of a complex pedigree with severe bipolar disorder, using a Markov chain Monte Carlo method. Am J Hum Genet 2001; 68: 1061–1064.
Anguelova M, Benkelfat C, Turecki G . A systematic review of association studies investigating genes coding for serotonin receptors and the serotonin transporter: I. Affective disorders. Mol Psychiatry 2003; 8: 574–591.
Goldin LR, Chase GA . Improvement of the power to detect complex disease genes by regional inference procedures. Genet Epidemiol 1997; 14: 785–789.
Goldin LR, Chase GA, Wilson AF . Regional inference with averaged P values increases the power to detect linkage. Genet Epidemiol 1999; 17: 157–164.
Yang X, Goldstein AM, Chase GA, Gastwirth JL, Goldin LR . Use of weighted P-values in regional inference procedures. Genet Epidemiol 2001; 21: S484–S489.
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.
Acknowledgements
We thank all patients and families for participating in the study. This work was supported in part by the Canadian Institutes of Health Research and Axys Pharmaceuticals Inc.
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Shink, E., Morissette, J., Sherrington, R. et al. A genome-wide scan points to a susceptibility locus for bipolar disorder on chromosome 12. Mol Psychiatry 10, 545–552 (2005). https://doi.org/10.1038/sj.mp.4001601
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DOI: https://doi.org/10.1038/sj.mp.4001601
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