Abstract
Evidence from epidemiological studies and segregation analysis suggests oligo- or polygenic inheritance in schizophrenia. Since model independent methods are thought to be most appropriate for linkage analysis in complex disorders, we performed a genome-wide autosomal screen in 71 families from Germany and Israel containing 86 independent affected sib-pairs with parental genotype information for statistical analysis strictly identity by descent. We genotyped 305 individuals with 463 markers at an average distance of approximately 10 cM genome-wide, and 1–2 cM in candidate regions (5q, 6p, q, 8p, 10p, 18p, 22q). The highest multipoint LOD scores (ASPEX) were obtained on 6p (D6S260, LOD = 2.0; D6S274, LOD = 2.2, MHC region, LOD = 2.15) and on 10p (D10S1714, LOD = 2.1), followed by 5q (D5S2066, LOD = 1.36), 6q (D6S271, LOD = 1.12; D6S1613, LOD = 1.11), 1q (D1S2675, LOD = 1.04), and 18p (broad disease model: D18S1116, LOD = 1.0). One hundred and thirty-three additional family members were available for some of the families (extended families) and were genotyped for these regions. GENEHUNTER produced a maximum NPL of 3.3 (P = 0.001) for the MHC region and NPL of 3.13 (P = 0.0015) for the region on 10p. There is support for these regions by independent groups. In genome-wide TDT analysis (sTDT, implemented in ASPEX), no marker passed the significance level of 0.0001 given by multiple testing, but nominal significance values for D10S211 (P = 0.03) and for GOLF (P = 0.0032) support further the linkage results on 10p and 18p. Our survey of 22 chromosomes identified candidate regions which should be useful to screen for schizophrenia susceptibility genes.
Similar content being viewed by others
References
Gottesman II . Schizophrenia Genesis: The Origin of Madness WH Freeman: New York 1991
Penrose LS . The general purpose sib-pair linkage test Ann Eugenics 1953; 18: 120
Risch N . Linkage strategies for genetically complex traits. I. Multilocus models Am J Hum Genet 1990; 46: 229–241
Knapp M, Seuchter SA, Baur MP . Linkage analysis in nuclear families, 1: optimality criteria for affected sib-pair tests Hum Hered 1994; 44: 37–43
Knapp M, Seuchter SA, Baur MP . Linkage analysis in nuclear families, 2: relationship between affected sib-pair tests and LOD score analysis Hum Hered 1994; 44: 44–51
Suarez BK, Van Eerdewegh P . A comparison of three affected sib-pair scoring methods to detect HLA-linked disease susceptibility genes Am J Genet 1984; 18: 135–146
Lander ES, Schork NJ . Genetic dissection of complex traits Science 1994; 265: 2037–2048
Brzustowicz LM, Hodgkinson KA, Chow EWC, Honer WG, Bassett AS . Location of a major susceptibility locus for familial schizophrenia on chromosome 1q21–q22 Science 2000; 288: 678–682
Straub RE, MacLean CJ, O'Neill FA, Walsh D, Kendler KS . Support for a possible schizophrenia vulnerability locus in region 5q22–31 in Irish families Mol Psychiatry 1997; 2: 148–155
Schwab SG, Eckstein GN, Hallmayer J, Lerer B, Albus M, Borrmann et al. Evidence suggestive of a locus on chromosome 5q31 contributing to susceptibility for schizophrenia in German and Israeli families by multipoint affected sib-pair linkage analysis Mol Psychiatry 1997; 2: 156–160
Straub RE, MacLean CJ, O'Neill FA, Burke J, Murphy B, Duke F et al. A potential vulnerability locus for schizophrenia on chromosome 6p24–22: evidence for genetic heterogeneity Nat Genet 1995; 11: 287–293
Schwab SG, Albus M, Hallmayer J, Hönig S, Borrmann M, Lichtermann D et al. Evaluation of a susceptibility gene for schizophrenia on chromosome 6p by multipoint affected sib-pair linkage analysis Nat Genet 1995; 11: 325–327
Moises HW, Yang L, Kristbjarnarson H, Wiese C, Byerley W, Macciardi F et al. An international two-stage genome-wide search for schizophrenia susceptibility genes Nat Genet 1995; 11: 321–324
Turecki G, Rouleau GA, Joobe R, Mari J, Morgan K . Schizophrenia and chromosome 6p Am J Med Genet 1997; 74: 195–198
Cao Q, Martinez M, Zhang J, Sanders AR, Badner JA, Cravchik A et al. Suggestive evidence for a schizophrenia susceptibility locus on chromosome 6q and a confirmation in an independent series of pedigrees Genomics 1997; 43: 1–8
Martinez M, Goldin, LR, Cao Q, Zhang J, Sanders AR, Nancarrow DJ et al. Follow-up study on a susceptibility locus for schizophrenia on chromosome 6q Am J Med Genet 1999; 88: 337–343
Ekelund J, Lichtermann D, Hovatta I, 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
Pulver AE, Lasseter VK, Kasch L, Wolyniec P, Nestadt G, Blouin JL et al. Schizophrenia: a genome scan targets chromosomes 3p and 8p as potential sites of susceptibility genes Am J Med Genet 1995; 60: 252–260
Kendler KS, MacLean CJ, O'Neill FA, Burke J, Murphy B, Duke F et al. Evidence for a schizophrenia vulnerability locus on chromosome 8p in the Irish Study of High-Density Schizophrenia Families Am J Psychiatry 1996; 153: 1534–1540
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
Straub RE, MacLean CJ, Martin RB, Ma Y, 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
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
Lin MW, Curtis D, Williams N, Arranz M, Nanko S, Collier D et al. Suggestive evidence for linkage of schizophrenia to markers on chromosome 13q14.1–q32 Psychiatr Genet 1995; 5: 117–126
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
Brzustowicz LM, Honer WG, Chow EW, Little D, Hogan J, Hodgkinson K et al. Linkage of familial schizophrenia to chromosome 13q32 Am J Hum Genet 1999; 65: 1096–1103
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
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
Pulver AE, Karayiorgou M, Wolyniec PS, Lasseter VK, Kasch L, Nestadt G et al. Sequential strategy to identify a susceptibility gene for schizophrenia: report of potential linkage on chromosome 22q12-q13.1: Part 1 Am J Med Genet 1994; 54: 36–43
Polymeropoulos MH, Coon H, Byerley W, Gershon ES, Goldin L, Crow TJ et al. Search for schizophrenia susceptibility locus on human chromosome 22 Am J Med Genet 1994; 54: 93–99
Schizophrenia Collaborative Linkage Group for Chromosome 22 . A transmission disequilibrium and linkage analysis of D22S278 marker alleles in 574 families: further support for a susceptibility locus for schizophrenia at 22q12 Schizophr Res 1998; 32: 115–121
Coon H, Jensen S, Holik J, Hoff M, Myles-Worsley M, Reimherr F et al. Genomic scan for genes predisposing to schizophrenia Am J Med Genet 1994; 54: 59–71
Coon H, Myles-Worsley M, Tiobech J, Hoff M, Rosenthal J, Bennett P et al. Evidence for a chromosome 2p13–14 schizophrenia susceptibility locus in families from Palau, Micronesia Mol Psychiatry 1998; 3: 521–527
Levinson DF, Mahtani MM, Nancarrow DJ, Brown DM, Kruglyak L, Kirby A et al. Genome scan of schizophrenia Am J Psychiatry 1998; 155: 741–750
Shaw SH, Kelly M, Smith AB, Shields G, Hopkins PJ, Loftus J et al. A genome-wide search for schizophrenia susceptibility genes Am J Med Genet 1998; 81: 364–376
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
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
Lander ES, Kruglyak L . Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results Nature Genet 1995; 11: 241–247
Spitzer RL, Endicott J, Robins E . Research Diagnostic Criteria for a Selected Group of Functional Disorders New York State Psychiatric Institute: New York 1978
Fyer A, Endicott J, Mannuzza S, Klein, DF . Schedule for Affective Disorders and Schizophrenia-Lifetime Version (SADS-LA) New York State Psychiatric Institute: New York 1985
Spitzer RL, Williams JB . Structured Clinical Interview for DSM-III Diagnoses-Personality Disorders New York State Psychiatric Institute: New York 1985
McGuffin P, Farmer AE, Harvey I . A polydiagnostic application of operational criteria in studies of psychotic illness: development and reliability of the OPCRIT system Arch Gen Psychiatry 1991; 48: 764–770
Leckman JF, Sholomskas D, Thompson D, Belanger A, Weissmann MM . Best estimate of lifetime psychiatric diagnosis Arch Gen Psychiatry 1982; 39: 879–883
Gershon ES, Hamovit J, Guroff JJ, Dibble E, Leckman JF, Sceery W et al. A family study of schizoaffective, bipolar I, bipolar II, unipolar, and normal control probands Arch Gen Psychiatry 1982; 39: 1157–1167
Maier W, Lichtermann D, Minges J, Hallmayer J, Heun R, Benkert O et al. Continuity and discontinuity of affective disorders and schizophrenia: results of a controlled family study Arch Gen Psychiatry 1993; 50: 871–883
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
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
Risch N, Spiker D, Lotspeich L, Nouri N, Hinds D, Hallmayer J et al. A genomic screen of autism: evidence for a multilocus etiology Am J Hum Genet 1999; 65: 493–507
Nimgaonkar VL, Rudert WA, Zhang XR, Tsoi WF, Trucco M, Saha N . Further evidence for an association between schizophrenia and the HLA DQB1 gene locus Schizophr Res 1995; 18: 43–49
Wright P, Donaldson PT, Underhill JA, Choudhuri K, Doherty DG, Murray RM . Genetic association of the HLA DRB1 gene locus on chromosome 6p21.3 with schizophrenia Am J Psychiatry 1996; 153: 1530–1533
Blackwood DH, Muir WJ, Stephenson A, Wentzel J, Ad'hiah A, Walker et al. Reduced expression of HLA-B35 in schizophrenia Psychiatr Genet 1996; 6: 51–59
Foroud T, Castelluccio PF, Koller DL, Edenberg HJ, Miller M, Bowman E et al. Suggestive evidence of a locus on chromosome 10p using the NIMH genetics initiative bipolar affective disorder pedigrees Am J Med Genet 2000; 96: 18–23
Zubenko GS, Hughes HB, Stiffler JS, Hurtt MR, Kaplan BB . A genome survey for novel Alzheimer disease risk loci: results at 10 cM resolution Genomics 1998; 50: 121–128
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
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
Schwab SG, Wildenauer DB . Chromosome 22 workshop report Am J Med Genet 1999; 88: 276–278
Pulver AE, Nestadt G, Goldberg R, Shprintzen RJ, Lamacz M, Wolyniec PS et al. Psychotic illness in patients diagnosed with velo-cardio-facial syndrome and their relatives J Nerv Ment Dis 1994; 182: 476–478
Chow EW, Bassett AS, Weksberg R . Velo-cardio-facial syndrome and psychotic disorders: implications for psychiatric genetics Am J Med Genet 1994; 54: 107–112
Hauser ER, Boehnke M, Guo SW, Risch N . Affected sib-pair interval mapping and exclusion for complex genetic traits: sampling considerations Genet Epidemiol 1996; 13: 117–137
Sham PC, Lin MW, Zhao JH, Curtis D . Power comparison of parametric and nonparametric linkage tests in small pedigrees Am J Hum Genet 2000; 66: 1661–1668
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
Wildenauer DB, Schwab SG, Maier W, Detera-Wadleigh SD . Do schizophrenia and affective disorder share susceptibility genes? Schizophr Res 1999; 39: 107–111
Wang S, Sun CE, Walczak CA, Ziegle JS, Kipps BR, Goldin LR, Diehl SR . Evidence for a susceptibility locus for schizophrenia on chromosome 6pter-p22 Nat Genet 1995; 10: 41–46
Antonarakis SE, Blouin JL, Pulver AE, Wolyniec P, Lasseter VK, Nestadt G et al. Schizophrenia susceptibility and chromosome 6p24–22 Nat Genet 1995; 11: 235–236
Schizophrenia Collaborative Linkage Group for Chromosomes 3, 6 and 8 . Support for schizophrenia linkage findings on chromosomes 6 and 8: a multicenter study Am J Med Genet 1996; 67: 580–594
Lindholm E, Ekholm B, Balciuniene J, Johansson G ., Castensson A, Koisti, M et al. Linkage analysis of a large Swedish kindred provides further support for a susceptibility locus for schizophrenia on chromosome 6p23 Am J Med Genet 1999; 88: 369–377
Hwu HG, Lin MW, Lee PC, Lee SF, Ou-Yang WC, Liu CM . Evaluation of linkage of markers on chromosome 6p with schizophrenia in Taiwanese families Am J Med Genet 2000; 96: 74–78
Acknowledgements
We wish to express our gratitude to all patients and their family members—without their cooperation this work would not have been possible. We thank Dirk Granath for preparing the Web site. The work has been supported by grants from the Deutsche Forschungsgemeinschaft, Schwerpunktsprogramm ‘Psychiatrische Genetik’ (to MA, WM, DBW), Sonderforschungsbereich 400 (WM, MR, DBW), and from the German–Israeli Foundation for Scientific Research (to BL and DBW).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Schwab, S., Hallmayer, J., Albus, M. et al. A genome-wide autosomal screen for schizophrenia susceptibility loci in 71 families with affected siblings: support for loci on chromosome 10p and 6. Mol Psychiatry 5, 638–649 (2000). https://doi.org/10.1038/sj.mp.4000791
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.mp.4000791
- Springer Nature Limited
Keywords
This article is cited by
-
Interleukin-1 receptor antagonist (IL-1RA) and interleukin-4 (IL-4) variable number of tandem repeat polymorphisms in schizophrenia and bipolar disorder: an association study in Turkish population
Egyptian Journal of Medical Human Genetics (2022)
-
Genetic polymorphisms of PIP5K2A and course of schizophrenia
BMC Medical Genetics (2020)
-
Molecular Variants in Human Trace Amine-Associated Receptors and Their Implications in Mental and Metabolic Disorders
Cellular and Molecular Neurobiology (2020)
-
Pro-inflammatory cytokines and their epistatic interactions in genetic susceptibility to schizophrenia
Journal of Neuroinflammation (2016)
-
An Update on the Epidemiology of Schizophrenia with a Special Reference to Clinically Important Risk Factors
International Journal of Mental Health and Addiction (2011)