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A Genome-Wide Scan for Linkage to Chromosomal Regions in 382 Sibling Pairs with Schizophrenia or Schizoaffective Disorder

DeLisi, Prof LE and Shaw, Dr SH and Crow, Prof TJ and Shields, Dr G and Smith, Ms AB and Larach, Dr VW and Wellman, Mr N and Loftus, Dr J and Nanthakumar, Dr B and Razi, Dr K and Stewart, Mr J and Comazzi, Dr M and Vita, Dr A and Heffner, Dr T and Sherrington, Dr R (2002) A Genome-Wide Scan for Linkage to Chromosomal Regions in 382 Sibling Pairs with Schizophrenia or Schizoaffective Disorder. [Journal (Paginated)]

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Abstract

OBJECTIVE: Some genome-wide scans and association studies for schizophrenia susceptibility genes have yielded significant positive findings, but there is disagreement between studies on their locations, and no mutation has yet been found in any gene. Since schizophrenia is a complex disorder, a study with sufficient power to detect a locus with a small or moderate gene effect is necessary. METHOD: In a genome-wide scan of 382 sibling pairs with a diagnosis of schizophrenia or schizoaffective disorder, 396 highly polymorphic markers spaced approximately 10 centimorgans apart throughout the genome were genotyped in all individuals. Multipoint nonparametric linkage analysis was performed to evaluate regions of the genome demonstrating increased allele sharing, as measured by a lod score. RESULTS: Two regions with multipoint maximum lod scores suggesting linkage were found. The highest lod scores occurred on chromosome 10p15-p13 (peak lod score of 3.60 at marker D10S189) and the centromeric region of chromosome 2 (peak lod score of 2.99 at marker D2S139). In addition, a maximum lod score of 2.00 was observed with marker D22S283 on chromosome 22q12, which showed evidence of an imprinting effect, whereby an excess sharing of maternal, but not paternal, alleles was present. No evidence of linkage was obtained at several locations identified in previous studies, including chromosomes 1q, 4p, 5p-q, 6p, 8p, 13q, 15p, and 18p. CONCLUSIONS: The findings of this large genome-wide scan emphasize the weakness and fragility of linkage reports on schizophrenia. No linkage appears to be consistently replicable across large studies. Thus, it has to be questioned whether the genetic contribution to this disorder is detectable by these strategies and the possibility raised that it may be epigenetic, i.e., related to gene expression rather than sequence variation. Nevertheless, the positive findings on chromosome 2, 10, and 22 should be pursued further.

Item Type:Journal (Paginated)
Subjects:Neuroscience > Neurogenetics
ID Code:3880
Deposited By:Crow, Prof Tim
Deposited On:04 Dec 2004
Last Modified:11 Mar 2011 08:55

References in Article

Select the SEEK icon to attempt to find the referenced article. If it does not appear to be in cogprints you will be forwarded to the paracite service. Poorly formated references will probably not work.

Gottesman II, Shields J: Schizophrenia: The Epigenetic Puzzle, Cambridge, UK, Cambridge University Press, 1982

Sherrington R, Brynjolfsson J, Petursson H, Potter M, Dudleston K, Barraclough B, Wasmuth J, Dobbs M, Gurling H: Localization of a susceptibility locus for schizophrenia on chromosome 5. Nature 1988; 336:164-167[Medline]

Pulver AE, Karayiorgou M, Wolyniec PS, Lasseter V, Kasch L, Nestadt G, Antonarakis S, Housman D, Kazazian HH, Meyers D, Ott J, Lamacz M, Liang K-Y, Hanfelt J, Ulrich G, DeMarchi N, Ranu E, McHugh PR, Adler L, Thomas M, Carpenter WT, Manschreck T, Gordon CT, Kimberland M, Babb R, Puck J, Childs B: Sequential strategy to identify a susceptibility gene for schizophrenia: report of a potential linkage on chromosome 22q12-q12.1, part I. Am J Med Genet 1994; 54:36-43[Medline]

Pulver AE, Lasseter VK, Kasch L, Wolyniec P, Nestadt G, Blouin JL, Kimberland M, Babb R, Vourlis S, Chen H, Lalioti M, Morris MA, Karayiorgou M, Ott J, Meyers D, Antonarakis SE, Housman D, Kazazian HH: Schizophrenia: a genome scan targets chromosome 3p and 8p as potential sites of susceptibility genes. Am J Med Genet 1995; 60:252-260[Medline]

Blouin J-L, Dombroski BA, Nath SK, Lasseter VK, Wolyniec PS, Nestadt G, Thornquist M, Ullrich G, McGrath J, Kasch L, Lamacz M, Thomas MG, Gerrig C, Radhakrishna U, Snyder SC, Balk KG, Neufeld K, Swartz KL, DeMarchi N, Papadimitriou GN, Dikeus DG, Stefanis CN, Chakravarti A, Childs B, Pulver AE: Schizophrenia susceptibility loci on chromosome 13q32 and 8p21. Nat Genet 1998; 20:70-73[CrossRef][Medline]

Brzustowicz LM, Honer WG, Chow EW, Little D, Hogan J, Hodfkinson K, Bassett AS: Linkage of familial schizophrenia to chromosome 13q32. Am J Hum Genet 1999; 65:1096-1103[CrossRef][Medline]

Brzustowicz LM, Hodgkinson KA, Chow EW, Honer WG, Bassell AS: Location of a major susceptibility locus for familial schizophrenia on chromosome 1q21-q22. Science 2000; 288:678-682[Abstract/Free Full Text]

Straub RE, MacLean CJ, Walsh D, Kendler KS: Support for schizophrenia vulnerability loci on chromosomes 6p and 8p from Irish families. Cold Spring Harbor Symp Quant Biol 1996; 61:823-833[Medline]

Straub RE, MacLean CJ, Martin RB, Ma Y, Myakishev MV, Harris-Kerr C, Webb BT, O’Neill FA, Walsh D, Kendler KS: A schizophrenia locus may be located in region 10p15-p11. Am J Med Genet 1998; 81:296-301[CrossRef][Medline]

Schizophrenia Collaborative Linkage Group for Chromosomes 3, 6, and 8: Additional support for schizophrenia linkage findings on chromosomes 6 and 8: a multicenter study. Am J Med Genet 1996; 67:580-594[CrossRef][Medline]

DeLisi LE: A critical overview of recent investigations into the genetics of schizophrenia. Curr Opin Psychiatry 1999; 12:29-39[CrossRef]

DeLisi LE, Crow TJ: Chromosome Workshops 1998: current state of psychiatric linkage. Am J Med Genet 1999; 88:215-218[CrossRef][Medline]

DeLisi LE, Craddock NJ, Detera-Wadleigh S, Foroud T, Gejman P, Kennedy JL, Lendon C, Macciardi F, McKeon P, Mynett-Johnson L, Nurnberger JI Jr, Paterson A, Schwab S, Van Broeckhoven C, Wildenauer D, Crow TJ: Update on chromosomal locations for psychiatric disorders: report of the interim meeting of chromosome workshop chairpersons from the VIIth World Congress of Psychiatric Genetics, Monterey, California, October 14-18, 1999. Am J Med Genet 2000; 96:434-449[CrossRef][Medline]

Gurling HMD, Kalsi G, Blaveri E, McQuillin A, Read T, Murphy P, Butler R, Brynjolfsson J, Sigmundsson T, Petursson H, Curtis D: Initial genome wide parametric genetic linkage analysis of schizophrenia and schizophrenia spectrum disorders finds lod scores above 3.00 on four chromosomes at 1q22-23, 5q22-35, 8p21-23 and 11q14-24: a further lod above 3.00 at 4q21-31 was found within a single family (abstract). Mol Psychiatry 1999; 4(suppl 1):S4

Ekelund J, Lichtermann D, Hovatta I, Ellonen P, Suvisaari J, Terwilliger JD, Juvonen H, Varilo T, Arajarvi R, Kokko-Sahin ML, Lonnqvist J, Peltonen L: Genome-wide scan for schizophrenia in the Finnish population: evidence for a locus on chromosome 7q22. Hum Mol Genet 2000; 9:1049-1057[Abstract/Free Full Text]

Shaw SH, Kelly M, Smith AB, Shields G, Hopkins PJ, Loftus J, Laval SH, Vita A, De Hert M, Cardon LR, Crow TJ, Sherrington R, DeLisi LE: A genome-wide screen for linkage to schizophrenia. Am J Med Genet 1998; 81:364-376[CrossRef][Medline]

DeLisi LE, Shaw S, Crow TJ, Shields G, Smith AB, Larach VW, Wellman N, Loftus J, Nathankumar B, Razi K, Kushner M, Stewart J, Vita A, Comazzi M, Sherrington R: Lack of evidence for linkage to chromosomes 13 and 8 for schizophrenia and schizoaffective disorder. Am J Med Genet 2000; 96:235-239[CrossRef][Medline]

DeLisi LE, Shaw S, Sherrington R, Nanthakumar B, Shields G, Smith AB, Wellman N, Larach VW, Loftus J, Razi K, Stewart J, Comazzi M, Vita A, De Hert M, Crow TJ: Failure to establish linkage on the X chromosome in 301 families with schizophrenia or schizoaffective disorder. Am J Med Genet 2000; 96:335-341[CrossRef][Medline]

Lander E, Kruglyak L: Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nat Genet 1995; 11:241-247[Medline]

DeLisi LE, Devoto M, Lofthouse R, Poulter M, Smith A, Shields G, Bass N, Chen G, Vita A, Morganti C, Ott J, Crow TJ: Search for linkage to schizophrenia on the X and Y chromosomes. Am J Med Genet 1994; 54:113-121[Medline]

Garner C, Kelly M, Cardon L, Joslyn G, Carey A, LeDuc C, Lichter J, Harris T, Loftus J, Shields G, Comazzi M, Vita A, Smith AM, Dann J, Crow TJ, DeLisi LE: Linkage analyses of schizophrenia to chromosome 6p24-p22: an attempt to replicate. Am J Med Genet 1996; 67:595-610[CrossRef][Medline]

Crow TJ, DeLisi LE, Johnstone EC: Concordance by sex for psychosis is paternally inherited: evidence for a pseudoautosomal locus. Br J Psychiatry 1989; 155:92-97[Abstract]

Spitzer RL, Endicott J: Schedule for Affective Disorders and Schizophrenia (SADS), 3rd ed. New York, New York State Psychiatric Institute, Biometrics Research, 1978

Pfohl B, Blum N, Zimmerman M, Stangl D: Structured Interview for DSM-III-R Personality, Revised (SIDP-R). Iowa City, University of Iowa College of Medicine, Department of Psychiatry, 1989

Nurnberger JI Jr, Blehar MC, Kaufmann CA, York-Cooler C, Simpson SG, Harkavy-Friedman J, Severe JB, Malaspina D, Reich T (NIMH Genetics Initiative): Diagnostic Interview for Genetic Studies: rationale, unique features, and training. Arch Gen Psychiatry 1994; 51:849-859[Abstract]

DeLisi LE: Depression in Schizophrenia. Washington, DC, American Psychiatric Press, 1992

Hall JM, Le Duc CA, Watson AR, Roter AH: An approach to high-throughput genotyping. Genome Res 1996; 6:781-790[CrossRef][Medline]

Risch N: Linkage strategies for genetically complex traits, II: the power of affected relative pairs. Am J Hum Genet 1990; 46:229-241[Medline]

Kruglyak L, Daly MJ, Lander ES: Complete multipoint sib-pair analysis of qualitative and quantitative traits. Am J Hum Genet 1995; 57:439-454[Medline]

Hinds DA, Risch N: The ASPEX package: affected sib-pair exclusion mapping. http://bioweb.pasteur.fr/docs/aspex/usage.html

Lathrop GM, Lalouel JM, Julier C, Ott J: Strategies for multilocus linkage analysis in humans. Proc Natl Acad Sci USA 1984; 81:3443-3446[Medline]

Cottingham R, Idury R, Schaffer A: Faster sequential genetic linkage computations. Am J Hum Genet 1993; 53:252-263[Medline]

Kruglyak L, Daly MJ, Reeve-Daly MP, Lander ES: Parametric and non-parametric linkage analysis: a unified multipoint approach. Am J Hum Genet 1996; 58:1347-1363[Medline]

Vallada HP, Collier DA: Genetics of schizophrenia—new findings, in Search for the Causes of Schizophrenia, vol IV: Balance of the Century. Edited by Gattaz WF, Hafner H. Berlin, Springer-Verlag, 1999, pp 181-189

Schwab SG, Hallmayer J, Albus M, Lerer B, Hanses C, Kanyas K, Segman R, Borrman M, Dreikorn B, Lichtermann D, Rietschel M, Trixler M, Maier W, Wildenauer DB: 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[CrossRef][Medline]

Faraone SV, Matise T, Svrakic D, Pepple J, Malaspina D, Suarez B, Hampe C, Zambuto CT, Schmitt K, Meyer J, Markel P, Lee H, Harkavy Friedman J, Kaufmann C, Cloninger CR, Tsuang MT: Genome scan of European-American schizophrenia pedigrees: results of the NIMH Genetics Initiative and Millenium Consortium. Am J Med Genet 1998; 81:290-295[CrossRef][Medline]

Schwab SG, Eckstein GN, Gable S, Halmeyer J, Lerer B, Albus M, Maier W, Wildenauer DB: Susceptibility locus for schizophrenia on 10p: searching for a candidate (abstract). Am J Med Genet 2000; 96:461[CrossRef]

Moises HW, Yang L, Kristbjarnarson H, Wiese C, Byerley W, Macciardi F, Arolt V, Blackwood D, Liu X, Sjorgen B, Ashaueer HN, Hwu H-G, Jang K, Livesley WJ, Kennedy JL, Zoega T, Ivarsson O, Bui M-T, Yu M-H, Havsteen B, Commenges D, Weissenbach J, Schwinger E, Gottesman II, Pakstis AJ, Wetterberg L, Kidd KK, Helgason T: An international two-stage genome-wide search for schizophrenia susceptibility genes. Nat Genet 1995; 11:321-324[Medline]

Coon H, Myles-Worsley M, Tiobech J, Hoff M, Rosenthal J, Bennett P, Reimherr F, Wender P, Dale P, Polloi A, Byerley W: Evidence for a chromosome 2p13-14 schizophrenia susceptibility locus in families from Palau, Micronesia. Mol Psychiatry 1998; 3:521-527[CrossRef][Medline]

Williams NM, Rees MI, Holmans P, Norton N, Cardno AG, Jones LA, Murphy KC, Sanders RD, McCarthy G, Gray MY, Fenton I, McGuffin P, Owen MJ: A two-stage sib-pair genome scan of schizophrenia susceptibility genes in 196 affected sibling pairs. Hum Mol Genet 1999; 8:1729-1740[Abstract/Free Full Text]

Kaufmann CA, Suarez B, Malaspina D, Pepple J, Svrakic D, Markel PD, Meyer J, Zambuto CT, Schmitt K, Matise TC, Harkavy Friedman JM, Hampe C, Lee H, Shore D, Wynne D, Faraone SV, Tsuang MT, Cloninger CR: NIMH Genetics Initiative Millennium Schizophrenia Consortium: linkage analysis of African-American pedigrees. Am J Med Genet 1998; 81:282-289[CrossRef][Medline]

Levinson DF, Mahtani MM, Nancarrow DJ, Brown DM, Kruglyak L, Kirby A, Hayward NK, Crowe RR, Andreasen NC, Black DW, Silverman JM, Endicott J, Sharpe L, Mohs RC, Siever LJ, Walters MK, Lennon DP, Jones HL, Nertney DA, Daly MJ, Gladis M, Mowry BJ: Genome scan of schizophrenia. Am J Psychiatry 1998; 155:741-750[Abstract/Free Full Text]

Murphy KC, Jones LA, Owen MJ: High rates of schizophrenia in adults with velo-cardio-facial syndrome. Arch Gen Psychiatry 1999; 56:940-945[Abstract/Free Full Text]

Karayiorgou M, Morris MA, Morrow B, Shprintzen RJ, Goldberg R, Borrow J, Gos A, Nestadt G, Wolyniec PS, Lasseter VK, Pulver AE: Schizophrenia susceptibility associated with interstitial deletions of chromosome 22q11. Proc Natl Acad Sci USA 1995; 92:7612-7616[Abstract]

Bassett AS, Chow EW: 22q11 deletion syndrome: a genetic subtype of schizophrenia. Biol Psychiatry 1999; 46:882-891[CrossRef][Medline]

Gill M, Vallada H, Collier D, Sham P, Holmans P, Murray R, McGuffin P, Nanko S, Owen M, Antonarakis S, Housman D, Kazazian H, Nestadt G, Pulver AE, Straub RE, MacLean CJ, Walsh D, Kendler KS, DeLisi L, Polymeropoulos M, Coon H, Byerley W, Lofthouse R, Gershon E, Read CM (Schizophrenia Collaborative Linkage Group [Chromosome 22]): A combined analysis of D22S278 marker alleles in affected sib-pairs: support for a susceptibility locus for schizophrenia at chromosome 22q12. Am J Med Genet 1996; 67:40-45[CrossRef][Medline]

Coon H, Jensen S, Holik M, Hoff M, Myles-Worsley M, Reimherr F, Wender P, Waldo M, Freedman R, Leppert M, Byerley W: Genomic scan for genes predisposing to schizophrenia. Am J Med Genet 1994; 54:59-71[Medline]

Leonard S, Gault J, Moore T, Hopkins J, Robinson M, Oliney A, Adler LE, Cloninger CR, Kaufmann CA, Tsuang MT, Faraone SV, Malaspina D, Svrakic DM, Freedman R: Further investigation of a chromosome 15 locus in schizophrenia: analysis of affected sibpairs from the NIMH Genetics Initiative. Am J Med Genet 1998; 81:308-312[CrossRef][Medline]

Goring HHH, Terwilliger JD, Blangero J: Large upward bias in estimation of locus-specific effects from genome-wide scans. Am J Hum Genet 2001; 69:1357[CrossRef][Medline]

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