Abstract
A genome scan meta-a nalysis (GSMA) was carried out on 32 independent genome-wide linkage scan analyses that included 3255 pedigrees with 7413 genotyped cases affected with schizophrenia (SCZ) or related disorders. The primary GSMA divided the autosomes into 120 bins, rank-ordered the bins within each study according to the most positive linkage result in each bin, summed these ranks (weighted for study size) for each bin across studies and determined the empirical probability of a given summed rank (PSR) by simulation. Suggestive evidence for linkage was observed in two single bins, on chromosomes 5q (142–168 Mb) and 2q (103–134 Mb). Genome-wide evidence for linkage was detected on chromosome 2q (119–152 Mb) when bin boundaries were shifted to the middle of the previous bins. The primary analysis met empirical criteria for ‘aggregate’ genome-wide significance, indicating that some or all of 10 bins are likely to contain loci linked to SCZ, including regions of chromosomes 1, 2q, 3q, 4q, 5q, 8p and 10q. In a secondary analysis of 22 studies of European-ancestry samples, suggestive evidence for linkage was observed on chromosome 8p (16–33 Mb). Although the newer genome-wide association methodology has greater power to detect weak associations to single common DNA sequence variants, linkage analysis can detect diverse genetic effects that segregate in families, including multiple rare variants within one locus or several weakly associated loci in the same region. Therefore, the regions supported by this meta-analysis deserve close attention in future studies.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Levinson DF, Levinson MD, Segurado R, Lewis CM . Genome scan meta-analysis of schizophrenia and bipolar disorder, part I: Methods and power analysis. Am J Hum Genet 2003; 73: 17–33.
Pardi F, Levinson DF, Lewis CM . GSMA: software implementation of the genome search meta-analysis method. Bioinformatics 2005; 21: 4430–4431.
Wise LH, Lanchbury JS, Lewis CM . Meta-analysis of genome searches. Ann Hum Genet 1999; 63 (Part 3): 263–272.
Lewis CM, Levinson DF, Wise LH, DeLisi LE, Straub RE, Hovatta I et al. Genome scan meta-analysis of schizophrenia and bipolar disorder, part II: Schizophrenia. Am J Hum Genet 2003; 73: 34–48.
Risch N, Merikangas K . The future of genetic studies of complex human diseases. Science 1996; 273: 1516–1517.
McCarroll SA, Altshuler DM . Copy-number variation and association studies of human disease. Nat Genet 2007; 39 (7 Suppl): S37–S42.
Manolio TA, Brooks LD, Collins FS . A HapMap harvest of insights into the genetics of common disease. J Clin Invest 2008; 118: 1590–1605.
McMillan I, Roberson A . Power of detection of major genes affecting quantitative characters. Heredity 1974; 32: 349–356.
Risch N . Genetic linkage and complex diseases, with special reference to psychiatric disorders. Genet Epidemiol 1990; 7: 3–16; discussion 17–45.
Jablensky A, Sartorius N, Ernberg G, Anker M, Korten A, Cooper JE et al. Schizophrenia: manifestations, incidence and course in different cultures. A World Health Organization ten-country study. Psychol Med Monogr Suppl 1992; 20: 1–97.
Cardno AG, Marshall EJ, Coid B, Macdonald AM, Ribchester TR, Davies NJ et al. Heritability estimates for psychotic disorders: the Maudsley twin psychosis series. Arch Gen Psychiatry 1999; 56: 162–168.
Farmer AE, McGuffin P, Gottesman, II . Twin concordance for DSM-III schizophrenia. Scrutinizing the validity of the definition. Arch Gen Psychiatry 1987; 44: 634–641.
Faraone SV, Blehar M, Pepple J, Moldin SO, Norton J, Nurnberger JI et al. Diagnostic accuracy and confusability analyses: an application to the Diagnostic Interview for Genetic Studies. Psychol Med 1996; 26: 401–410.
Kendler KS, Neale MC, Walsh D . Evaluating the spectrum concept of schizophrenia in the Roscommon Family Study. Am J Psychiatry 1995; 152: 749–754.
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.
Devlin B, Bacanu SA, Roeder K, Reimherr F, Wender P, Galke B et al. Genome-wide multipoint linkage analyses of multiplex schizophrenia pedigrees from the oceanic nation of Palau. Mol Psychiatry 2002; 7: 689–694.
Brzustowicz LM, Hodgkinson KA, Chow EW, Honer WG, Bassett AS . Location of a major susceptibility locus for familial schizophrenia on chromosome 1q21-q22. Science 2000; 288: 678–682.
Paunio T, Ekelund J, Varilo T, Parker A, Hovatta I, Turunen JA et al. Genome-wide scan in a nationwide study sample of schizophrenia families in Finland reveals susceptibility loci on chromosomes 2q and 5q. Hum Mol Genet 2001; 10: 3037–30348.
Garver DL, Holcomb J, Mapua FM, Wilson R, Barnes B . Schizophrenia spectrum disorders: an autosomal-wide scan in multiplex pedigrees. Schizophr Res 2001; 52: 145–160.
Gurling HM, Kalsi G, Brynjolfson J, Sigmundsson T, Sherrington R, Mankoo BS et al. Genomewide genetic linkage analysis confirms the presence of susceptibility loci for schizophrenia, on chromosomes 1q32. 2, 5q33. 2, and 8p21–22 and provides support for linkage to schizophrenia, on chromosomes 11q23. 3–24 and 20q12. 1–11. 23. Am J Hum Genet 2001; 68: 661–673.
Lindholm E, Ekholm B, Shaw S, Jalonen P, Johansson G, Pettersson U et al. A schizophrenia-susceptibility locus at 6q25, in one of the world's largest reported pedigrees. Am J Hum Genet 2001; 69: 96–105.
DeLisi LE, Shaw SH, Crow TJ, Shields G, Smith AB, Larach VW et al. A genome-wide scan for linkage to chromosomal regions in 382 sibling pairs with schizophrenia or schizoaffective disorder. Am J Psychiatry 2002; 159: 803–812.
DeLisi LE, Mesen A, Rodriguez C, Bertheau A, LaPrade B, Llach M et al. Genome-wide scan for linkage to schizophrenia in a Spanish-origin cohort from Costa Rica. Am J Med Genet 2002; 114: 497–508.
Wijsman EM, Rosenthal EA, Hall D, Blundell ML, Sobin C, Heath SC et al. Genome-wide scan in a large complex pedigree with predominantly male schizophrenics from the island of Kosrae: evidence for linkage to chromosome 2q. Mol Psychiatry 2003; 8: 695–705. 643.
Lerer B, Segman RH, Hamdan A, Kanyas K, Karni O, Kohn Y et al. Genome scan of Arab Israeli families maps a schizophrenia susceptibility gene to chromosome 6q23 and supports a locus at chromosome 10q24. Mol Psychiatry 2003; 8: 488–498.
Arinami T, Ohtsuki T, Ishiguro H, Ujike H, Tanaka Y, Morita Y et al. Genomewide high-density SNP linkage analysis of 236 Japanese families supports the existence of schizophrenia susceptibility loci on chromosomes 1p, 14q, and 20p. Am J Hum Genet 2005; 77: 937–944.
Fallin MD, Lasseter VK, Wolyniec PS, McGrath JA, Nestadt G, Valle D et al. Genomewide linkage scan for schizophrenia susceptibility loci among Ashkenazi Jewish families shows evidence of linkage on chromosome 10q22. Am J Hum Genet 2003; 73: 601–611.
Williams NM, Norton N, Williams H, Ekholm B, Hamshere ML, Lindblom Y et al. A systematic genomewide linkage study in 353 sib pairs with schizophrenia. Am J Hum Genet 2003; 73: 1355–1367.
Sklar P, Pato MT, Kirby A, Petryshen TL, Medeiros H, Carvalho C et al. Genome-wide scan in Portuguese Island families identifies 5q31–5q35 as a susceptibility locus for schizophrenia and psychosis. Mol Psychiatry 2004; 9: 213–218.
Abecasis GR, Burt RA, Hall D, Bochum S, Doheny KF, Lundy SL et al. Genomewide scan in families with schizophrenia from the founder population of Afrikaners reveals evidence for linkage and uniparental disomy on chromosome 1. Am J Hum Genet 2004; 74: 403–417.
Maziade M, Roy MA, Chagnon YC, Cliche D, Fournier JP, Montgrain N et al. Shared and specific susceptibility loci for schizophrenia and bipolar disorder: a dense genome scan in Eastern Quebec families. Mol Psychiatry 2005; 10: 486–499.
Faraone SV, Skol AD, Tsuang DW, Young KA, Haverstock SL, Prabhudesai S et al. Genome scan of schizophrenia families in a large Veterans Affairs Cooperative Study sample: evidence for linkage to 18p11. 32 and for racial heterogeneity on chromosomes 6 and 14. Am J Med Genet B Neuropsychiatr Genet 2005; 139: 91–100.
Suarez BK, Duan J, Sanders AR, Hinrichs AL, Jin CH, Hou C et al. Genomewide linkage scan of 409 European-ancestry and African American families with schizophrenia: suggestive evidence of linkage at 8p23. 3-p21. 2 and 11p13. 1-q14. 1 in the combined sample. Am J Hum Genet 2006; 78: 315–333.
Escamilla MA, Ontiveros A, Nicolini H, Raventos H, Mendoza R, Medina R et al. A genome-wide scan for schizophrenia and psychosis susceptibility loci in families of Mexican and Central American ancestry. Am J Med Genet B Neuropsychiatr Genet 2007; 144: 193–199.
Faraone SV, Hwu HG, Liu CM, Chen WJ, Tsuang MM, Liu SK et al. Genome scan of Han Chinese schizophrenia families from Taiwan: confirmation of linkage to 10q22. 3. Am J Psychiatry 2006; 163: 1760–1766.
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.
Mowry BJ, Ewen KR, Nancarrow DJ, Lennon DP, Nertney DA, Jones HL et al. Second stage of a genome scan of schizophrenia: study of five positive regions in an expanded sample. Am J Med Genet 2000; 96: 864–869.
Holmans P, Riley B, Pulver AE, Owen MJ, Wildenauer DB, Gejman PV . Genomewide linkage scan of schizophrenia in a large multicenter pedigree sample using single nucleotide polymorphisms.Mol Psychiatry (in press).
Schwab SG, Hallmayer J, Albus M, Lerer B, Eckstein GN, Borrmann 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 2000; 5: 638–649.
Bonnet-Brilhault F, Laurent C, Campion D, Thibaut F, Lafargue C, Charbonnier F et al. No evidence for involvement of KCNN3 (hSKCa3) potassium channel gene in familial and isolated cases of schizophrenia. Eur J Hum Genet 1999; 7: 247–250.
Campion D, d’Amato T, Bastard C, Laurent C, Guedj F, Jay M et al. Genetic study of dopamine D1, D2, and D4 receptors in schizophrenia. Psychiatry Res 1994; 51: 215–230.
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.
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.
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.
Kaufmann CA, Suarez B, Malaspina D, Pepple J, Svrakic D, Markel PD et al. NIMH Genetics Initiative Millenium Schizophrenia Consortium: linkage analysis of African-American pedigrees. Am J Med Genet 1998; 81: 282–289.
Straub RE, MacLean CJ, Ma Y, Webb BT, Myakishev MV, Harris-Kerr C et al. Genome-wide scans of three independent sets of 90 Irish multiplex schizophrenia families and follow-up of selected regions in all families provides evidence for multiple susceptibility genes. Mol Psychiatry 2002; 7: 542–559.
Irmansyah, Schwab SG, Heriani, Handoko HY, Kusumawardhani I, Widyawat I et al. Genome-wide scan in 124 Indonesian sib-pair families with schizophrenia reveals genome-wide significant linkage to a locus on chromosome 3p26–21. Am J Med Genet B Neuropsychiatr Genet 2008; 147B: 1245–1252.
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.
Cooper-Casey K, Mesen-Fainardi A, Galke-Rollins B, Llach M, Laprade B, Rodriguez C et al. Suggestive linkage of schizophrenia to 5p13 in Costa Rica. Mol Psychiatry 2005; 10: 651–656.
Vazza G, Bertolin C, Scudellaro E, Vettori A, Boaretto F, Rampinelli S et al. Genome-wide scan supports the existence of a susceptibility locus for schizophrenia and bipolar disorder on chromosome 15q26. Mol Psychiatry 2007; 12: 87–93.
Bulayeva KB, Glatt SJ, Bulayev OA, Pavlova TA, Tsuang MT . Genome-wide linkage scan of schizophrenia: a cross-isolate study. Genomics 2007; 89: 167–177.
Stefansson H, Sigurdsson E, Steinthorsdottir V, Bjornsdottir S, Sigmundsson T, Ghosh S et al. Neuregulin 1 and susceptibility to schizophrenia. Am J Hum Genet 2002; 71: 877–892.
Matise TC, Chen F, Chen W, De La Vega FM, Hansen M, He C et al. A second-generation combined linkage physical map of the human genome. Genome Res 2007; 17: 1783–1786.
Lander E, Kruglyak L . Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nat Genet 1995; 11: 241–247.
Zintzaras E, Ioannidis JP . Heterogeneity testing in meta-analysis of genome searches. Genet Epidemiol 2005; 28: 123–137.
Lewis CM, Levinson DF . Testing for genetic heterogeneity in the genome search meta-analysis method. Genet Epidemiol 2006; 30: 348–355.
Risch N . Linkage strategies for genetically complex traits. I. Multilocus models. Am J Hum Genet 1990; 46: 222–228.
Wellcome Trust Case Control Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 2007; 447: 661–678.
Frayling TM . Genome-wide association studies provide new insights into type 2 diabetes aetiology. Nat Rev Genet 2007; 8: 657–662.
Mathew CG . New links to the pathogenesis of Crohn disease provided by genome-wide association scans. Nat Rev Genet 2008; 9: 9–14.
Lewis CM, Whitwell SC, Forbes A, Sanderson J, Mathew CG, Marteau TM . Estimating risks of common complex diseases across genetic and environmental factors: the example of Crohn disease. J Med Genet 2007; 44: 689–694.
Brzustowicz LM, Simone J, Mohseni P, Hayter JE, Hodgkinson KA, Chow EW et al. Linkage disequilibrium mapping of schizophrenia susceptibility to the CAPON region of chromosome 1q22. Am J Hum Genet 2004; 74: 1057–1063.
Xu B, Wratten N, Charych EI, Buyske S, Firestein BL, Brzustowicz LM . Increased expression in dorsolateral prefrontal cortex of CAPON in schizophrenia and bipolar disorder. PLoS Med 2005; 2: e263.
Guo S, Tang W, Shi Y, Huang K, Xi Z, Xu Y et al. RGS4 polymorphisms and risk of schizophrenia: an association study in Han Chinese plus meta-analysis. Neurosci Lett 2006; 406: 122–127.
Levitt P, Ebert P, Mirnics K, Nimgaonkar VL, Lewis DA . Making the case for a candidate vulnerability gene in schizophrenia: convergent evidence for regulator of G-protein signaling 4 (RGS4). Biol Psychiatry 2006; 60: 534–537.
Puri V . Fine mapping by genetic association implicates the chromosome 1q23.3 gene UHMK1, encoding a serine/threonine protein kinase, as a novel schizophrenia susceptibility gene. Biol Psychiatry 2007; 61: 873–879.
Stefansson H, Rujescu D, Cichon S, Pietilainen OP, Ingason A, Steinberg S et al. Large recurrent microdeletions associated with schizophrenia. Nature 2008; 455: 232–236.
Stone JL, O’Donovan MC, Gurling H, Kirov GK, Blackwood DH, Corvin A et al. Rare chromosomal deletions and duplications increase risk of schizophrenia. Nature 2008; 455: 237–241.
Gerber DJ, Hall D, Miyakawa T, Demars S, Gogos JA, Karayiorgou M et al. Evidence for association of schizophrenia with genetic variation in the 8p21. 3 gene, PPP3CC, encoding the calcineurin gamma subunit. Proc Natl Acad Sci USA 2003; 100: 8993–8998.
Stefansson H, Sarginson J, Kong A, Yates P, Steinthorsdottir V, Gudfinnsson E et al. Association of neuregulin 1 with schizophrenia confirmed in a Scottish population. Am J Hum Genet 2003; 72: 83–87.
O’Donovan MC, Craddock N, Norton N, Williams H, Peirce T, Moskvina V et al. Identification of loci associated with schizophrenia by genome-wide association and follow-up. Nat Genet 2008; 40: 1053–1055.
Acknowledgements
The work reported here was supported by: Medical Research Council (UK) Grants G0400960 (CML) and G9309834 (MO); National Institute of Mental Health Grants 7R01MH062276 (to DFL [Aust/US], CL [France/La Réunion], MO [Cardiff] and DW [Bonn]), 5R01MH068922 (to PG [ENH]), 5R01MH068921 (to AEP [Johns Hopkins]), 5R01MH068881 (to BR [VCU/Ireland]), MH-41953 (to KSK [VCU/Ireland]); MH63356 and MH80299 (to WB [Palau]); MH58586 (to JMS [Aust/US]); MH 56242 (to VLM [US/Sweden]), MH61399 (EMW, MK [Kosrae, South Africa]), NIMH Grant MH062440, Canadian Institutes of Health Research Grants MOP-53216 and MOP-12155, a National Alliance for Research on Schizophrenia and Depression Distinguished Investigator Award and Canada Research Chair in Schizophrenia Genetics (LMB, ASB [Canada]); Australian National Health and Medical Research Council Grants 910234, 941087, and 971095 (to BJM [Aust/US]), MRC project Grant G880473N, The European Science Foundation, SANE, the Iceland Department of Health, the General Hospital Reykjavik, the Joseph Levy Charitable Foundation, the Wellcome Trust Grant 055379, The Priory Hospital, the Neuroscience Research Charitable Trust, the University of Iceland and the Icelandic Science Council (HMDG [UCL]); Warner-Lambert, Parke-Davis Pharmaceuticals Company and NIMH Grant R01-MH44245 (LEL [US/International]); the Deutsche Forschungsgemeinschaft (HWM [Kiel]; MA WM, SGS, DBW [Indonesia]); the German Israeli Foundation for Scientific Research (BL; DBW); Mammalian Genotyping Service HV48141 (DBW [Indonesia]; CREST of JST (Japan Science and Technology Agency) TA [Japan]; Pfizer, Inc. and the SANE Foundation (LEL [Costa Rica]); the Israel Science Foundation, US. Israel Binational Science Foundation, the National Alliance for Research on Schizophrenia and Depression, and the Harry Stern Family Foundation (BL and YK [Israel]); the VA Merit Review Program (AF); recruitment of the NIMH Genetics Initiative sample was supported by NIMH Grants 5 UO1MH46318, UO1MH46289 and UO1MH46276; the Taiwan Schizophrenia Linkage Study was supported by NIMH Grant 1R01 MH59624-01 and Grant NHRI-90-8825PP, NHRI -EX91,92-9113PP from the National Health Research Institute, Taiwan, and support from the Genomic Medicine Research Program of Psychiatric Disorders, National Taiwan University Hospital; the VA Linkage Study was supported by funds from the Department of Veterans Affairs Cooperative Studies Program; the US/Mexico/Central America study was supported by a collaborative NIMH grant (‘Genetics of Schizophrenia in Latino Populations’) (MH60881 and MH60875) to ME [University of Texas Health Science Center at San Antonio], R Mendoza [University of California at Los Angeles-Harbor], HR [University of Costa Rica, San Jose, Costa Rica], A Ontiveros [Instituto de Informacion de Investigacion en Salud Mental, Monterrey, Mexico], HN [Medical and Family Research Group, Carracci SC, Mexico City, Mexico], and R Munoz [Family Health Centers of San Diego, CA].
Author information
Authors and Affiliations
Corresponding author
Additional information
Supplementary Information accompanies the paper on the Molecular Psychiatry website (http://www.nature.com/mp)
Supplementary information
Rights and permissions
About this article
Cite this article
Ng, M., Levinson, D., Faraone, S. et al. Meta-analysis of 32 genome-wide linkage studies of schizophrenia. Mol Psychiatry 14, 774–785 (2009). https://doi.org/10.1038/mp.2008.135
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/mp.2008.135
Keywords
This article is cited by
-
Common and rare variant associations with latent traits underlying depression, bipolar disorder, and schizophrenia
Translational Psychiatry (2023)
-
Recent status of Genotyping by Sequencing (GBS) Technology in cucumber (Cucumis sativus L.): a review
Molecular Biology Reports (2022)
-
Elevated endogenous GDNF induces altered dopamine signalling in mice and correlates with clinical severity in schizophrenia
Molecular Psychiatry (2022)
-
Sex-differential DNA methylation and associated regulation networks in human brain implicated in the sex-biased risks of psychiatric disorders
Molecular Psychiatry (2021)
-
Differential gene regulatory pattern in the human brain from schizophrenia using transcriptomic-causal network
BMC Bioinformatics (2020)