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Linkage studies of schizophrenia

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Abstract

The study of schizophrenia genetics has revealed much about the disease but none of the essential secrets of its etiology, so far, for numerous reasons. First, schizophrenia is a complex trait, influenced by both genes and environment. Second, it appears to be a highly heterogeneous disease, with locus and allelic heterogeneity both between and within families likely. Third, since it is common, it is likely that the genetic liability variants are common, and so are found with relatively high frequency in the general population. Fourth, linkage methods, which deliver rapid coverage of the genome, have great power to identify single genes causing Mendelian disorders but are poorly suited to the genetic architecture of complex traits. Although association methods are undeniably more powerful in such situations, affordable technologies to deliver the much higher density whole genome coverage required are not yet available and candidate gene studies of schizophrenia have not produced robust and replicable results. In spite of these limitations, there are now sufficient data to support several conclusions.Numerous regions of the human genome give consistent, though by no means unanimous,support for linkage. The precise nature of these signals is not yet understood,and power to position the effects is poor, but metanalyses show the co-occurrence is unlikely to be due to chance. Combined approaches utilizing linkage for rapid genome coverage and association for fine-scale follow-up have identified several promising candidate genes. Although the definition of replication in a complex trait is itself complex, a number of these candidates have been supported by numerous studies. These converging lines of evidence suggest that the genetics of schizophrenia, long considered a most intractable problem, are at last beginning to be unraveled.

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References

  • Antonarakis SE, JL Blouin, M Curran, H Luebbert, HH Kazazian, BA Dombroski, DE Housman, C Ton, M Karayiorgou, A Chakravarti, PS Wolyniec, VK Lasseter, G Nestadt and AE Pulver (1996) Linkage and sib-pair analysis reveal a potential schizophrenia susceptibility gene on chromosome 13q32.Am. J. Hum. Genet. 59, A210.

    Google Scholar 

  • Badner JA and ES Gershon (2002) Meta-analysis of whole-genome linkage scans of bipolar disorder and schizophrenia.Mol. Psychiatry 7, 405–411.

    Article  PubMed  CAS  Google Scholar 

  • Baron M (1996) Linkage results in schizophrenia.Am. J. Med. Genet. 67, 121–123.

    Article  PubMed  CAS  Google Scholar 

  • Brzustowicz LM, WG Honer, EWC Chow, D Little, K Hodgkinson and A Bassett (1999) Linkage of familial schizophrenia to chromosome 13q32.Am. J. Hum. Genet. 65, 1096–1103.

    Article  PubMed  CAS  Google Scholar 

  • Brzustowicz LM, KA Hodgkinson, EWC Chow, WG Honer and AS Bassett (2000) Location of a major susceptibility locus for familial schizophrenia on chromosome 1q21-q22.Science 288, 678–682.

    Article  PubMed  CAS  Google Scholar 

  • Busfield F, DL Duffy, JB Kesting, SM Walker, P Lovelock, D Good, H Tate, D Watego, M Marczak, N Hayman and JT Shaw (2002) A genomewide search for type 2 diabetes-susceptibility genes in indigenous Australians.Am. J. Hum. Genet. 70, 349–357.

    Article  PubMed  CAS  Google Scholar 

  • Cao Q, M Martinez, J Zhang, AR Sanders, JA Badner, A Cravchik, CJ Markey, E Beshah, JJ Guroff, ME Maxwell, DM Kazuba, R Whiten, LR Goldin, ES Gershon and PV Gejman (1997) Suggestive evidence for a schizophrenia susceptibility locus on chromosome 6q and a confirmation in an independent series of pedigrees.Genomics 43, 1–8.

    Article  PubMed  CAS  Google Scholar 

  • Cardno AG and II Gottesman (2000) Twin studies of schizophrenia, from bow-and-arrow concordances to Star Wars Mx and functional genomics.Am. J. Med. Genet. 97, 12–17.

    Article  PubMed  CAS  Google Scholar 

  • Cardno AG, EJ Marshall, B Coid, AM Macdonald, TR Ribchester, NJ Davies, P Venturi, LA Jones, SW Lewis, PC Sham, II Gottesman, AE Farmer, P McGuffin, AM Reveley and RM Murray (1999) Heritability estimates for psychotic disorders, the Maudsley twin psychosis series.Arch. Gen. Psychiatry 56, 162–168.

    Article  PubMed  CAS  Google Scholar 

  • Chowdari KV, K Mirnics, P Semwal, J Wood, E Lawrence, T Bhatia, SN Deshpande, BK Thelma, RE Ferrell, FA Middleton, B Devlin, P Levitt, DA Lewis and V Nimgaonkar (2002) Association and linkage analyses of RGS4 polymorphisms in schizophrenia.Hum. Mol. Genet. 11, 1373–1380.

    Article  PubMed  CAS  Google Scholar 

  • Chumakov I, M Blumenfeld, O Guerassimenko, L Cavarec, M Palicio, H Abderrahim, L Bougueleret, C Barry, H Tanaka, P La Rosa, A Puech, N Tahri, A Cohen-Akenine, S Delabrosse, S Lissarrague, FP Picard, K Maurice, L Essioux, P Millasseau, P Grel, V Debailleul, AM Simon, D Caterina, I Dufaure, K Malekzadeh, M Belova, JJ Luan, M Bouillot, JL Sambucy, G Primas, M Saumier, N Boubkiri, S Martin-Saumier, M Nasroune, H Peixoto, A Delaye, V Pinchot, M Bastucci, S Guillou, M Chevillon, R Sainz-Fuertes, S Meguenni, J Aurich-Costa, D Cherif, A Gimalac, C Van Duijn, D Gauvreau, G Ouelette, I Fortier, J Realson, T Sherbatich, N Riazanskaia, E Rogaev, P Raeymaekers, J Aerssens, F Konings, W Luyten, F Macciardi, PC Sham, RE Straub, DR Weinberger, N Cohen and D Cohen (2002) Genetic and physiological data implicating the new human gene G72 and the gene for D-amino acid oxidase in schizophrenia.Proc. Natl. Acad. Sci. USA A99, 13675–13680.

    Article  CAS  Google Scholar 

  • Coon H, J Holik, M Hoff, F Reimherr, P Wender, M Myles-Worsley, M Waldo, R Freedman and W Byerley (1994) Analysis of chromosome 22 markers in nine schizophrenia pedigrees.Am. J. Med. Genet. 54, 72–79.

    Article  PubMed  CAS  Google Scholar 

  • Coraddu F, S Sawcer, S D’Alfonso, M Lai, A Hensiek, E Solla, S Broadley, C Mancosu, M Pugliatti, MG Marrosu and A Compston (2001) A genome screen for multiple sclerosis in Sardinian multiplex families.Eur. J. Hum. Genet. 9, 621–626.

    Article  PubMed  CAS  Google Scholar 

  • Egan MF, TE Goldberg, BS Kolachana, JH Callicott, CM Mazzanti, RE Straub, D Goldman and DR Weinberger (2001) Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for schizophrenia.Proc. Natl. Acad. Sci. USA 98(12), 6917–6922.

    Article  PubMed  CAS  Google Scholar 

  • Ekelund J, D Lichtermann, I Hovatta, P Ellonen, J Suvisaari, JD Terwilliger, H Juvonen, T Varilo, R Arajarvi, M-L Kokko-Sahin, J Lonnqvist and L Peltonen (2000) Genome-wide scan for schizophrenia in the Finnish population, evidence for a locus on chromosome 7q22.Hum. Mol. Genet. 9, 1049–1057.

    Article  PubMed  CAS  Google Scholar 

  • Faraone SV, T Matise, D Svrakic, J Pepple, D Malaspina, B Suarez, C Hampe, CT Zambuto, K Schmitt, J Meyer, P Markel, H Lee, J Harkavy-Friedman, C Kaufmann, CR Cloninger and MT Tsuang (1998) Genome scan of European-American schizophrenia pedigrees, results of the NIMH genetics initiative and millennium consortium.Am. J. Med. Genet. 81, 290–295.

    Article  PubMed  CAS  Google Scholar 

  • Farmer AE, P McGuffin and II Gottesman (1987) Twin concordance for DSM-III schizophrenia. Scrutinizing the validity of the definition.Arch. Gen. Psychiatr. 44, 634–640.

    PubMed  CAS  Google Scholar 

  • Freedman R, H Coon, M Myles-Worsley, A Orr-Urtreger, A Olincy, A Davis, M Polymeropoulos, J Holik, J Hopkins, M Hoff, J Rosenthal, MC Waldo, F Reimherr, P Wender, J Yaw, DA Young, CR Breese, C Adams, D Patterson, LE Adler, L Kruglyak, S Leonard and W Byerley (1997) Linkage of a neurophysiological deficit in schizophrenia to a chromosome 15 locus.Proc. Natl. Acad. Sci. USA 94, 587–592.

    Article  PubMed  CAS  Google Scholar 

  • Gault J, J Logel, C Drebing, R Berger, J Hopkins, A Olincy, B Sullivan, M Short, K Walton, M Robinson, M Maslak, J Meriwether, L Baldermann, S Jacobs, R Freedman and S Leonard (1999) Mutation analysis of the a7 nicotinic acetyl-choline receptor gene and its partial duplication in schizophrenia patients.Am. J. Hum. Genet. 65, A271.

    Article  Google Scholar 

  • Gejman PV, AR Sanders, JA Badner, Q Cao and J Zhang (2001) Linkage analysis of schizophrenia to chromosome 15.Am. J. Med. Genet. 105, 789–793.

    Article  PubMed  CAS  Google Scholar 

  • Gill M, H Vallada, D Collier, P Sham, P Holmans, R Murray, P McGuffin, S Nanko, M Owen, S Antonarakis, D Housman, H Kazazian, G Nestadt, AE Pulver, RE Straub, CJ MacLean, D Walsh, KS Kendler, L DeLisiet al. (1996) 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. 67, 40–45.

    Article  PubMed  CAS  Google Scholar 

  • Gottesman II (1991)Schizophrenia Genesis (WH Freeman, New York, NY).

    Google Scholar 

  • Hashimoto L, C Habita, JP Beressi, M Delepine, C Besse, A Cambon-Thomsen, I Deschamps, JI Rotter, S Djoulah and MR James (1994) Genetic mapping of a susceptibility locus for insulin-dependent diabetes mellitus on chromosome 11q.Nature 371, 161–164.

    Article  PubMed  CAS  Google Scholar 

  • Heston LL (1966) Psychiatric disorders in foster home reared children of schizophrenic mothers.Br. J. Psychiatr. 112, 819–825.

    Article  CAS  Google Scholar 

  • Hovatta I, T Varilo, J Suvisaari, JD Terwilliger, V Olikainen, R Arajärvi, H Juvonen, M-L Kokko-Sahin, L Väisänen, H Mannila, J Lonnqvist and L Peltonen (1999) A genome-wide screen for schizophrenia genes in an isolated Finnish subpopulation suggesting multiple susceptibility loci.Am. J. Hum. Genet. 65, 1114–1124.

    Article  PubMed  CAS  Google Scholar 

  • Hugot JP, M Chamaillard, H Zouali, S Lesage, JP Cezard, J Belaiche, S Almer, C Tysk, CA O’Morain, M Gassull, V Binder, Y Finkel, A Cortot, R Modigliani, P Laurent-Puig, C Gower-Rousseau, J Macry, JF Colombel, M Sahbatou and G Thomas (2001) Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn’s disease.Nature 411, 599–603.

    Article  PubMed  CAS  Google Scholar 

  • Kalsi G, CH Chen, C Smyth, J Brynjolfsson, T Sigmundson, D Curtis, R Butler, T Read, P Murphy, H Petursson and H Gurling (1996) Genetic linkage analysis in an Icelandic/British sample fails to exclude the putative chromosome 13q14.1-q32 schizophrenia susceptibility locus.Am. J. Hum. Genet. 59, A388.

    Google Scholar 

  • Karayiorgou M, MA Morris, B Morrow, RJ Shprintzen, R Goldberg, J Borrow, A Gos, G Nestadt, PS Wolyniec, VK Lasseter, H Eisen, B Childs, HH Kazazian, R Kucherlapati, SE Antonarakis, AE Pulver and DE Housman (1995) Schizophrenia susceptibility associated with interstitial deletions of chromosome 22q11.Proc. Natl. Acad. Sci. USA 92, 7612–7616.

    Article  PubMed  CAS  Google Scholar 

  • Kaufmann CA, B Suarez, D Malaspina, J Pepple, D Svrakic, PD Markel, J Meyer, CT Zambuto, K Schmitt, TC Matise, JMH Friedman, C Hampe, H Lee, D Shore, D Wynne, SV Faraone, MT Tsuang and CR Cloninger (1998) NIMH genetics initiative millennium schizophrenia consortium, Linkage analysis of African-American pedigrees.Am. J. Med. Genet. 81, 282–289.

    Article  PubMed  CAS  Google Scholar 

  • Kendler KS and SR Diehl (1993) The genetics of schizophrenia, A current, genetic-epidemiologic perspective.Schizophr. Bull. 19, 261–285.

    PubMed  CAS  Google Scholar 

  • Kendler KS, AM Gruenberg and MT Tsuang (1986) A DSM-III family study of the nonschizophrenic psychotic disorders.Am. J. Psychiatr. 143, 1098–1105.

    PubMed  CAS  Google Scholar 

  • Kendler KS, M McGuire, AM Gruenberg, M Spellman, A O’Hare and D Walsh (1993) The Roscommon family study, II. The risk of nonschizophrenic nonaffective psychoses in relatives.Arch. Gen. Psychiatr. 50, 645–652.

    PubMed  CAS  Google Scholar 

  • Kendler KS, RE Straub, CJ MacLean and D Walsh (1996) Reflections on the evidence for a vulnerability locus for schizophrenia on chromosome 6p24-22.Am. J. Med. Genet. 67, 124–126.

    Article  PubMed  CAS  Google Scholar 

  • Kety SS, D Rosenthal, PH Wender, F Schulsinger and B Jacobsen (1968) The types and prevalence of mental illness in the biological and adoptive families of adopted schizophrenics.J. Psychiatr. Res. 6, 345–362.

    Article  Google Scholar 

  • Kety SS, PH Wender, B Jacobsen, LJ Ingraham, L Jansson, B Faber and DK Kinney (1994) Mental illness in the biological and adoptive relatives of schizophrenic adoptees, replication of the Copenhagen study in the rest of Denmark.Arch. Gen. Psychiatr. 51, 442–455.

    PubMed  CAS  Google Scholar 

  • Laitinen T, MJ Daly, JD Rioux, P Kauppi, C Laprise, T Petays, T Green, M Cargill, T Haahtela, ES Lander, LA Laitinen, TJ Hudson and J Kere (2001) A susceptibility locus for asthma-related traits on chromosome 7 revealed by genome-wide scan in a founder population.Nat.Genet. 28, 87–91.

    Article  PubMed  CAS  Google Scholar 

  • Leonard S, J Gault, T Moore, J Hopkins, M Robinson, A Olincy, LE Adler, CR Cloninger, CA Kaufmann, MT Tsuang, SV Faraone, D Malaspina, DM Svrakic and R Freedman (1998) Further investigation of a chromosome 15 locus in schizophrenia, analysis of affected sibpairs from the NIMH genetics initiative.Am. J. Med. Genet. 81, 308–312.

    Article  PubMed  CAS  Google Scholar 

  • Levinson DF, DB Wildenauer, SG Schwab, M Albus, J Hallmayer, B Lerer, W Maier, D Blackwood, W Muir, DS Clair, S Morris, HW Moises, L Yang, H Kristbjarnarson, T Helgason, C Wiese, DA Collier, P Holmans, J Danielset al. (1996) Additional support for schizophrenia linkage on chromosomes 6 and 8, a multi-center study.Am. J. Med. Genet. 67, 580–594.

    Article  Google Scholar 

  • Levinson DF, P Holmans, RE Straub, MJ Owen, DB Wildenauer, PV Gejman, AE Pulver, C Laurent, KS Kendler, D Walsh, N Norton, NM Williams, SG Schwab, B Lerer, BJ Mowry, AR Sanders, SE Antonarakis, JL Blouin, JF Deleuze and J Mallet (2000) Multicenter linkage study of schizophrenia candidate regions on chromosomes 5q, 6q, 10p, and 13q, schizophrenia linkage collaborative group III.Am. J. Hum. Genet. 67, 652–663.

    Article  PubMed  CAS  Google Scholar 

  • Levinson DF, PA Holmans, C Laurent, B Riley, AE Pulver, PV Gejman, SG Schwab, NM Williams, MJ Owen, DB Wildenauer, AR Sanders, G Nestadt, BJ Mowry, B Wormley, S Bauche, S Soubigou, R Ribble, DA Nertney, KY Liang, L Martinolich, W Maier, N Norton, H Williams, M Albus, EB Carpenter, N DeMarchi, KR Ewen-White, D Walsh, M Jay, J-F Deleuze, FA O’Neill, G Papadimitriou, A Weilbaecher, B Lerer, MC O’Donovan, D Dikeos, JM Silverman, KS Kendler, J Mallet, RR Crowe and M Walters (2002) No major schizophrenia locus detected on chromosome 1q in a large multicenter sample.Science 296, 739–741.

    Article  PubMed  CAS  Google Scholar 

  • Levinson DF, MD Levinson, R Segurado and CM Lewis (2003) Genome scan meta-analysis of schizophrenia and bipolar disorder, part I, Methods and power analysis.Am. J. Hum. Genet. 73, 17–33.

    Article  PubMed  CAS  Google Scholar 

  • Lin MW, D Curtis, N Williams, M Arranz, S Nanko, D Collier, P McGuffin, R Murray, M Owen, M Gill and J Powell (1995) Suggestive evidence for linkage of schizophrenia to markers on chromosome 13q14.1-q32.Psychiatr. Genet. 5, 117–126.

    Article  PubMed  CAS  Google Scholar 

  • Lin MW, P Sham, HG Hwu, D Collier, R Murray and JF Powell (1997) Suggestive evidence for linkage of schizophrenia to markers on chromosome 13 in Caucasian but not Oriental populations.Hum. Genet. 99, 417–420.

    Article  PubMed  CAS  Google Scholar 

  • Lindholm E, B Ekholm, J Balciuniene, G Johansson, A Castensson, M Koisti, PO Nylander, U Pettersson, R Adolfsson and E Jazin (1999) Linkage analysis of a large Swedish kindred provides further support for a susceptibility locus for schizophrenia on chromosome 6p23.Am. J. Med. Genet. 88, 369–377.

    Article  PubMed  CAS  Google Scholar 

  • Liu CM, HG Hwu, MW Lin, WC Ou-Yang, SF Lee, CS Fann, SH Wong and SH Hsieh (2001) Suggestive evidence for linkage of schizophrenia to markers at chromosome 15q13-14 in Taiwanese families.Am. J. Med. Genet. 105, 658–661.

    Article  PubMed  CAS  Google Scholar 

  • Martin ER, SA Monks, LL Warren and NL Kaplan (2000) A test for linkage and association in general pedigrees, The Pedigree Disequilibrium Test.Am. J. Hum. Genet. 67, 146–154.

    Article  PubMed  CAS  Google Scholar 

  • Martinez M, LR Goldin, Q Cao, J Zhang, AR Sanders, DJ Nancarrow, JM Taylor, DF Levinson, A Kirby, RR Crowe, NJ Andreasen, DW Black, JM Silverman, DP Lennon, DA Nertney, DM Brown, BJ Mowry, ES Gershon and PV Gejman (1999) Follow-up study on a susceptibility locus for schizophrenia on chromosome 6q.Am. J. Med. Genet. 88, 337–343.

    Article  PubMed  CAS  Google Scholar 

  • Maziade M, L Bissonnette, E Rouillard, M Martinez, M Turgeon, L Charron, V Pouliot, P Boutin, D Cliche, C Dion, JP Fournier, Y Garneau, JC Lavallee, N Montgrain, L Nicole, A Pires, AM Ponton, A Potvin, H Wallot, MA Roy and C Merette (1997) 6p24-22 region and major psychoses in the Eastern Quebec population. Le Groupe IREP.Am. J. Med. Genet. 74, 311–318.

    Article  PubMed  CAS  Google Scholar 

  • McGue M, I Gottesman and DC Rao (1985) Resolving genetic models for the transmission of schizophrenia.Genet. Epidem. 2, 99–110.

    Article  CAS  Google Scholar 

  • Millar JK, J Brown, JC Maule, Y Shibasaki, S Christie, D Lawson, S Anderson, JC Wilson-Annan, RS Devon, DM St Clair, DHR Blackwood, WJ Muir and DJ Porteous (1998) A long-range restriction map across 3 Mb of the chromosome 11 breakpoint region of a translocation linked to schizophrenia, localization of the breakpoint and the search for neighboring genes.Psychiatr. Genet. 8, 175–181.

    Article  PubMed  CAS  Google Scholar 

  • Millar JK, JC Wilson-Annan, S Anderson, S Christie, MS Taylor, CAM Semple, RS Devon, DM St Clair, WJ Muir, DHR Blackwood and DJ Porteous (2000) Disruption of two novel genes by a translocation co-segregating with schizophrenia.Hum. Mol. Genet. 9, 1415–1423.

    Article  PubMed  CAS  Google Scholar 

  • Mirnics K, FA Middleton, DA Lewis and P Levitt (2001) Analysis of complex brain disorders with gene expression microarrays, schizophrenia as a disease of the synapse.Trends Neurosci. 24, 479–486.

    Article  PubMed  CAS  Google Scholar 

  • Moises HW, L Yang, H Kristbjarnarson, C Wiese, W Byerley, F Macciardi, V Arolt, D Blackwood, X Liu, B Sjogren, HN Aschauer, HG Hwu, K Jang, WJ Livesley, JL Kennedy, T Zoega, O Ivarsson, MT Bui, MH Yuet al. (1995) An international two-stage genome-wide search for schizophrenia susceptibility genes.Nat. Genetics 11, 321–324.

    Article  CAS  Google Scholar 

  • Murphy KC, LA Jones and MJ Owen (1999) High rates of schizophrenia in adults with velo-cardio-facial syndrome.Arch. Gen. Psychiatr. 56, 940–945.

    Article  PubMed  CAS  Google Scholar 

  • Ogura Y, DK Bonen, N Inohara, DL Nicolae, FF Chen, R Ramos, H Britton, T Moran, R Karaliuskas, RH Duerr, JP Achkar, SR Brant, TM Bayless, BS Kirschner, SB Hanauer, G Nunez and JH Cho (2001) A frameshift mutation in NOD2 associated with susceptibility to Crohn’s disease.Nature 411, 603–606

    Article  PubMed  CAS  Google Scholar 

  • Polymeropoulos MH, H Coon, W Byerley, ES Gershon, L Goldin, TJ Crow, J Rubenstein, M Hoff, J Holik, AM Smith, G Shields, NJ Bass, M Poulter, R Lofthouse, A Vita, C Morganti, CR Merril and LE DeLisi (1994) Search for a schizophrenia susceptibility locus on human chromosome 22.Am. J. Med. Genet. 54, 93–99.

    Article  PubMed  CAS  Google Scholar 

  • Prescott CA and II Gottesman (1993) Genetically mediated vulnerability to schizophrenia.Psychiatric Clin. N. Am. 16, 245–267.

    CAS  Google Scholar 

  • Pulver AE, M Karayiorgou, VK Lasseter, P Wolyniec, L Kasch, S Antonarakis, D Housman, HH Kazazian, D Meyers, G Nestadt, J Ott, KY Liang, M Lamacz, M Thomas, B Childs, SR Diehl, S Wang, B Murphy, CE Sunet al. (1994a) Follow-up of a report of a potential linkage for schizophrenia on chromosome 22q12-q13.1. Part 2.Am. J. Med. Genet. 54, 44–50.

    Article  PubMed  CAS  Google Scholar 

  • Pulver AE, M Karayiorgou, PS Wolyniec, VK Lasseter, L Kasch, G Nestadt, S Antonarakis, D Housman, HH Kazazian, D Meyers, J Ott, M Lamacz, KY Liang, J Hanfelt, G Ullrich, N DeMarchi, E Ramu, PR McHugh, L Adleret al. (1994b) Sequential strategy to identify a susceptibility gene for schizophrenia. Report of potential linkage on chromosome 22q12-q13.1. Part 1.Am. J. Med. Genet. 54, 36–43.

    Article  PubMed  CAS  Google Scholar 

  • Pulver AE, G Nestadt, R Goldberg, RJ Shprintzen, PS Lamacz, PS Wolyniec, B Morrow, M Karayiorgou, SE Antonarakis, D Housman and R Kucherlapati (1994c) Psychotic illness in patients diagnosed with velo-cardio-facial syndrome and their relatives.J. Nerv. Ment. Dis. 182, 476–478.

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Ray PN, B Belfall, C Duff, C Logan, V Kean, MW Thompson, JE Sylvester, JL Gorski, RD Schmickel and RG Worton (1985) Cloning of the breakpoint of an X;21 translocation associated with Duchenne muscular dystrophy.Nature 318, 672–675.

    Article  PubMed  CAS  Google Scholar 

  • Riley BP and P McGuffin (2000) Linkage and associated studies of schizophrenia.Am. J. Med. Genet. Seminars in Medical Genetics 97, 23–44.

    Article  CAS  Google Scholar 

  • Riley BP, E Tahir, S Rajagopalan, M Mogudi-Carter, S Faure, J Weissenbach, T Jenkins and R Williamson (1997) A linkage study of theN-methyl-D-aspartate receptor subunit gene loci and schizophrenia in southern African Bantu-speaking families.Psychiatr. Genet. 7, 57–74.

    Article  PubMed  CAS  Google Scholar 

  • Riley BP, A Makoff, M Mogudi-Carter, T Jenkins, R Williamson, D Collier and R Murray (2000) Haplotype transmission disequilibrium and evidence for linkage of the CHRNA7 gene region to schizophrenia in southern African Bantu families.Am. J. Med. Genet. 96, 196–201.

    Article  PubMed  CAS  Google Scholar 

  • Risch N (1990) Linkage strategies for genetically complex traits. I. Multilocus models.Am. J. Hum. Genet. 46, 222–228.

    PubMed  CAS  Google Scholar 

  • Sawcer S, HB Jones, R Feakes, J Gray, N Smaldon, J Chataway, N Robertson, D Clayton, PN Goodfellow and A Compston (1996) A genome screen in multiple sclerosis reveals susceptibility loci on chromosome 6p21 and 17q22.Nat. Genet. 13, 464–468.

    Article  PubMed  CAS  Google Scholar 

  • Schwab SG, M Albus, J Hallmayer, S Honig, M Borrmann, D Lichtermann, RP Ebstein, M Ackenheil, B Lerer, N Risch, W Maier and DB Wildenauer (1995) Evaluation of a susceptibility gene for schizophrenia on chromosome 6p by multipoint affected sib-pair linkage analysis.Nat. Genet. 11, 325–327.

    Article  PubMed  CAS  Google Scholar 

  • Schwab SG, GN Eckstein, J Hallmayer, B Lerer, M Albus, M Borrmann, D Lichtermann, MA Ertl, W Maier and DB Wildenauer (1997) 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 2, 156–160.

    Article  PubMed  CAS  Google Scholar 

  • Schwab SG, J Hallmayer, M Albus, B Lerer, C Hanses, K Kanyas, R Segman, M Borrman, B Dreikorn, D Lichtermann, M Rietschel, M Trixler, W Maier and DB Wildenauer (1998) Further evidence for a susceptibility locus on chromosome 10p14-p11 in 72 families with schizophrenia by nonparametric linkage analysis.Am. J. Med. Genet. 81, 302–307.

    Article  PubMed  CAS  Google Scholar 

  • Schwab SG, M Knapp, S Mondabon, J Hallmayer, M Borrmann-Hassenbach, M Albus, B Lerer, M Rietschel, M Trixler, W Maier and DB Wildenauer (2003) Support for association of schizophrenia with genetic variation in the 6p22.3 gene, dysbindin, in sib-pair families with linkage and in an additional sample of triad families.Am. J. Hum. Genet. 72, 185–190.

    Article  PubMed  CAS  Google Scholar 

  • Shaw SH, M Kelly, AB Smith, G Shields, PJ Hopkins, J Loftus, SH Laval, A Vita, M De Hert, LR Cardon, TJ Crow, R Sherrington and LE DeLisi (1998) A genome-wide search for schizophrenia susceptibility genes.Am. J. Med. Genet. 81, 364–376.

    Article  PubMed  CAS  Google Scholar 

  • Sherrington R, J Brynjolfsson, H Petursson, M Potter, K Dudleston, B Barraclough, J Wasmuth, M Dobbs and H Gurling (1988) Localization of a susceptibility locus for schizophrenia on chromosome 5.Nature 336, 164–167.

    Article  PubMed  CAS  Google Scholar 

  • Shifman S, M Bronstein, M Sternfeld, A Pisante-Shalom, E Lev-Lehman, A Weizman, I Reznik, B Spivak, N Grisaru, L Karp, R Schiffer, M Kotler, RD Strous, M Swartz-Vanetik, HY Knobler, E Shinar, JS Beckmann, B Yakir, N Risch, NB Zak and A Darvasi (2002) A Highly significant association between a COMT haplo-type and schizophrenia.Am. J. Hum. Genet. 71, 1296–1302.

    Article  PubMed  CAS  Google Scholar 

  • Spielman RS and WJ Ewens (1996) The TDT and other family-based tests for linkage disequilibrium and association.Am. J. Hum. Genet. 59, 983–989.

    PubMed  CAS  Google Scholar 

  • St Clair D, D Blackwood, W Muir, A Carothers, M Walker, G Spowart, C Gosden and HJ Evans (1990) Association within a family of a balanced autosomal translocation with major mental illness.Lancet 336, 13–16.

    Article  PubMed  CAS  Google Scholar 

  • Stefansson H, E Sigurdsson, V Steinthorsdottir, S Bjornsdottir, T Sigmundsson, S Ghosh, J Brynjolfsson, S Gunnarsdottir, O Ivarsson, TT Chou, O Hjaltason, B Birgisdottir, H Jonsson, VG Gudnadottir, E Gudmundsdottir, A Bjornsson, B Ingvarsson, A Ingason, S Sigfusson, H Hardardottir, RP Harvey, D Lai, M Zhou, D Brunner, V Mutel, A Gonzalo, G Lemke, J Sainz, G Johannesson, T Andresson, D Gudbjartsson, A Manolescu, ML Frigge, ME Gurney, A Kong, JR Gulcher, H Petursson and K Stefansson (2002) Neuregulin 1 and susceptibility to schizophrenia.Am. J. Hum. Genet. 71, 877–892.

    Article  PubMed  Google Scholar 

  • Straub RE, CJ MacLean, FA O’Neill, J Burke, B Murphy, F Duke, R Shinkwin, BT Webb, J Zhang, D Walsh and KS Kendler (1995) A potential vulnerability locus for schizophrenia on chromosome 6p24-22. Evidence for genetic heterogeneity.Nat. Genetics 11, 287–293.

    Article  CAS  Google Scholar 

  • Straub RE, CJ MacLean, FA O’Neill, D Walsh and KS Kendler (1997) Support for a possible schizophrenia vulnerability locus in region 5q22-31 in Irish families.Mol. Psychiatry 2, 148–155.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Straub RE, Y Jiang, CJ MacLean, Y Ma, BT Webb, MV Myakishev, C Harris-Kerr, B Wormley, H Sadek, B Kadambi, AT Cesare, A Gibberman, FA O’Neill, D Walsh and KS Kendler (2002) Genetic variation in the 6p22.3 gene DTNBP1, the human ortholog of mouse dysbindin, is associated with schizophrenia.Am. J. Hum. Genet. 71, 337–348.

    Article  PubMed  CAS  Google Scholar 

  • Tienari P (1991) Interaction between genetic vulnerability and family environment, the Finnish adoptive family study of schizophrenia.Acta Psychiatrica Scand. 84, 460–465.

    Article  CAS  Google Scholar 

  • Tsuang DW, AD Skol, SV Faraone, S Bingham, KA Young, S Prabhudesai, SL Haverstock, F Mena, AS Menon, D Bisset, J Pepple, F Sauter, C Baldwin, D Weiss, J Collins, M Boehnke, GD Schellenberg and MT Tsuang (2001) Examination of genetic linkage of chromosome 15 to schizophrenia in a large Veterans Affairs Cooperative Study sample.Am. J. Med. Genet. 105, 662–668.

    Article  PubMed  CAS  Google Scholar 

  • van den Oord E, PF Sullivan, X Chen, KS Kendler and B Riley (2003) Identification of a high risk haplotype for the dystro-brevin binding protein 1 (DTNBP1) gene in the Irish study of high density schizophrenia families.Mol. Psychiatry 8, 499–510.

    Article  CAS  Google Scholar 

  • Vionnet N, E Hani, S Dupont, S Gallina, S Francke, S Dotte, F De Matos, E Durand, F Lepretre, C Lecoeur, P Gallina, L Zekiri, C Dina and P Froguel (2000) Genomewide search for type 2 diabetes-susceptibility genes in French whites, evidence for a novel susceptibility locus for early-onset diabetes on chromosome 3q27-qter and independent replication of a type 2-diabetes locus on chromosome 1q21-q24.Am. J. Hum. Genet. 67, 1470–1480.

    Article  PubMed  CAS  Google Scholar 

  • Wiltshire S, AT Hattersley, GA Hitman, M Walker, JC Levy, M Sampson, S O’Rahilly, TM Frayling, JI Bell, GM Lathrop, A Bennett, R Dhillon, C Fletcher, CJ Groves, E Jones, P Prestwich, N Simecek, PV Rao, M Wishart, R Foxon, S Howell, D Smedley, LR Cardon, S Menzel, MI McCarthy and GF Bottazzo (2001) A genomewide scan for loci predisposing to type 2 diabetes in a U.K. population (the Diabetes UK Warren 2 Repository), analysis of 573 pedigrees provides independent replication of a susceptibility locus on chromosome 1q.Am. J. Hum. Genet. 69, 553–569.

    Article  PubMed  CAS  Google Scholar 

  • Xu J, MT Pato, CD Torre, H Medeiros, C Carvalho, VS Basile, A Bauer, A Dourado, J Valente, MJ Soares, AA Macedo, I Coelho, CP Ferreira, MH Azevedo, F Macciardi, JL Kennedy and CN Pato (2001) Evidence for linkage disequilibrium between the a 7-nicotinic receptor gene (CHRNA7) locus and schizophrenia in Azorean families.Am. J. Med. Genet. 105, 669–674.

    Article  PubMed  CAS  Google Scholar 

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  1. Departments of Psychiatry and Human Genetics, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, USA

    Brien Riley

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Riley, B. Linkage studies of schizophrenia. neurotox res 6, 17–34 (2004). https://doi.org/10.1007/BF03033293

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