Skip to main content

Advertisement

SpringerLink
Log in

Genome scans and gene expression microarrays converge to identify gene regulatory loci relevant in schizophrenia

  • Original Investigation
  • Published:
Human Genetics Aims and scope Submit manuscript

Abstract

Multiple linkage regions have been reported in schizophrenia, and some appear to harbor susceptibility genes that are differentially expressed in postmortem brain tissue derived from unrelated individuals. We combined traditional genome-wide linkage analysis in a multiplex family with lymphocytic genome-wide expression analysis. A genome scan suggested linkage to a chromosome 4q marker (D4S1530, LOD 2.17, θ=0) using a dominant model. Haplotype analysis using flanking microsatellite markers delineated a 14 Mb region that cosegregated with all those affected. Subsequent genome-wide scan with SNP genotypes supported the evidence of linkage to 4q33–35.1 (LOD=2.39) using a dominant model. Genome-wide microarray analysis of five affected and five unaffected family members identified two differentially expressed genes within the haplotype AGA and GALNT7 (aspartylglucosaminidase and UDP-N-acetyl-alpha-D-galactosamine: polypeptide N-acetylgalactosaminyltransferase 7) with nominal significance; however, these genes did not remain significant following analysis of covariance. We carried out genome-wide linkage analyses between the quantitative expression phenotype and genetic markers. AGA expression levels showed suggestive linkage to multiple markers in the haplotype (maximum LOD=2.37) but to no other genomic region. GALNT7 expression levels showed linkage to regulatory loci at 4q28.1 (maximum LOD=3.15) and in the haplotype region at 4q33–35.1 (maximum LOD=2.37). ADH1B (alcohol dehydrogenase IB) was linked to loci at 4q21–q23 (maximum LOD=3.08) and haplotype region at 4q33–35.1 (maximum LOD=2.27). Seven differentially expressed genes were validated with RT-PCR. Three genes in the 4q33–35.1 haplotype region were also differentially expressed in schizophrenia in postmortem dorsolateral prefrontal cortex: AGA, HMGB2, and SCRG1. These results indicate that combining differential gene expression with linkage analysis may help in identifying candidate genes and potential regulatory sites. Moreover, they also replicate recent findings of complex trans- and cis- regulation of genes.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  • Abecasis GR, Cherny SS, Cookson WO, Cardon LR (2002) Merlin—rapid analysis of dense genetic maps using sparse gene flow trees. Nat Genet 30:97–101

    Article  PubMed  CAS  Google Scholar 

  • Cheung VG, Spielman RS (2002) The genetics of variation in gene expression. Nat Genet 32(Suppl):522–525

    Article  PubMed  CAS  Google Scholar 

  • Cheung VG, Conlin LK, Weber TM, Arcaro M, Jen KY, Morley M, Spielman RS (2003) Natural variation in human gene expression assessed in lymphoblastoid cells. Nat Genet 33:422–425

    Article  PubMed  CAS  Google Scholar 

  • Consalvi V, Mardh G, Vallee BL (1986) Human alcohol dehydrogenases and serotonin metabolism. Biochem Biophys Res Commun 139:1009–1016

    Article  PubMed  CAS  Google Scholar 

  • Coon H, Jensen S, Holik J, Hoff M, Myles-Worsley M, Reimherr F, Wender P, Waldo M, Freedman R, Leppert M et al (1994) Genomic scan for genes predisposing to schizophrenia. Am J Med Genet 54:59–71

    Article  PubMed  CAS  Google Scholar 

  • Dai M, Wang P, Boyd AD, Kostov G, Athey B, Jones EG, Bunney WE, Myers RM, Speed TP, Akil H, Watson SJ, Meng F (2005) Evolving gene/transcript definitions significantly alter the interpretation of GeneChip data. Nucleic Acids Res 33(20):e175

    Article  PubMed  Google Scholar 

  • Ekelund J, Lichtermann D, Hovatta I, Ellonen P, Suvisaari J, Terwilliger JD, Juvonen H, Varilo T, Arajarvi R, Kokko-Sahin ML et al (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 

  • Fallin MD, Lasseter VK, Wolyniec PS, McGrath JA, Nestadt G, Valle D, Liang KY, Pulver AE (2003) Genomewide linkage scan for schizophrenia susceptibility loci among Ashkenazi Jewish families shows evidence of linkage on chromosome 10q22. Am J Hum Genet 73:601–611

    Article  PubMed  CAS  Google Scholar 

  • Gurling HM, Kalsi G, Brynjolfson J, Sigmundsson T, Sherrington R, Mankoo BS, Read T, Murphy P, Blaveri E, McQuillin A et al (2001) 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 68:661–673

    Article  PubMed  CAS  Google Scholar 

  • Harrison PJ, Owen MJ (2003) Genes for schizophrenia? Recent findings and their pathophysiological implications. Lancet 361:417–419

    Article  PubMed  CAS  Google Scholar 

  • Helander A, Walzer C, Beck O, Balant L, Borg S, von Wartburg JP (1994) Influence of genetic variation in alcohol and aldehyde dehydrogenase on serotonin metabolism. Life Sci 55:359–366

    Article  PubMed  CAS  Google Scholar 

  • Horvath S, Baur MP (2000) Future directions of research in statistical genetics. Stat Med 19:3337–3343

    Article  PubMed  CAS  Google Scholar 

  • Hovatta I, Varilo T, Suvisaari J, Terwilliger JD, Ollikainen V, Arajarvi R, Juvonen H, Kokko-Sahin ML, Vaisanen L, Mannila H et al (1999) A genomewide 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 

  • Irizarry RA, Hobbs B, Collin F, Beazer-Barclay YD, Antonellis KJ, Scherf U, Speed TP (2003) Exploration, normalization, and summaries of high density oligonucleotide array probe level data. Biostatistics 4:249–264

    Article  PubMed  Google Scholar 

  • Kaufmann CA, Suarez B, Malaspina D, Pepple J, Svrakic D, Markel PD, Meyer J, Zambuto CT, Schmitt K, Matise TC et al (1998) NIMH genetics initiative millenium schizophrenia consortium: linkage analysis of African-American pedigrees. Am J Med Genet 81:282–289

    Article  PubMed  CAS  Google Scholar 

  • Kennedy JL, Macciardi FM (1998) Chromosome 4 workshop. Psychiatr Genet 8:67–71

    Article  PubMed  CAS  Google Scholar 

  • Knight JC (2005) Regulatory polymorphisms underlying complex disease traits. J Mol Med 83:97–109

    Article  PubMed  CAS  Google Scholar 

  • Kraft P, Schadt E, Aten J, Horvath S (2003) A family-based test for correlation between gene expression and trait values. Am J Hum Genet 72:1323–1330

    Article  PubMed  CAS  Google Scholar 

  • Kruglyak L, Daly M, Lander E (1995) Rapid multipoint linkage analysis of recessive traits in nuclear families, including homozygosity mapping. Am J Hum Genet 56:519–527

    PubMed  CAS  Google Scholar 

  • Kruglyak L, Daly MJ, Reeve-Daly MP, Lander ES (1996) Parametric and nonparametric linkage analysis: a unified multipoint approach. Am J Hum Genet 58:1347–1363

    PubMed  CAS  Google Scholar 

  • Lander E, Green P (1987) Construction of multilocus genetic linkage maps in humans. Proc Natl Acad Sci USA 84:2363–2367

    Article  PubMed  CAS  Google Scholar 

  • Levinson DF, Mahtani MM, Nancarrow DJ, Brown DM, Kruglyak L, Kirby A, Hayward NK, Crowe RR, Andreasen NC, Black DW et al (1998) Genome scan of schizophrenia. Am J Psychiatry 155:741–750

    PubMed  CAS  Google Scholar 

  • Lewis CM, Levinson DF, Wise LH, DeLisi LE, Straub RE, Hovatta I, Williams NM, Schwab SG, Pulver AE, Faraone SV et al (2003) Genome scan meta-analysis of schizophrenia and bipolar disorder, part II: Schizophrenia. Am J Hum Genet 73:34–48

    Article  PubMed  CAS  Google Scholar 

  • Leykin I, Hao K, Cheng J, Meyer N, Pollak MR, Smith RJ, Wong WH, Rosenow C, Li C (2005) Comparative linkage analysis and visualization of high-density oligonucleotide SNP array data. BMC Genet 6:7

    Article  PubMed  Google Scholar 

  • Matsuo Y, Yokoyama S (1989) Molecular structure of the human alcohol dehydrogenase 1 gene. FEBS Lett 243:57–60

    Article  PubMed  CAS  Google Scholar 

  • Matsuo Y, Yokoyama R, Yokoyama S (1989) The genes for human alcohol dehydrogenases beta 1 and beta 2 differ by only one nucleotide. Eur J Biochem 183:317–320

    Article  PubMed  CAS  Google Scholar 

  • Middleton FA, Pato MT, Gentile KL, Morley CP, Zhao X, Eisener AF, Brown A, Petryshen TL, Kirby AN, Medeiros, et al (2004) Genomewide linkage analysis of bipolar disorder by use of a high-density single-nucleotide-polymorphism (SNP) genotyping assay: a comparison with microsatellite marker assays and finding of significant linkage to chromosome 6q22. Am J Hum Genet 74:886–897

    Article  PubMed  CAS  Google Scholar 

  • Middleton FA, Pato CN, Gentile KL, McGann L, Brown AM, Trauzzi M, et al (2005) Gene expression analysis of peripheral blood leukocytes from discordant sib-pairs with schizophrenia and bipolar disorder reveals points of convergence between genetic and functional genomic approaches. Am J Med Genet B Neuropsychiatr Genet 136(1):12–25

    Google Scholar 

  • Monks SA, Leonardson A, Zhu H, Cundiff P, Pietrusiak P, Edwards S, Phillips JW, Sachs A, Schadt EE (2004) Genetic inheritance of gene expression in human cell lines. Am J Hum Genet 75:1094–1105

    Article  PubMed  CAS  Google Scholar 

  • Morley M, Molony CM, Weber TM, Devlin JL, Ewens KG, Spielman RS, Cheung VG (2004) Genetic analysis of genome-wide variation in human gene expression. Nature 430:743–747

    Article  PubMed  CAS  Google Scholar 

  • Mowry BJ, Ewen KR, Nancarrow DJ, Lennon DP, Nertney DA, Jones HL, O’Brien MS, Thornley CE, Walters MK, Crowe RR et al (2000) Second stage of a genome scan of schizophrenia: study of five positive regions in an expanded sample. Am J Med Genet 96:864–869

    Article  PubMed  CAS  Google Scholar 

  • O’Donovan MC, Williams NM, Owen MJ (2003) Recent advances in the genetics of schizophrenia. Hum Mol Genet 12(2):R125–R133

    Article  PubMed  CAS  Google Scholar 

  • Paunio T, Ekelund J, Varilo T, Parker A, Hovatta I, Turunen JA, Rinard K, Foti A, Terwilliger JD, Juvonen H et al (2001) Genome-wide scan in a nationwide study sample of schizophrenia families in Finland reveals susceptibility loci on chromosomes 2q and 5q. Hum Mol Genet 10:3037–3048

    Article  PubMed  CAS  Google Scholar 

  • Schadt EE, Monks SA, Drake TA, Lusis AJ, Che N, Colinayo V, Ruff TG, Milligan SB, Lamb JR, Cavet G et al (2003a) Genetics of gene expression surveyed in maize, mouse and man. Nature 422:297–302

    Article  CAS  Google Scholar 

  • Schadt EE, Monks SA, Friend SH (2003b) A new paradigm for drug discovery: integrating clinical, genetic, genomic and molecular phenotype data to identify drug targets. Biochem Soc Trans 31:437–443

    Article  CAS  Google Scholar 

  • Sham PC, Purcell S, Cherny SS, Abecasis GR (2002) Powerful regression-based quantitative-trait linkage analysis of general pedigrees. Am J Hum Genet 71:238–253

    Article  PubMed  CAS  Google Scholar 

  • Stefansson H, Sigurdsson E, Steinthorsdottir V, Bjornsdottir S, Sigmundsson T, Ghosh S, Brynjolfsson J, Gunnarsdottir S, Ivarsson O, Chou TT et al (2002) Neuregulin 1 and susceptibility to schizophrenia. Am J Hum Genet 71:877–892

    Article  PubMed  Google Scholar 

  • Straub RE, MacLean CJ, Ma Y, Webb BT, Myakishev MV, Harris-Kerr C, Wormley B, Sadek H, Kadambi B, O’Neill FA et al (2002) 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 7:542–559

    Article  PubMed  CAS  Google Scholar 

  • Straub RE, Jiang Y, MacLean CJ, Ma Y, Webb BT, Myakishev MV, Harris-Kerr C, Wormley B, Sadek H, Kadambi B et al (2002) Genetic variation in the 6p22.3 gene DTNBP1, the human ortholog of the mouse dysbindin gene, is associated with schizophrenia. Am J Hum Genet 71:337–348

    Article  PubMed  CAS  Google Scholar 

  • Svensson S, Some M, Lundsjo A, Helander A, Cronholm T, Hoog JO (1999) Activities of human alcohol dehydrogenases in the metabolic pathways of ethanol and serotonin. Eur J Biochem 262:324–329

    Article  PubMed  CAS  Google Scholar 

  • Tsuang MT, Nossova N, Yager T, Tsuang M, Guo S, Shyu K, Glatt SJ, Liew CC (2005) Assessing the validity of blood-based gene expression profiles for the classification of schizophrenia and bipolar disorder: a preliminary report. Am J Med Genet B Neuropsychiatr Genet 133:1–5

    Google Scholar 

  • Vawter MP, Ferran E, Galke B, Cooper K, Bunney WE, Byerley W (2004) Microarray screening of lymphocyte gene expression differences in a multiplex schizophrenia pedigree. Schizophr Res 67:41–52

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by the William Lion Penzner Foundation (UCI Department of Psychiatry and Human Behavior) and the NIMH RMH074307A award (MPV). Postmortem brain tissue was donated by The Stanley Medical Research Institute’s brain collection courtesy of Dr. Michael B. Knable, Dr. E. Fuller Torrey, Dr. Maree J. Webster, Dr. Serge Weis, and Dr. Robert H. Yolken.

Author information

Authors and Affiliations

  1. Department of Psychiatry and Human Behavior, Functional Genomics Laboratory, College of Medicine, University of California, Irvine, CA, 92697, USA

    Marquis P. Vawter, Mary E. Atz, Brandi L. Rollins & Ling Shao

  2. Department of Biological Chemistry, University of California Irvine, Irvine, CA, 92697, USA

    Kathleen M. Cooper-Casey

  3. Veterans Administration Medical Center, University of California, San Francisco, CA, 94121, USA

    William F. Byerley

Authors
  1. Marquis P. Vawter
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mary E. Atz
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Brandi L. Rollins
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kathleen M. Cooper-Casey
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ling Shao
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. William F. Byerley
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Marquis P. Vawter.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Vawter, M.P., Atz, M.E., Rollins, B.L. et al. Genome scans and gene expression microarrays converge to identify gene regulatory loci relevant in schizophrenia. Hum Genet 119, 558–570 (2006). https://doi.org/10.1007/s00439-006-0172-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00439-006-0172-7

Keywords

Search

Navigation