- Nicotinic receptor
- Permutation testing
- Candidate genes
Smoking is a common correlate of schizophrenia, which leads to medical morbidity. Although twin and adoption studies have consistently implicated genes in the etiology of both smoking and schizophrenia, finding genes has been difficult. Several authors have suggested that clinical or neurobiological features associated with schizophrenia, such as smoking, might improve the ability to detect schizophrenia susceptibility genes by identifying genes related to the etiology of that feature. The objective of this study is to assess evidence for linkage of sixteen nicotinic acetylcholine receptor genes and smoking in schizophrenia families, using data from the NIMH Genetics Initiative for schizophrenia. Sixteen nicotinic acetylcholine receptor genes were selected prior to analysis. We used a multipoint sibling pair linkage analysis program, SIBPAL2, with a smoking trait in schizophrenia families. The significance of the group of candidate genes, in addition to each individual candidate gene, was assessed using permutation testing, which adjusted for multiple comparisons. The group of genes showed significant linkage to the smoking trait after adjusting for multiple comparisons through permutation testing (p = 0.039). In addition, two of the individual candidate genes were significant (CHRNA2, p = 0.044) and (CHRNB2, p = 0.015) and two genes were marginally significant (CHRNA7, p = 0.095; CHRNA1, p = 0.076). The significance of the complex hypothesis, involving sixteen genes, implicates the nicotinic system in smoking for schizophrenic families. Individual gene analysis suggests that CHRNA2 and CHRNB2 may play a particular role in this involvement. Such findings help prioritize genes for future case control studies. In addition, we provide a novel permutation method that is useful in future analyses involving a single hypothesis, with multiple candidate genes.
Copyright © 2004 S. Karger AG, Basel
- Adler LE, Hoffer LJ, et al: Normalization by nicotine of deficient auditory sensory gating in the relatives of schizophrenics. Biological Psychiatry 1992;32:607–616.
- Adler LE, Hoffer LJ, et al: Normalization of auditory physiology by cigarette smoking in schizophrenic patients. American Journal of Psychiatry 1993;150:1856–1861.
- Adler LE, Olincy A, et al: Schizophrenia, sensory gating, and nicotinic receptors. Schizophrenia Bulletin 1998;24:189–202.
- Badner J, Gershon E: Meta-analysis of whole-genome linkage scans of bipolar disorder and schizophrenia. Mol Psychiatry 2002;7:405–411.
- Bergen A, Korczak J, et al: A genome-wide search for loci contributing to smoking and alcoholism. Genetic Epidemiology 1999;17(suppl 1):S55–S60.
- Bernaards CM, Kemper HC, et al: Smoking behaviour and biological maturation in males and females: A 20-year longitudinal study. Analysis of data from the Amsterdam Growth and Health Longitudinal Study. Ann Hum Biol 2001;28:634–648.
- Blaveri E, Kalsi G, et al: Genetic association studies of schizophrenia using the 8p21–22 genes: Prepronociceptin (PNOC), neuronal nicotinic cholinergic receptor alpha polypeptide 2 (CHRNA2) and arylamine N-acetyltransferase 1 (NAT1). European Journal of Human Genetics 2001;9:469–472.
- Blouin J, Dombroski BA, et al: Schizophrenia susceptibility loci on chromosomes 13q32 and 8p21. Nature Genetics 1998;28:70–73.
- Brzustowicz LM, Hodgkinson KA, et al: Location of a major susceptibility locus for familial schizophrenia on chromosome 1q21-q22. Science 2000;288:678–682.
- Brzustowicz LM, Honer WG, et al: Linkage of familial schizophrenia to chromosome 13q32. American Journal of Human Genetics 1999;65:1096–1103.
- Cloninger CR, Kaufmann CA, et al: Genome-wide search for schizophrenia susceptibility loci: the NIMH Genetics Initiative and Millennium Consortium. American Journal of Medical Genetics (Neuropsychiatric Genetics) 1998;81:275–281.
- Cloninger CR, Van Eerdewegh P, et al: Anxiety proneness linked to epistatic loci in genome scan of human personality traits. American Journal of Medical Genetics (Neuropsychiatric Genetics) 1998;81:313–317.
- Coon H, Jensen S, et al: Genomic scan for genes predisposing to schizophrenia. American Journal of Medical Genetics (Neuropsychiatric Genetics) 1994;54:59–71.
- Crumpacker DW, Cederlof R, et al: A twin methodology for the study of genetic and environmental control of variation in human smoking behavior. Acta Genet Med Gemellol (Roma) 1979;28(3):173–195.
- Curtis L, Blouin JL, et al: No evidence for linkage between schizophrenia and markers at chromosome 15q13–14. American Journal of Medical Genetics (Neuropsychiatric Genetics) 1999;88(2):109–112.
- de Leon J, Diaz FJ, et al: Initiation of daily smoking and nicotine dependence in schizophrenia and mood disorders. Schizophr Res 2002;56:47–54.
- DeLisi LE, Shaw S, et al: Lack of evidence for linkage to chromosomes 13 and 8 for schizophrenia and schizoaffective disorder. American Journal of Medical Genetics (Neuropsychiatric Genetics) 2000;96:235–239.
- Depatie L, O’Driscoll GA, et al: Nicotine and behavioral markers of risk for schizophrenia: a double-blind, placebo-controlled, cross-over study. Neuropsychopharmacology 2002;27:1056–1070.
- Duggirala R, Almasy L, et al: Smoking behavior is under the influence of a major quantitative trait locus on chromosome 5q. Genetic Epidemiology 1999;17(suppl 1):S139–S144.
- Edwards K, Austin M, et al: Evidence for genetic influences on smoking in adult women twins. Clinical Genetics 1995;47:236–244.
- Ekelund J, Lichtermann D, et al: Genome-wide scan for schizophrenia in the Finnish population: evidence for a locus on chromosome 7q22. Human Molecular Genetics 2000;9:1049–1057.
- Elston RC, Buxbaum S, et al: Haseman and elston revisited. Genetic Epidemiology 2000;19:1–17.
- Faraone SV, Blehar M, et al: Diagnostic accuracy and confusability analyses: An application to the diagnostic interview for genetic studies. Psychological Medicine 1996;26:401–410.
- Faraone SV, Kremen WS, et al: Diagnostic accuracy and linkage analysis: How useful are schizophrenia spectrum phenotypes? American Journal of Psychiatry 1995;152:1286–1290.
- Faraone SV, Matise T, et al: Genome scan of European-American schizophrenia pedigrees: results of the NIMH Genetics Initiative and Millennium Consortium. American Journal of Medical Genetics (Neuropsychiatric Genetics) 1998;81:290–295.
- Faraone SV, Skol AD, et al: Linkage of chromosome 13q32 to schizophrenia in a large veterans affairs cooperative study sample. American Journal of Medical Genetics (Neuropsychiatric Genetics) 2002;114:598–604.
- Faraone SV, Tsuang D, et al: Genetics of Mental Disorders: A Guide for Students, Clinicians, and Researchers. New York, NY, Guilford, 1999.
- Freedman R, Coon H, et al: Linkage of a neurophysiological deficit in schizophrenia to a chromosome 15 locus. Proceedings of the National Academy of Sciences of the United States of America 1997;94:587–592.
- Freedman R, Hall M, et al: Evidence in postmortem brain tissue for decreased numbers of hippocampal nicotinic receptors in schizophrenia. Biological Psychiatry 1995;38:22–33.
- Freedman R, Leonard S, et al: Linkage disequilibrium for schizophrenia at the chromosome 15q13–14 locus of the alpha7-nicotinic acetylcholine receptor subunit gene (CHRNA7). American Journal of Medical Genetics (Neuropsychiatric Genetics) 2001;105:20–22.
- Gejman PV, Sanders AR, et al: Linkage analysis of schizophrenia to chromosome 15. American Journal of Medical Genetics (Neuropsychiatric Genetics) 2001;105:789–793.
- Giles GG, Severi G, et al: Smoking and prostate cancer: findings from an Australian case-control study. Ann Oncol 2001;12:761–765.
- Gurling HM, Kalsi G, 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. American Journal of Human Genetics 2001;68:661–673.
- Heath A, Madden P, et al: Personality and the inheritance of smoking behavior: A genetic perspective. Behavioral Genetics 1995;25:103–117.
- Heath A, Martin N: Genetic models for the natural history of smoking: Evidence for a genetic influence on smoking persistence. Addiction Behavior 1993;18:19–34.
- Hernan MA, Zhang SM, et al: Cigarette smoking and the incidence of Parkinson’s disease in two prospective studies. Ann Neurol 2001;50:780–786.
- Hittelman WN: Genetic instability in epithelial tissues at risk for cancer. Ann N Y Acad Sci 2001;952:1–12.
- Hopper J, White V, et al: Alcohol use, smoking habits and the Adult Eysenck Personality Questionnaire in adolescent Australian twins (corrected). Acta Genet Med Gemellol (Roma) 1992;41:311–324.
- Hovatta I, Varilo T, et al: A genomewide screen for schizophrenia genes in an isolated Finnish subpopulation, suggesting multiple susceptibility loci. American Journal of Human Genetics 1999;65:1114–1124.
- Hovatta L, Terwilliger J, et al: Schizophrenia in the genetic isolate of Finland.’ American Journal of Medical Genetics (Neuropsychiatric Genetics) 1997;74:353–360.
- Izenwasser S, Jacocks HM, et al: Nicotine indirectly inhibits [3H]dopamine uptake at concentrations that do not directly promote [3H]dopamine release in rat striatum. J Neurochem 1991;56:603–610.
- Kaprio J, Hammar N, et al: Cigarette smoking and alcohol use in Finland and Sweden: A cross-national twin study. International Journal of Epidemiology 1982;11:378–386.
- Kaufmann CA, Suarez B, et al: NIMH genetics initiative Millennium schizophrenia consortium: linkage analysis of African-American pedigrees. American Journal of Medical Genetics (Neuropsychiatric Genetics) 1998;81:282–289.
- Kendler K, Neale M, et al: A population-based twin study in women of smoking initiation and nicotine dependence. Psychological Medicine 1999;29:299–308.
- Kendler KS, MacLean CJ, et al: Evidence for a schizophrenia vulnerability locus on chromosome 8p in the Irish study of high-density schizophrenia families. American Journal of Psychiatry 1996;153:1534–1540.
- Kendler KS, Myers JM, et al: Clinical features of schizophrenia and linkage to chromosomes 5q, 6p, 8p, and 10p in the Irish study of high-density schizophrenia families. American Journal of Psychiatry 2000;157:402–408.
- Leonard C, Adams C, et al: Nicotinic receptor function in schizophrenia. Schizophrenia Bulletin 1996;22:431–445.
- Leonard S, Gault J, et al: Further investigation of a chromosome 15 locus in schizophrenia: Analysis of affected sibpairs from the NIMH Genetics Initiative. American Journal of Medical Genetics (Neuropsychiatric Genetics) 1998;81:308–312.
- Levinson DF, Holmans P, et al: Multicenter linkage study of schizophrenia candidate regions on chromosomes 5q, 6q, 10p, and 13q: schizophrenia linkage collaborative group III. American Journal of Human Genetics 2000;67(3):652–663.
- Levinson DF, Mahtani MM, et al: Genome scan of schizophrenia. American Journal of Psychiatry 1998;155(6):741–750.
- Lin MW, Curtis D, et al: Suggestive evidence for linkage of schizophrenia to markers on chromosome 13q14.1-q32. Psychiatr Genet 1995;5(3):117–126.
- Lin MW, Sham P, et al: Suggestive evidence for linkage of schizophrenia to markers on chromosome 13 in Caucasian but not Oriental population. Hum Genet 1997;99:417–420.
- Liu C, Hwu H, et al: Suggestive evidence for linkage of schizophrenia to markers at chromosome 15q13–14 in Taiwanese families. American Journal of Medical Genetics (Neuropsychiatric Genetics) 2001;105:658–661.
- Lundman T: Smoking in relation to coronary heart disease and lung function in twins. A co-twin control study. Acta Med Scand Suppl 1966;455:1–75.
- Lyons MJ, Bar JL, et al: Nicotine and familial vulnerability to schizophrenia: A discordant twin study. J Abnorm Psychol 2002;111:687–693.
- Mereu G, Yoon K, et al: Preferential stimulation of ventral tegmental area dopaminergic neurons by nicotine. European Journal of Pharmacology 1987;141:395–399.
- Millar JK, Christie S, et al: Chromosomal location and genomic structure of the human translin-associated factor X gene (TRAX; TSNAX) revealed by intergenic splicing to DISC1, a gene disrupted by a translocation segregating with schizophrenia. Genomics 2000;67:69–77.
- Moises HW, Yang L, et al: An international two-stage genome-wide search for schizophrenia susceptibility genes. Nature Genetics 1995;11:321–324.
- Mowry BJ, Ewen KR, et al: Second stage of a genome scan of schizophrenia: Study of five positive regions in an expanded sample. American Journal of Medical Genetics (Neuropsychiatric Genetics) 2000;96:864–869.
- Neves-Pereira M, Bassett AS, et al: No evidence for linkage of the CHRNA7 gene region in Canadian schizophrenia families. American Journal of Medical Genetics (Neuropsychiatric Genetics) 1998;81:361–363.
- Nurnberger JI Jr, Blehar MC, et al: Diagnostic interview for genetic studies. Rationale, unique features, and training. Archives of General Psychiatry 1994;51:849–859.
- Ott J: Invited editorial: Cutting a Gordian knot in the linkage analysis of complex human traits. American Journal of Human Genetics 1990;46:219–221.
- Paterson D, Nordberg A: Neuronal nicotinic receptors in the human brain. Prog Neurobiol 2000;61:75–111.
- Pulver AE, Lasseter VK, et al: Schizophrenia: A genome scan targets chromosomes 3p and 8p as potential sites of susceptibility genes. American Journal of Medical Genetics (Neuropsychiatric Genetics) 1995;60:252–260.
- Pulver AE, Mulle J, et al: Genetic heterogeneity in schizophrenia: stratification of genome scan data using co-segregating related phenotypes. Molecular Psychiatry 2000;5:650–653.
- Quik M: Thymopoietin, a thymic polypeptide, potently interacts at muscle and neuronal nicotinic alpha-bungarotoxin receptors. Mol Neurobiol 1992;6:19–40.
- Quik M, Afar R, et al: Thymopoietin, a thymic polypeptide, specifically interacts at neuronal nicotinic alpha-bungarotoxin receptors. J Neurochem 1989;53:1320–1323.
- Quik M, Babu U, et al: Evidence for thymopoietin and thymopoietin/alpha-bungarotoxin/nicotinic receptors within the brain. Proceedings of the National Academy of Sciences of the United States of America 1991;88:2603–2607.
- Riley B, Mogudi-Carter M, et al: Further suggestive evidence for the involvement of the alpha7nicotinic cholinergic receptor gene on chromosome 15q13-q14 in schizophrenia. American Journal of Human Genetics 1997;61:232.
- Riley BP, Lin MW, et al: Failure to exclude a possible schizophrenia susceptibility locus on chromosome 13q14.1-q32 in southern African Bantu-speaking families. Psychiatric Genetics 1998;8:155–162.
- Riley BP, Makoff A, et al: Haplotype transmission disequilibrium and evidence for linkage of the CHRNA7 gene region to schizophrenia in Southern African Bantu families. American Journal of Medical Genetics (Neuropsychiatric Genetics) 2000;96:196–201.
- Risch N: Genetic linkage and complex diseases, with special reference to psychiatric disorders. Genetic Epidemiology 1990;7:3–7.
- Schwab SG, Hallmayer J, 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. Molecular Psychiatry 2000;5:638–649.
- Sherr JD, Myers C, et al: The effects of nicotine on specific eye tracking measures in schizophrenia. Biol Psychiatry 2002;52:721–728.
- Smith RC, Singh A, et al: Effects of cigarette smoking and nicotine nasal spray on psychiatric symptoms and cognition in schizophrenia. Neuropsychopharmacology 2002;27:479–497.
- St. Clair D, Blackwood D, et al: Association within a family of a balanced autosomal translocation with major mental illness. Lancet 1990;336:13–16.
- Stassen HH, Bridler R, et al: Schizophrenia and smoking: evidence for a common neurobiological basis? American Journal of Medical Genetics (Neuropsychiatric Genetics) 2000;96:173–177.
- Stober G, Meyer J, et al: Linkage and family-based association study of schizophrenia and the synapsin III locus that maps to chromosome 22q13. American Journal of Medical Genetics (Neuropsychiatric Genetics) 2000;96:392–397.
- Stober G, Saar K, et al: Splitting schizophrenia: periodic catatonia-susceptibility locus on chromosome 15q15. American Journal of Human Genetics 2000;67:1201–1207.
- Straub RE, Sullivan PF, et al: Susceptibility genes for nicotine dependence: A genome scan and followup in an independent sample suggest that regions on chromosomes 2, 4, 10, 16, 17 and 18 merit further study. Molecular Psychiatry 1999;4:129–144.
- True WT, Heath AC, et al: Genetic and environmental contributions to smoking. Addiction 1997;92:1277–1287.
- Tsuang DW, Skol AD, et al: Examination of genetic linkage of chromosome 15 to schizophrenia in a large veterans affairs cooperative study sample. American Journal of Medical Genetics (Neuropsychiatric Genetics) 2001;105:662–668.
- Tsuang MT, Faraone SV: The case for heterogeneity in the etiology of schizophrenia. Schizophrenia Research 1995;17:161–175.
- Tsuang MT, Faraone SV: The Future of Psychiatric Genetics. Current Psychiatry Reports 2000;2:133–136.
- Tsuang MT, Faraone SV, et al: Identification of the phenotype in psychiatric genetics. European Archives of Psychiatry and Clinical Neuroscience 1993;243:131–142.
- Tsuang MT, Stone WS, et al: Schizophrenia: A review of genetic studies. Harvard Review of Psychiatry 1999;7:185–207.
- Waldo MC, Carey G, et al: Codistribution of a sensory gating deficit and schizophrenia in multi-affected families. Psychiatry Research 1991;39:257–268.
- Xu J, Pato MT, et al: Evidence for linkage disequilibrium between the alpha 7-nicotinic receptor gene (CHRNA7) locus and schizophrenia in Azorean families. American Journal of Medical Genetics (Neuropsychiatric Genetics) 2001;105:669–674.
Stephen V. Faraone, PhD
Harvard Medical School
Department of Psychiatry at the Massachusetts General Hospital
37 Shields Ave, Brockton, MA 02301 (USA)
Tel. +1 508 584 6354, Fax +1 508 584 1023, E-Mail email@example.com
Received: August 18, 2002
Accepted after revision: December 29, 2003
Number of Print Pages : 10
Number of Figures : 0, Number of Tables : 4, Number of References : 88
Human Heredity (International Journal of Human and Medical Genetics)
Founded 1950 as Acta Genetica et Statistica Medica by Gunnar Dahlberg; Continued by M. Hauge (1965–1983)
Vol. 57, No. 2, Year 2004 (Cover Date: Released June 2004)
Journal Editor: J. Ott, New York, N.Y.
ISSN: 0001–5652 (print), 1423–0062 (Online)
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