Abstract
Cholinergic dysfunction is one of the hypotheses for the cognitive deficits of schizophrenia. Neurocognitive deficits, which are well-described clinical features of schizophrenia, may be remediated by nicotine; therefore investigations of nicotinic receptor subtypes is of considerable clinical interest. We typed polymorphisms in CHRNA4 and CHRNB2 genes controlling the expression of neuronal high-affinity nicotinic receptors in 117 Canadian families having at least one schizophrenic patient. Using a family-based association strategy, we performed allele, haplotype and interaction analysis of these two loci. In the families tested, the two cholinergic genes interact to affect schizophrenia in combination (P=0.010), while neither was sufficient alone to confer susceptibility. Our present study provided the first line of direct evidence suggesting that the CHRNA4 gene combined with CHRNB2 receptor gene may be linked to schizophrenia.
Similar content being viewed by others
References
American Psychiatric Association (1994) Diagnostic and statistical manual of mental disorder. 4th edn. (DSM-IV) Washington
Benwell ME, Balfour DJ, Anderson JM (1988) Evidence that tobacco smoking increases the density of (−)-[3H]nicotine binding sites in human brain. J Neurochem 50:1243–1247
Bray NJ, Owen MJ (2001) Searching for schizophrenia genes. Trends Mol Med 7:169–174
Breese CR, Lee MJ, Adams CE, Sullivan B, Logel J, Gillen KM, Marks MJ, Collins AC, Leonard S (2000) Abnormal regulation of high affinity nicotinic receptors in subjects with schizophrenia. Neuropsychopharmacology 23:351–364
Chumakov I, Blumenfeld M, Guerassimenko O, Cavarec L, Palicio M, Abderrahim H, Bougueleret L, Barry C, Tanaka H, La Rosa P, Puech A, Tahri N, Cohen-Akenine A, Delabrosse S, Lissarrague S, Picard FP, Maurice K, Essioux L, Millasseau P, Grel P, Debailleul V, Simon AM, Caterina D, Dufaure I, Malekzadeh K, Belova M, Luan JJ, Bouillot M, Sambucy JL, Primas G, Saumier M, Boubkiri N, Martin-Saumier S, Nasroune M, Peixoto H, Delaye A, Pinchot V, Bastucci M, Guillou S, Chevillon M, Sainz-Fuertes R, Meguenni S, Aurich-Costa J, Cherif D, Gimalac A, Van Duijn C, Gauvreau D, Ouellette G, Fortier I, Raelson J, Sherbatich T, Riazanskaia N, Rogaev E, Raeymaekers P, Aerssens J, Konings F, Luyten W, Macciardi F, Sham PC, Straub RE, Weinberger DR, Cohen N, Cohen D (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 99:13675–13680
Freedman R, Coon H, Myles-Worsley M, Orr-Urtreger A, Olincy A, Davis A, Polymeropoulos M, Holik J, Hopkins J, Hoff M, Rosenthal J, Waldo MC, Reimherr F, Wender P, Yaw J, Young DA, Breese CR, Adams C, Patterson D, Adler LE, Kruglyak L, Leonard S, Byerley W (1997) Linkage of a neurophysiological deficit in schizophrenia to a chromosome 15 locus. Proc Natl Acad Sci USA 94:587–592
Freedman R, Leonard S, Olincy A, Kaufmann CA, Malaspina D, Cloninger CR, Svrakic D, Faraone SV, Tsuang MT (2001) Evidence for the multigenic inheritance of schizophrenia. Am J Med Genet 105:794–800
Gejman PV, Sanders AR, Badner JA, Cao Q, Zhang J (2001) Linkage analysis of schizophrenia to chromosome 15. Am J Med Genet 105:789–793
Glassman AH (1993) Cigarette smoking: implications for psychiatric illness. Am J Psychiatry 150:546–553
Hovarth S, Xu X, Laird NM. (2001) The family based association test method: strategies for studying general genotype-phenotype associations. Eur J Hum Genet 9:301–306
Lahiri DK, Nurnberger JI Jr (1991) A rapid non-enzymatic method for the preparation of HMW DNA from blood for RFLP studies. Nucleic Acids Res 19:5444
Lange C (2001) PBAT: analytical power calculations for family-based association test (V 2.5). Department of Biostatistics, Harward School of Public Health
Lanktree MB, VanderBeek L, Macciardi FM, Kennedy JL (2004) PedSplit: pedigree management for stratified analysis. Bioinformatics 20:2315–2316
Leonard S (2003) Consequences of low levels of nicotinic acetylcholine receptors in schizophrenia for drug development. Drug Dev Res 60:127–136
Leonard S, Bertrand D (2001) Neuronal nicotinic receptors: from structure to function. Nicotine Tob Res 3:203–223
Levin ED, Wilson W, Rose JE, McEvoy J (1996) Nicotine-haloperidol interactions and cognitive performance in schizophrenics. Neuropsychopharmacology 15:429–436
Li MD, Beuten J, Ma JZ, Payne TJ, Lou XY, Garcia V, Duenes AS, Crews KM, Elston RC (2005) Ethnic- and gender-specific association of the nicotinic acetylcholine receptor alpha4 subunit gene (CHRNA4) with nicotine dependence. Hum Mol Genet 14:1211–1219
Lindstrom J, Schoepfer R, Whiting P (1987) Molecular studies of the neuronal nicotinic acetylcholine receptor family. Mol Neurobiol 1:281–339
Liu C-F, Hwu H-G, Lin M-W, Ou-Yang W-C, Lee SF-C, Fann CSJ et al (2001) Suggestive evidence for linkage of schizophrenia to markers at chromosome 15q13–14 in Taiwanese families. Am J Med Genet Neuropsychiat Genet 105:658–661
Lohr JB, Flynn K (1992) Smoking and schizophrenia. Schizophr Res 8:93–102
Schilstrom B, Svensson HM, Svensson TH, Nomikos GG (1998) Nicotine and food induced dopamine release in the nucleus accumbens of the rat: putative role of alpha7 nicotinic receptors in the ventral tegmental area. Neuroscience 85(4):1005–1009
Seeman P (1987) Dopamine receptors and the dopamine hypothesis of schizophrenia. Synapse 1:133–152
Tsuang DW, Skol AD, Faraone SV, Bingham S, Young KA, Prabhudesai S et al (2001) Examination of genetic linkage of chromosome 15 to schizophrenia in a large veterans affairs cooperative study. Am J Med Genet Neuropsychiat Genet 105:662–668
Wonnacott S (1997) Presynaptic nicotinic ACh receptors. Trends Neurosci 20:92–98
Acknowledgments
This work was funded by the Ontario Mental Health Foundation and Canadian Institute Health Research (CIHR) grant # MOP-15007 CIHR.
Author information
Authors and Affiliations
Corresponding author
Additional information
Vincenzo De Luca and Sophocles Voineskos have contributed equally to this work
Rights and permissions
About this article
Cite this article
De Luca, V., Voineskos, S., Wong, G. et al. Genetic interaction between α4 and β2 subunits of high affinity nicotinic receptor: analysis in schizophrenia. Exp Brain Res 174, 292–296 (2006). https://doi.org/10.1007/s00221-006-0458-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00221-006-0458-y