Hostname: page-component-8448b6f56d-wq2xx Total loading time: 0 Render date: 2024-04-16T22:54:25.871Z Has data issue: false hasContentIssue false

Identification of candidate genes for schizophrenia based on natural resistance to infectious diseases

Published online by Cambridge University Press:  24 June 2014

James S Brown Jr*
Affiliation:
McGuire Veterans Affairs Medical Center, Richmond, Virginia, USA
*
Mental Health Clinic, McGuire Veterans Affairs Medical Center, 1201 Broad Rock Blvd, Richmond, Virginia 23249, USA, Tel. 804-675-5000 ext. 4208; Fax: 804-675-5678; E-mail: jbrown2185@aol.com

Abstract

Background:

Identification of candidate genes for schizophrenia may be more successful than genome screens as the latter have not found consistent linkages.

Objective:

To assist in the gene search, a model of schizophrenia based on resistance to infectious diseases, rather than susceptibility, is proposed. The theory blends the geography of schizophrenia with the assumption that genes that cause schizophrenia likely evolved and persist from selection pressure. The theory includes the notion that schizophrenia enhances biological survival at the cost of psychological and social functioning.

Method:

To demonstrate the utility of using this model, the Medline literature was searched for resistance genes, mostly identified in mice.

Results:

Based on homologous locations in the human genome, these resistance genes are shown to be located in human chromosome regions linked significantly, in at least one genome screen, with schizophrenia or some physiologically related function or condition associated with schizophrenia.

Conclusions:

The infectious disease resistance theory of schizophrenia is offered as a viable model for understanding the origins of schizophrenia. The theory also allows for the inclusion of persistent infections, seasonal variability and translational pathophysiology to contribute to the etiology of schizophrenia.

Type
Research Article
Copyright
Copyright © 2003 Blackwell Munksgaard

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Delisi, LE, Shaw, SH, Crow, TJ, Shields, G, Smith, AB, Larach, VWet al. A genome-wide scan for linkage to chromosomal regions in 382 sibling pairs with schizophrenia or schizoaffective disorder. Am J Psychiatry 2002;159: 803812.CrossRefGoogle ScholarPubMed
Torrey, EF, Bowler, A.Geographical distribution of insanity in America: evidence for an urban factor. Schizophr Bull 1990;16: 591604.CrossRefGoogle ScholarPubMed
Ciminelli, BM, Jodice, C, Scozzari, R, Corbo, RM, Nahum, M, Pompei, Fet al. Latitude-correlated genetic polymorphisms: Selection or gene flow? Hum Biol 2000;72: 557571.Google ScholarPubMed
Richman, A.Evolution of balanced genetic polymorphism. Mol Ecol 2000;9: 19531963.CrossRefGoogle ScholarPubMed
Purrington, CB.Costs of resistance. Curr Opin Plant Biol 2000;3: 305308.CrossRefGoogle ScholarPubMed
Lell, B, May, J, Schmidt-Ott, RJ, Lehman, LG, Luckner, D, Greve, Bet al. The role of red blood cell polymorphisms in resistance and susceptibility to malaria. Clin Infect Disord 1999;28: 794799. CrossRefGoogle ScholarPubMed
Do Jong, PW, Nielsen, JK.Reduction in fitness of flea beetles which are homozygous for an autosomal gene conferring resistance to defenses in Barbarea vulgaris. Heredity 2000;84: 2028.CrossRefGoogle Scholar
Huxley, J, Mayr, E, Osmond, H, Hoffer, A.Schizophrenia as a genetic morphism. Nature 1964;204: 220221. CrossRefGoogle ScholarPubMed
Erlenmeyer-Kimling, L.Mortality rates in the offspring of schizophrenic parents and a physiological advantage hypothesis. Nature 1968;220: 798800.CrossRefGoogle Scholar
Carter, M, Watts, CAH.Possible biological advantages among schizophrenics' relatives. Br J Psychiatry 1971;118: 453460.CrossRefGoogle ScholarPubMed
Rubinstein, G.Schizophrenia, infection and temperature. An animal model for investigating their interrelationships. Schizophr Res 1993;10: 95102.CrossRefGoogle ScholarPubMed
Rubinstein, G.Schizophrenia, rheumatoid arthritis and natural resistance genes. Schizophr Res 1997;25: 177181.CrossRefGoogle ScholarPubMed
Brown, JS Jr.Geographic correlation of schizophrenia to ticks and tick-borne encephalitis. Schizophr Bull 1994;4: 755775. CrossRefGoogle Scholar
Brown, JS Jr.A novel mechanism to explain protein abnormalities in schizophrenia based on the flavivirus resistance gene. Mol Psychiatry 2001;6: 701711.CrossRefGoogle ScholarPubMed
Kramnik, I, Boyartchuk, V.Immunity to intracellular pathogens as a complex genetic trait. Curr Opin Microbiol 2002;5: 111117.CrossRefGoogle ScholarPubMed
Paunio, T, Ekelund, J, Varilo, T, Parker, A, Hovatta, I, Turunen, JAet 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: 30373048.CrossRefGoogle Scholar
McLeod, R, Buschman, E, Arbuckle, LD, Skamene, E.Immunogenetics in the analysis of resistance to intracellular pathogens. Curr Opin Immunol 1995;7: 539552.CrossRefGoogle ScholarPubMed
Blake, JA, Richardson, JE, Bult, CJ, Dadin, JA, Eppig, JT and the Mouse Genome Database Group. The Mouse Genome Database (MGD). The Model Organism Database for Laboratory Mouse. Nucl Acids Res 2002;30: 113115. CrossRefGoogle ScholarPubMed
Eppig, JT, Blake, JA, Burkhart, DL, Goldsmith, CW, Lutz, CM, Smith, CL.Corralling conditional mutations: a unified resource for mouse phenotypes. Genesis 2002;32: 6365.CrossRefGoogle ScholarPubMed
Groves, MG, Rosenstreich, DL, Taylor, BA, Osterman, JV.Host defenses in experimental scrub typhus: mapping the gene that controls natural resistance in mice. J Immunol 1980;125: 13951399.CrossRefGoogle ScholarPubMed
Karlsson, H, Bachmann, S, Schroder, J, McArthur, J, Torrey, EF, Yolken, RH.Retroviral RNA identified in the cerebrospinal fluids and brains of individuals with schizophrenia. Pro Natl Acad Sci USA 2001;98: 46344639. CrossRefGoogle ScholarPubMed
Singal, DP, Li, J, Zhu, Y, Zhang, G.NRAMP1 gene polymorphisms in patients with rheumatoid arthritis. Tissue Antigens 2000;55: 4447.CrossRefGoogle ScholarPubMed
Torrey, EF, Yolken, RH.The schizophrenia-rheumatoid arthritis connection: infectious, immune, or both? Brain Behav Immun 2001;15: 401410.CrossRefGoogle ScholarPubMed
Roy, BA, Kirchner, JW.Evolutionary dynamics of pathogen resistance and tolerance. Evol Int J Org Evolution 2000;54: 5163. Google ScholarPubMed
Schneider-Schaulies, S, Schneider-Schaulies, J, Schuster, A, Bayer, M, Pavlovic, J, Ter Meulen, V.Cell type-specific MxA-mediated inhibition of measles virus transcription in human brain cells. J Virol 1994;68: 69106917.CrossRefGoogle ScholarPubMed
Gloria-bottini, F, Lucarini, N, Palmarino, R, La Torre, M, Amante, A, Bottini, E.ACP1 and human adaptability. 2. Association with season of conception. Hum Genet 1997;101: 158164.CrossRefGoogle ScholarPubMed
Frese, M, Kochs, G, Feldmann, H, Hertkorn, C, Haller, O.Inhibition of bunyaviruses, phleboviruses, and hantaviruses by human MxA protein. J Virol 1996;70: 915923.CrossRefGoogle ScholarPubMed
Riley, BP, Tahir, E, Rajagopalan, S, Mogudi-Carter, M, Faure, S, Weissenbach, Jet al. A linkage study of the N-methyl-D-aspartate receptor subunit gene loci and schizophrenia in southern African Bantu-speaking families. Psychiatric Genet 1997;7: 5774. CrossRefGoogle ScholarPubMed
Meszaros, K, Lenzinger, E, Fureder, T, Hornik, K, Willinger, U, Stompe, Tet al. Schizophrenia and the dopamine-beta-hydroxylase gene: results of a linkage and association study. Psychiatric Genet 1996;6: 1722. CrossRefGoogle ScholarPubMed
Kaufmann, CA, Suarez, B, Malaspina, D, Pepple, J, Svrakic, D, Markel, PDet al. NIMH Genetics Initiative Millenium Schizophrenia Consortium: linkage analysis of African-American pedigrees. Am J Med Genet 1998;81: 282289.3.0.CO;2-W>CrossRefGoogle ScholarPubMed
Bowes, C, Li, T, Frankel, WN, Danciger, M, Coffin, JM, Applebury, MLet al. Localization of a retroviral element within the rd gene coding for the beta subunit of cGMP phosphodiesterase. Proc Natl Acad Sci USA 1993;90: 29552959.CrossRefGoogle ScholarPubMed
Sanjeevi, CB, Miller, EN, Dabadghao, P, Rumba, I, Shtauvere, A, Denisova, Aet al. Polymorphisms at NRAMP1 and D2S1471 loci associated with juvenile rheumatoid arthritis. Arthritis Rheum 2000;43: 13971404.3.0.CO;2-6>CrossRefGoogle ScholarPubMed
Sherrington, R, Mankoo, B, Dixon, M, Curtis, D, Kalsi, G, Melmer, Get al. Microsatellite polymorphisms for chromosome 5 bands q112-Q13.3. Hum Hered 1993;43: 197202.CrossRefGoogle Scholar
Ekelund, J, Lichtermann, D, Hovatta, I, Ellonen, P, Suvisaari, J, Terwilliger, JDet al. Genome-wide scan for schizophrenia in the Finnish population: evidence for a locus on chromosome 7q22. Hum Mol Genet 2000;9: 10491057.CrossRefGoogle ScholarPubMed
Potash, JB, Depaulo, JR Jr.Searching high and low: a review of the genetics of bipolar disorder. Bipolar Disord 2000;2: 826.CrossRefGoogle Scholar
Morris-Rosendahl, DJ, Burgert, E, Uyanik, G, Mayerova, A, Duval, F, Macher, JPet al. Analysis of the CAG repeats in the SCA1 and B37 genes in schizophrenic and bipolar I disorder patients: tentative association between B37 and schizophrenia. Am J Ed Genet 1997;74: 324330. 3.0.CO;2-Q>CrossRefGoogle ScholarPubMed
Bailer, U, Leisch, F, Meszaros, K, Lenzinger, E, Willinger, U, Strobl, Ret al. Genome scan for susceptibility loci for schizophrenia. Neuropsychobiology 2000;42: 175182.CrossRefGoogle ScholarPubMed
Depatie, C, Muise, E, Lepage, P, Gros, P, Vidal, SM.High-resolution linkage map in the proximity of the host resistance locus Cmv1. Genomics 1997;39: 154163.CrossRefGoogle ScholarPubMed
Yovel, G, Sirota, P, Mazeh, D, Shakhar, G, Rosenne, R, Ben-Eliyahu, S.Higher natural killer cell activity in schizophrenic patients. the impact of serum factors, medication, and smoking. Brain Behav Immun 2000;14: 153169.CrossRefGoogle Scholar
Pulver, AE, Mulle, J, Nestadt, G, Swartz, KL, Biouin, JL, Dombroski, Bet al. Genetic heterogeneity in schizophrenia: stratification of genome scan data using co-segregating related phenotypes. Mol Psychiatry 2000;5: 650653.CrossRefGoogle ScholarPubMed
Kelsoe, JR, Spence, MA, Loetscher, E, Foguet, M, Sadovnick, AD, Remick, RAet al. A genome survey indicates a possible susceptibility locus for bipolar disorder on chromosome 22. Proc Natl Acad Sci USA 2001;98: 585590.CrossRefGoogle ScholarPubMed
Kleiderlein, JJ, Nisson, PE, Jessee, J, Li, WB, Becker, KG, Derby, MLet al. CCG repeats in cDNAs from human brain. Hum Genet 1998;103: 666673.CrossRefGoogle ScholarPubMed
Goodman, AB.Elevated risks for amyotrophic lateral sclerosis and blood disorders in Ashkenazi schizophrenic pedigrees suggest new candidate genes in schizophrenia. Am J Med Genet 1994;54: 271278.CrossRefGoogle ScholarPubMed
Yan, WL, Guan, XY, Green, ED, Nicolson, R, Yap, TK, Zhang, Jet al. Childhood-onset schizophrenia/autistic disorder and t (1;7) reciprocal translocation: identification of a BAC contig spanning the translocation breakpoint at 7q21. Am J Medical Genet 2000;96: 749753. 3.0.CO;2-K>CrossRefGoogle Scholar
Boin, F, Zanardini, R, Pioli, R, Altamura, CA, Maes, M, Gennarelli, M.Association between –G308A tumor necrosis factor alpha gene polymorphism and schizophrenia. Mol Psychiatry 2001;6: 7982.CrossRefGoogle ScholarPubMed
Wright, P, Dawson, E, Donaldson, PT, Underhill, JA, Sham, PC, Zhao, Jet al. A transmission/disequilibrium study of the DRB1*04 gene locus on chromosome 6p21.3 with schizophrenia. Schizophr Res 1998;32: 7580.CrossRefGoogle ScholarPubMed
Ekelund, J, Hovatta, I, Parker, A, Paunio, T, Varilo, T, Martin, Ret al. Chromosome 1 loci in Finnish schizophrenia families. Hum Mol Genet 2001;10: 16111617.CrossRefGoogle ScholarPubMed
Blouin, JL, Dombroski, BA, Nath, SK, Lasseter, VK, Wolyniec, PS, Nestadt, Get al. Schizophrenia susceptibility loci on chromosomes 13q32 and 8p21. Nat Genet 1998;20: 7073.CrossRefGoogle ScholarPubMed
Hovatta, I, Lichtermann, D, Juvonen, H, Suvisaari, J, Terwilliger, JD, Arajarvi, Ret al. Linkage analysis of putative schizophrenia gene candidate regions on chromosomes 3p, 5q, 6p, 8p, 20p and 22q in a population–based sampled Finnish family set. Mol Psychiatry 1998: 3: 452–457. CrossRefGoogle Scholar
Inglot, AD, Leszek, J, Piasecki, E, Sypula, A.Interferon responses in schizophrenia and major depressive disorders. Biol Psychiatry 1994;35: 464473.CrossRefGoogle ScholarPubMed
Chowdari, KV, Xu, K, Zhang, F, Ma, C, Li, T, Xie, BYet al. Immune related genetic polymorphisms and schizophrenia among the Chinese. Hum Immunol 2001;62: 714724.CrossRefGoogle ScholarPubMed
Goei, VL, Choi, J, Ahn, J, Bowlus, CL, Raha-Chowdhury, R, Gruen, JR.Human gamma-aminobutyric acid B receptor gene: complementary DNA cloning, expression, chromosomal location, and genomic organization. Biol Psychiatry 1998;44: 659666.CrossRefGoogle ScholarPubMed
Gurling, HM, Kalsi, G, Brynjolfson, J, Sigmundsson, T, Sherrington, R, Mankoo, BSet 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 20q12 1–11.23 Am J Hum Genet 2001;68: 661673.CrossRefGoogle Scholar
Muller-Myhsok, B, Stelma, FF, Guisse-Sow, F, Muntau, B, Thye, T, Burchard, GDet al. Further evidence suggesting the presence of a locus, on human chromosome 5q31-q33, influencing the intensity of infection with Schistosoma mansoni. Am J Hum Genet 1997;61: 452454.CrossRefGoogle ScholarPubMed
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: 864869.3.0.CO;2-D>CrossRefGoogle Scholar
Eubanks, JH, Djabali, M, Selleri, L, Grandy, DK, Civelli, O, McElligott, DLet al. Structure and linkage of the D2 dopamine receptor and neural cell adhesion molecule genes on human chromosome 11q23. Genomics 1992;14: 10101018.CrossRefGoogle ScholarPubMed
Nurnberger, JI Jr,Foroud, T.Genetics of bipolar affective disorder. Curr Psychiatry Rep 2000;2: 147157.CrossRefGoogle ScholarPubMed
Delisi, LE, Smith, AB, Razi, K, Stewart, J, Wang, Z, Sandhu, HKet al. Investigation of a candidate gene for schizophrenia on Xq13 previously associated with mental retardation and hypothyroidism. Am J Med Genet 2000;96: 398403.3.0.CO;2-Z>CrossRefGoogle ScholarPubMed
Detera-Wadleigh, SD, Badner, JA, Berrettini, WH, Yoshikawa, T, Goldin, LR, Turner, Get al. A high-density genome scan detects evidence for a bipolar-disorder susceptibility locus on 13q32 and other potential loci on 1q32 and 18p11. 2 Proc Natl Acad Sci U S A 1999;96: 56045609. CrossRefGoogle ScholarPubMed