Complex traits, complex answers. There are no simple answers when it comes to the genetic study of complex traits, and schizo- phrenia is no exception. Debate ...
Molecular Psychiatry (1997) 2, 89–90 1997 Stockton Press All rights reserved 1359–4184/97 $12.00
NEWS & VIEWS
Complex traits, complex answers
There are no simple answers when it comes to the genetic study of complex traits, and schizophrenia is no exception. Debate will continue over the interaction between genes and environment. But now there are new clues.
The study of complex traits promises to retain its central position for human genetics for many years. Among these, schizophrenia linkage studies will certainly continue to attract attention and debate. Much of this ongoing discussion will reflect the age-old question of the relative contribution of genes and the environment to the etiology of this disease.1 Over the past several years, numerous studies looked into the complex issue of schizophrenia susceptibility. At last count, the Medline Molecular Genetics database contained 284 schizophrenia-related linkage studies.2 Many of these reported on negative linkage to suspected candidate genes, such as the dopamine receptor family. Others, initially supporting linkage, were subsequently challenged. A notable example is the 1988 report on schizophrenia susceptibility linkage to 5q11– 13, based on data from Icelandic and English affected families,3 later negated by studies in Swedish,4 Scottish5 and North American6 families. This confusion may be avoided by strict adherence to the guidelines put forward recently by Lander and Kruglyak for genetic dissection of complex traits.7 Thus, inclusion of individuals with bipolar or major depression as affected family members may hinder accurate conclusions in schizophrenia susceptibility linkage studies. In the present issue of Molecular Psychiatry, two companion studies, both clearly following these guidelines, are reported. Straub et al (pages 148–155) and Schwab et al (pages 156–160) report on new evidence for a schizophrenia susceptibility locus on the long arm of chromosome 5, at 5q21–31 and at 5q31, respectively. The studies employed data from 265 affected Irish families, and from 44 affected German and Israeli families, respectively. The larger Irish families study yielded impressive lod scores of up to 3.35 for linkage of schizophrenia susceptibility to the proposed region (before adjustment for the number of genetic and phenotypic models). The German–Israeli study
Correspondence: Dr D Gurwitz, National Laboratory for the Genetics of Israeli Populations, Sackler Faculty of Medicine, Tel-Aviv University, PO Box 39040, Tel-Aviv 69978, Israel
observed lower lod scores, below 2.0, leading its authors to caution that the new susceptibility locus may have a minor contribution to the etiology of the disease in their family sample. Yet both studies, when evaluated together, are supportive for the proposed new susceptibility locus on 5q. Although a joint analysis has not yet been tackled, there seems to be good reason for hope that more progress in understanding this complex disease, ensuing from the future identification of the new locus on 5q, is down the road. The optimism is supported by the use of different ethnic groups in the two new studies. In such a complex disease, ethnic considerations strongly influence the degree of penetrance of susceptibility genes. Numerous studies have demonstrated that a considerable component of the etiology of schizophrenia is genetic, but an intricate interplay between genetic, social and environmental factors dictates its expression or attenuation. Moreover, ethnic differences in schizophrenia epidemiology may in part reflect social selection.8 It remains to be seen whether the new candidate 5q locus will be confirmed in subsequent studies including affected families from additional ethnic groups. This would justify embarking on the demanding positional cloning venture. It is intriguing to note that the distal portion of the long arm of human chromosome 5, in particular 5q22– 5q35, contains an impressive number of genes encoding growth factors, interleukins, and their receptors.9 Given our limited knowledge, one may presently only speculate whether the new locus near 5q31 would turn out to belong to one of these rapidly growing gene families. Such a scenario may help decipher the accumulating body of evidence implicating immune activation in some forms of schizophrenia10,11 and possibly also the enigmatic emerging connection between schizophrenia and Borna disease virus. 12 The new 5q susceptibility locus is definitely not the last player in the unfolding schizophrenia story; more will be coming our way as the human genome reveals its secrets. Yet, any new clues to the nature of genetic susceptibility in schizophrenia would stimulate additional studies, and eventually enhance our under-
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standing of the complex interaction between genes and environment in this complex disease. D Gurwitz, PhD National Laboratory for the Genetics of Israeli Populations Sackler Faculty of Medicine Tel-Aviv University PO Box 39040, Tel-Aviv 69978, Israel
References 1 Reiss D, Plomin R, Hetherington EM. Genetics and psychiatry: an unheralded window on the environment. Am J Psychiatry 1991; 148: 283–291. 2 Medline Subset in Molecular Genetics. http: //ncbi.nlm.nih.gov/medline/query form.html 3 Sherrington R, Brynjolfsson J, Petursson H, Potter M, Dudleston K, Barraclough B, Wasmuth J, Dobbs M, Gurling H. Localization of a susceptibility locus for schizophrenia on chromosome 5. Nature 1988; 336: 164–167. 4 Kennedy JL, Giuffra LA, Moises HW, Cavalli-Sforza LL, Pakstis AJ, Kidd JR, Castiglione CM, Sjogren B, Wetterberg L, Kidd KK. Evidence against linkage of schizophrenia to markers on chromosome 5 in a northern Swedish pedigree. Nature 1988; 336: 167–170. 5 St Clair D, Blackwood D, Muir W, Baillie D, Hubbard A, Wright A, Evans HJ. No linkage of chromosome 5q11–q13
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markers to schizophrenia in Scottish families. Nature 1989; 339: 305–309. Detera-Wadleigh SD, Goldin LR, Sherrington R, Encio I, de Miguel C, Berrettini W, Gurling H, Gershon ES. Exclusion of linkage to 5q11–13 in families with schizophrenia and other psychiatric disorders. Nature 1989; 340: 391–393. Lander E, Kruglyak L. Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nat Genet 1995; 11: 241–247. Dohrenwend BP, Levav I, Shrout PE, Schwartz S, Naveh G, Link BG, Skodol AE, Stueve A. Socioeconomic status and psychiatric disorders: the causation-selection issue. Science 1992; 255: 946–952. Warrington JA, Bailey SK, Armstrong E, Aprelikova O, Alitalo K, Dolganov GM, Wilcox AS, Sikela JM, Wolfe SF, Lovett M et al. A radiation hybrid map of 18 growth factor, growth factor receptor, hormone receptor, or neurotransmitter receptor genes on the distal region of the long arm of chromosome 5. Genomics 1992; 13: 803–808. Licinio J, Seibyl JP, Altemus M, Charney DS, Krystal JH. Elevated CSF levels of interleukin-2 in neuroleptic-free schizophrenic patients. Am J Psychiatry 1993; 150: 1408–1410. Rapaport MH, Torrey EF, McAllister CG, Nelson DL, Pickar D, Paul SM. Increased serum soluble interleukin-2 receptors in schizophrenic monozygotic twins. Eur Arch Psychiatry Clin Neurosci 1993; 243: 7–10. Bode L, Zimmermann W, Ferszt R, Steinbach F, Ludwig H. Borna disease virus genome transcribed and expressed in psychiatric patients. Nature Med 1995; 1: 232–236.
