BIOL PSYCHIATRY 1991 ;29:1o55-1o57

1055

EDITORIAL

Genes, Environment and Psychopathology It ~,eems like deja vu all over again: The biomedical model pitted against environmental views of mental illness. The impact of molecular biology on medical science has spilled over to psychiauT, but universal acceptance is lagging. Two recent articles on advances in psychiatric genetics (Pardes et al 1989; Mullan and Marray 1989) were criticized on two accounts: 1. Undue optimism over the practical applications of molecular biology in general, and genetic linkage strategies in particular, to the major psychiatric syndromes; and 2. Underestiw~tion of environmental causes for psychopathology. The critics (Reiss et al 1991), while recognizing ~l~e role of genetic factors in shaping behavior, poinPed to what they per~ive as misplaced attempts by modern psychiatry to fit nito "standard biomedical molds.' Pardes et al (1989), and Mullan and Murray (1989) reviewed current progress in molecular genetics and noted the implications of these advances for etiology, pathogenesis, diagnostics, counseling and therapeutics. While recognizing some of the pitfalls facing research in complex behavioral disorders, the authors expressed confidence in the link between the 'new genetics' and psychiatry, drawing P,nalogies to the successes in mapping the genes for other disorders affecting mental function, suc~ ~.~ Huntington's and Alzheimer's disease. Reiss et al (1991), who advocate environmental (mainly social) paradigms in the search for causative factors in mental illness, considered these views one-sided. First, they argued that the new genetic approaches rely heavily on single gene mechanisms for psychiatric disorders. ,~-,ch mechanisms, they maintained, are less tenable than polygenic inheritance which may play a larger role in the etiolog~ f mental illness. To reinforce this argument, they noted the recent d~mise of the purported single gene effect for bipolar affective illness in the Old Order Amish. Second, they pointed to the importance of environmental mechanisms in normal and pathological development, with an eye to 'nonsha~ed environmental effects,' namely, environment that is specific or unique to each sibling in a family (eg, preferential treatment by parents and peers). They underscored the need for accelerated research in this area, suggesting that the environmental view of mental illness should be on equal footing with the 'competing' ideology. What is at stake here goes beyond scientific dispute. Reiss et al (1991) raise concern over the types of research that currently receive public funding, implying that the biomedical view of psychiatry is unduly favored in this vein over the environmental paradigms • at they and others espouse. To be sure, the issues debated in these articles are not new. The impact of molecular genetics on psychiatry was addressed in earlier papers (Gurling 1985, Gershon et al 1987, Baron & Rainer 1988). Nonshared environmental effects in the major psychoses have long been recognized, as evidenced by incomplete concordance in monozygotic twins. However, juxtaposing the 'molecular biology' view of psychiatry with the 'environmental' one, as Reiss et al did in their critique, can serve to highlight misplaced emphases and potential misconceptions in both formulations. The image of a psychiatric model based on molecular biology has its moorings in the © 1991 Society of Biological Psychiatry

0006-3223/91/$03.50

1056

BIOL PSYCHIATRY 1991 ;29: !o55-IO57

Editorial

euphoria over the first harvest of genetic findings in bipolar disorder and schizophrenia (review: B~on et al 1990). Indeed, the failure to replicate some of these findings, most notably, the retraction of the chromosome 1l p linkage in the Old Order Amish, gave way to a more somber view of this field and to the realization that the pace of progress will likely be slower than envisaged at the outset. For the following reasons, however, it would be a mistake to suggest that applications of molecular biology in psychiatry have lost their lure, and that polygenic or multifactorial (including environmental influences) transmission, which does not lend itself readily to these research strategies, is the genetic mechanism of choice. 1. Although single major genes may account for only a small fraction of psychiatric cases (segregation analysis has ruled out a single gene ~s the sole or major factor in familial transmission), they can elucidate pathogenesis in other disease forms. 2. For disorders such as schizophrenia (and, possibly, other psychiatric disorders), a small number of epistatically interacting genes fit the data as well as or better than a 'pure' polygenic model (Risch 1990a). With sufficient data, the effect of such genes could be detected by available genetic linkage strategies. A case in point is the successful application of an oligogenic model (using ill sibling pairs) to another complex disorder, diabetes mellitus. This is an important point to consider because epistatic models may play a larger role in psychopathology than either single genes or polygenes. 3. Only a small portion of the genome has been scanned so far for possible psychiatric linkages. With the increasing availability of highly polymorphic DNA markers, including the new generation of mini- and microsatellite polymorphisms, more extensive searches can be conducted. 4. Some of the early failures with the linkage approach can be traced to potential methodological pitfalls and other complications such as non-mendelian transmission, phenotypic uncertainties, variable expressivity (diverse clinical manifestations), etiological heterogeneity, incomplete penetrance, ~.isspecification or genetic parameters, assortative mating, and cohort effect. Guidelines have been proposed to circumvent some of these problems and to enhance the utility of molecular biology techniques in linkage ~alysis (Baron 1990, Baron et al 1990, Risch 1990b). With complete genomic mapping and further advances in molecular and quantitative genetics, the contribution of 'minor' gene effects to behavioral variations, as in polygenic systems, might also be unraveled. 5. Environmental models are not problem-free by any stretch of the imagination. As rioted earlier, the strongest data used to support an environmental cause stem from studies of illness discordance in monozygotic twins. However, molecular genetic approaches have revealed new mechanisms that may explah~ this discordance in genetic terms, that is, differential genomic imprinting. One should also note that investigations into nonshared environmental influences are preliminary. As acknowledged by Reiss et al (1991), available data on nonshared parental and sibling experiences are scattered and not always consistent. Especially lacking is information on nonshared environmental correlates of clearly defined psychiatric syndromes. In the absence of such information, a cau~al role of specific nonshared variables in psychopathology remains speculative. As studies of environmental effects gather momentum, useful information concerning the issues at stake, including potential clues to etiology and treatment, may come to light. At this time, however, it is unclear if and when environmental effects of etiological significance will emerge and what will be the magnitude of these effects in producing psychopathology. 6. A molecular genetic approach might enhance and refine the environmental model. For example, prospective studies of at-risk individuals identified by a linked marker can

BIOLPS'~'C-~nA,'rRY

Editorial

1991;29:1055-1057

1057

offer insights into gene/environment interaction by revealing specific environmental factors that interact with genetic vulnerability to prevent or produce pathology. Conversely, the successful application of environmental models could enhance linkage analysis by gleaning insights into the underpinnings of reduced penetrance and phenocopies. Newer me,thods f-3r iinkage analysis that take into account environmental contributions are being developed. Pending further study, the relative merit of the 'molecular' and 'environmental' modds may be hard to gauge. However, the power of the DNA technology and its apparent recent success with other complex disorders, such as Alzheimer's disease and breast cancer, have an obvious and justified appeal for psychiatric genetics. Although environmental factors are clearly at play and their role need not be ignored, suggestions of a dichotomy between genes and environment, and the danger of then reaching the conclusion, based on the available evidence, that equal funding should go to environmental studies, are i:ound to generate controversy. Co-existence and cross-fertilization might be the optimal modus operandi for tht:e two views of psychiatry. Miron Baron New York State Psychiatric Institute 722 West 168 Street New York, N Y 10032 Supported by NIMH Research Scientist Development Award MH00176.

References Baron M (1990): Genetic linkage in mental illness. Nature 346:618. Baron M, Rainer JD (1988): Molecular genetics and human disease: Implications for modem psychiatric research and practice. Br J Psychiatry 152:741-753. Baron M, Endicott J, Ott J (1990): Genetic linkage in mental illness: Limitations and prospects. Br J Psychiatry 157:645-655. Gershon ES, Merril CR, Goldin LR et al (1987): The role of molecular ge .~..cs in psychiatry. Biol Psychiatry 22:1388-1405. Gurling HMD (1985): Application of molecular biology to mental illness. Analysis of genomic DNA and brain mRNA. Psychiatr Dev 3:257-27.). Mullah MJ, Murray RM (1989): The impact of molecular genetics on our understanding of the psychoses. Br J Psychiatry 154:591-595. Pardes H, Kaufmann CA, Pincus i-iA, et J (1989): Genetics and psychiatry: past discoveries, current dilemmas, and futa~-~ directions. Am J Psychiatry 146:435-443. Reiss D, Plomin R, Hetherington EM (1991): Genetics and psychiatry: and unheralded window on the environment. Am J PsychiattT 148:283-291. Risch N (1990a): Linkage strategies for genetically complex traits. I. Multilocus models. Am J Hum Genet 46:222-228. Risch N (1990b): Genetic linkage and complex diseases, with special reference to psychiatric disorders. Comments by Elston RC and Wilson AF; Gershon ES; Green P, Matthysse S; Morton NE; Ott J; Suarez BK et ~; and Risch N. Genet Epidemiology 7:3-46.

Genes, environment and psychopathology.

BIOL PSYCHIATRY 1991 ;29:1o55-1o57 1055 EDITORIAL Genes, Environment and Psychopathology It ~,eems like deja vu all over again: The biomedical mode...
320KB Sizes 0 Downloads 0 Views