The idea that ‘insanity’ may be hereditary is an ancient one, but it was not until the twentieth century that this began to be explored in a systematic and scientific fashion. Two major developments at the beginning of the century allowed this to occur. The first was the rediscovery in 1900 of Mendel’s laws of inheritance (which had lain ignored since their publication in 1866) signalling the birth of a new science which in 1909 Bateson called genetics. The second was the elaboration of a workable and widely accepted system of classification of mental disorders largely based upon the work of the German psychopathologist Emile Kraepelin. However, from the outset, attempting to reconcile observations on the patterns of inheritance of common mental disorders within families with Mendelian laws proved to be problematic. Although some comparatively uncommon disorders with neuropsychiatric manifestations such as Huntington’s disease clearly showed dominant inheritance (50 per cent of the offspring of affected parents showing the disorder), and some forms of mental retardation showed a recessive pattern (25 per cent of the offspring affected when both parents are unaffected ‘carriers’), the more severe forms of common mental disorders such as schizophrenia or manic depressive illness showed a more complicated picture. Both of these disorders appeared to be more common in the relatives of sufferers than in the population at large, but there appeared to be no regular pattern within families and many patients had no known family history at all.
The question therefore arose as to whether schizophrenia and manic depression ran in families simply because of some shared environmental effects rather than through genetic mechanisms. The answer came by researchers capitalizing on an ‘experiment of nature’ afforded by twins. Identical, or monozygotic (MZ), twins have all of their genes in common as well as sharing a common environment. Non-identical, or dizygotic (DZ), twins share, on average, 50 per cent of their genes and it is assumed, particularly when they are the same sex, that they share environments to roughly the same extent as MZ twins. Therefore if MZ twins are more often concordant (i.e. both affected) than DZ twins for a disorder such as schizophrenia or manic depression, this should indicate that genetic factors are playing a part. The use of twins as a tool for studying the genetics of human behaviour was first suggested by Francis Galton in the late nineteenth century, but the methodologies were not fully worked out until the 1920s and 1930s by Luxenberger and other psychiatrists of the Munich school. These researchers were able to demonstrate higher MZ than DZ concordance for schizophrenia, manic depression and a variety of other conditions. Tragically, the mounting evidence that genes played a part in mental disorders was taken up by the Nazi party and used to support its eugenics policies, eventually leading to sufferers from mental disorder being sterilized or exterminated under the naïve assumption that this would lead to the eradication of such disorders in future generations. Although this was both morally repugnant and scientifically idiotic, Nazi eugenics received some support from the medical profession. The eventual outcome after the Second World War was the eradication, not of mental illness, but of modern psychiatric genetics in the country of its birth. A popular mistrust of genetics generally and psychiatric genetics in particular still persists in Germany.
Fortunately researchers elsewhere, such as the British psychiatrist Eliot Slater and the Dane, Eric Strömgren, both of whom had been Visiting Fellows in Munich, kept psychiatric genetics alive. Twin studies focusing mainly on schizophrenia but also on manic depression, alcoholism and neurotic disorders were carried out deriving their samples from registers. These provided a method of systematic ascertainment (or sampling) overcoming the potential bias of earlier twin studies which tended to oversample the most conspicuous pairs, that is, those who are both monozygotic and concordant. For the first time researchers also attempted to overcome diagnostic biases by using explicit criteria and keeping investigators ‘blind fold’ to zygosity and the diagnosis in the other member of the twin pair.
The other method developed to separate the effects of genes and family environment was to study those removed from their biological parents early in life by fostering or adoption. The first adoption study of schizophrenia was carried out by Heston in the late 1960s who found strikingly that five out of forty-seven individuals adopted away from their schizophrenic mothers themselves developed schizophrenia. This contrasted with none of fifty control adoptees. Publication of other adoption study results quickly followed, and particularly influential was the work of Kety and others who matched up psychiatric and adoption registers in Denmark and in a series of studies confirmed that the vital factor in predisposing to schizophrenia was having a biological rather than an adoptive relative with the disorder. This took place at a time when ‘anti-psychiatrists’ such as R.D.Laing were attacking orthodox medical approaches towards schizophrenia, and others, such as T.Szasz, were claiming that the whole concept of mental illness was mythical. Kety was thus provoked to remark that if ‘schizophrenia is a myth, then it is a myth with a strong genetic basis’.
Studies using twin and/or adoption methods have gone on to demonstrate a probable genetic contribution to a wide range of disorders, including both typical bipolar manic depression (episodes of mania and depression) and unipolar depression (episodes of depression alone) as well as certain types of anxiety disorders and, more controversially, alcoholism and even antisocial personality and criminality. Research in psychiatric genetics is attempting to move beyond merely demonstrating that a genetic contribution exists to using statistical model fitting techniques to estimate how much of the variance in liability to a disorder can be attributed to genes, to shared family environment and to individual specific environments. Model fitting techniques have also been used to try and differentiate between modes of transmission such as single gene, polygenic (many genes of small effect) or oligogenic (a handful of genes). Such statistical approaches provide a preliminary for the next stage, which is to attempt to localize and eventually identify the genes responsible for mental disorders using the methods of genetic linkage or association. Such methods have been dramatically successful in rarer single-gene neuropsychiatric disorders such as Huntington’s disease and familial early onset Alzheimer dementia. The task is much more difficult with more common and complex disorders such as schizophrenia because of uncertainties over the mode of transmission. Nevertheless advances in molecular genetics have provided a nearly complete linkage map of the human genome (i.e. the twenty-three pairs of chromosomes carrying genetic material) which means that it is now feasible to search for markers linked to even complex traits. It seems likely therefore that genes for the more severe types of common inherited mental disorders will be localized within the foreseeable future.
Peter McGuffin
University of Wales
References
Bateson, W. (1909) Mendel’s Principles of Heredity, Cambridge.
Galton, F. (1876) ‘The history of twins as a criterion of the relative powers of nature and nurture’, Royal Anthropological Institute of Great Britain and Ireland Journal 6.
Heston, L.L. (1966) ‘Psychiatric disorders in foster-home-reared children of schizophrenic mothers’, British Journal of Psychiatry 112.
Kety, S.S. (1971) ‘Mental illness in the biological and adoptive families of adopted schizophrenics’, American Journal of Psychiatry 112.
Krapelin, E. (1904) Clinical Psychiatry: A Textbook for Students and Physicians (trans. A.R.Diezendof), New York.
Laing, R.D. (1965) The Divided Self, Harmondsworth.
Strömgren, E. (1994) ‘Recent history of European psychiatry—ideas, developments and personalities: The annual Eliot Slater Lecture’, American Journal of Medical Genetics (Neuropsychiatric Genetics) 54.
Szasz, T.S. (1961) The Myth of Mental Illness. Foundations of a Theory of Personal Conduct, New York.
Further reading
Gottesman, I.I. (1991) Schizophrenia Genesis: The Origins of Madness, San Francisco, CA.
McGuffin, P., Owen, M.J., O’Donovan, M.C., Thapar, A. and Gottesman, I.I. (1994), Seminars in Psychiatric Genetics, London.
Tsuang, M.T. and Faroane S.V. (1990) The Genetics of Mood Disorders, Baltimore, M.D.
