Psychiatric Genetics

   Since the eighteenth century, psychiatrists have suspected that family genetic history played something of a role in their patients’ illnesses. Articulated first as "inheritance," then "degeneration" and "eugenics," then finally after the Second World War as psychiatric genetics, patterns of inheritance represent the main physical evidence of the biological nature of major psychiatric illness. Yet the concept of patterns of inheritance spills easily into "race" and "degeneration," putting science at the service of its social masters.

   Degeneration theory introduced to psychiatry (1857). In his Treatise on Degeneration (Traité des dégénéréscences physiques, intellectuelles et morales de l’éspece humaine, 1857), French psychiatrist Bénédict-Augustin Morel ascribed major psychiatric illnesses to the process of degeneration, the corruption of the germ plasm from generation to generation. This popularized a concept already in use in scientific circles, and introduced a notion of inheritance comparable to that of an express train gathering speed across the generations, as ever more degenerate "seed" was transmitted from one generation to the next. The notion of degeneration is comparable to the modern doctrine of "genetic anticipation," as the penetrance of a disorder increases over successive generations, as for example in "fragile-X," a form of mental retardation, or Huntington’s disease. As Morel wrote in 1857, "The degenerate human being, if he is abandoned to himself, falls into a progressive degradation. He becomes . . . not only incapable of forming part of the chain of transmission of progress in human society, he is the greatest obstacle to this progress through his contact with the healthy portion of the population." (On Morel, see Psychosis: Emergence: mania and melancholia as a result of degeneration [1857].)

   See Lombroso, Ezecchia-Marco on the genetics of genius and criminality (from 1864).

   Francis Galton on the inheritability of genius (1869). Galton (1822–1911), an independently wealthy Englishman involved in the administration of science, introduced in his 1869 book, Hereditary Genius: An Inquiry into its Laws and Consequences, the "pedigree," or family history, method into the study of inheritance. Yet, Galton himself did not use the diagrams showing how positive and negative traits migrated down the family tree that later became so popular. Galton concluded, "It follows that the human race has a large control over its future forms of activity—far more than any individual has over his own, since the freedom of individuals is narrowly restricted by the cost, in energy, of exercising their wills" (p. 375). This doctrine of control of the genetic pool became a basic tenet of eugenic theory. In 1905, Galton established the Eugenics Record Office at University College London (later baptized the Galton Laboratory), and in 1907 he became a cofounder of the Eugenics Education Society, an organization founded, as medical historian Pauline Mazumdar has put it in her book on the history of the Eugenic Society, "to press for legislative remedies for what it saw as the fundamental cause of pauperism," namely low physical fitness and high fertility (p. 2). Galton coined the term "eugenics," meaning positive heredity. Galton was responsible for the (in retrospect quite correct) idea that certain traits have a heavy genetic component, but he was not responsible for the notion that undesirable traits may be weeded out through such measures as sterilization—later a central eugenist tenet. (He was knighted, becoming "Sir Francis," in 1909.)

   Emil Kraepelin declared that 70% of schizophrenia patients have a hereditary predisposition (1896). Kraepelin had always believed that "dementia praecox," as he called schizophrenia, was highly inheritable, as indeed were all psychiatric illnesses in his view. In the fifth edition of his textbook Psychiatry (Psychiatrie) in 1896, he wrote, "Hereditary predisposition [erbliche Veranlagung] was present in around 70 percent of the cases in which information was available; correspondingly, the socalled signs of degeneration were frequently observed" (p. 437). "It goes without saying," he said, "that hereditarily loaded individuals have a general tendency to be constitutionally ill, continually ill, or ill in frequently recurring episodes. The more that the actual cause of insanity has its locus in the overall predisposition of the person, the more trivial need be the external impetus that brings about a lasting and customarily incurable disorder of the entire personality" (p. 88).

   The first large family study of psychiatric illness (1916). Although Swiss-born psychiatrist Ernst Rüdin (1874–1952) later made himself notorious as an apologist for Nazi sterilization practices, he was in fact the founder of psychiatric genetics on a demographic basis (following up systematically the patients’ relatives at large in the population rather than haphazardly studying "interesting cases"). Rüdin spent most of his academic career in Munich, first at Kraepelin’s psychiatric clinic, then after 1918 at the German Psychiatric Research Institute (Deutsche Forschungsanstalt für Psychiatrie) that Kraepelin had founded. Rüdin’s 1916 monograph, On the Inheritability and Causation of Dementia Praecox (Zur Vererbung und Neuentstehung der Dementia praecox), was based on 701 families with 4823 children, the majority of probands coming from the Munich clinic and from a provincial Bavarian asylum. Rüdin obtained information on the first-degree relatives of schizophrenics in correspondence with the parish priests, among other sources. He found that 4.5% of the children with healthy parents had schizophrenia and 6.2% of the children with at least one ill parent. Commented psychiatry historian Matthias Weber, "Through Rüdin’s work, the genetic viewpoint won a prominent position in scientific psychiatry and gained its own methodology" (Ernst Rüdin, eine kritische Biographie [1993], p. 113).

   The twin-study technique of demographic research on psychiatric genetics (from 1928). The logic of a twin-study is that monozygotic twins (identical twins that developed from the same egg) have identical genes; if indeed schizophrenia has a genetic cause, both twins will often have the illness. Dizygotic twins, on the other hand (nonidentical twins), develop from different ova and would have no higher risk of schizophrenia than any two sibs. A measure, therefore, of genetic risk is the difference between the percent of monozygotic and dizygotic co-twins who have schizophrenia (or any other psychiatric illness). This approach was initiated by a junior member of Kraepelin’s German Psychiatric Research Institute, Hans Luxenburger (1894–1976), in a 1928 article in the Journal of Combined Neurology and Psychiatry (Zeitschrift für die gesamte Neurologie und Psychiatrie). He collected from all Bavarian asylums lists of schizophrenic patients who were twins, then tracked the other co-twin down by writing to the parish priests and communal record offices, collecting in this manner 211 twin-sets in which one twin had been institutionalized for schizophrenia, manicdepressive illness, or epilepsy. Luxenburger found that among identical twins, 64% of the co-twins had schizophrenia; among nonidentical twins, none of the co-twins had become ill.

   Following Luxenburger’s work, other important twin studies included the following. In 1932, Aaron J. Rosanoff (1878–1943), who then had a private psychiatric practice in Los Angeles, published in California and Western Medicine a study of 127 twin pairs in which one twin had been institutionalized. Of the 48 monozygotic pairs, both twins had been affected in 41 cases, or 85%; of the 79 dizygotic twin pairs, only 34% had a co-twin with a psychiatric illness. Rosanoff published his findings more fully in 1941 in The Etiology of Child Behavior Difficulties, Juvenile Delinquency and Adult Criminality with Special Reference to Their Occurrence in Twins. (Rosanoff is also remembered for having started the process of deinstitutionalization in California after he became director of the state department of institutions in 1939.)

   The schizophrenia twin-study of Franz J. Kallmann (1897–1965), a German emigré psychiatrist who had landed at the New York State Psychiatric Institute, published in the American Journal of Psychiatry in 1946, found that, among 691 "twin index families," in 86% of the monozygotic twin pairs both twins had schizophrenia, but in only 15% of the dizygotic. (When Kallmann’s results were presented at the first World Congress of Psychiatry in Paris in 1950, they caused consternation: the largely psychoanalytically oriented participants found such findings incredible and totally inconsistent with psychoanalytic theory.)

   Finally, among these early twin-studies, the most ample of all was conducted by English psychiatrist and geneticist Eliot Slater, presented in his 1953 book, Psychotic and Neurotic Illnesses in Twins. In schizophrenia, Slater found a concordance for the monozygotic twin pairs of 75% and for the dizygotic of 11%. Slater concluded, "These facts suggest that genetical causes provide a potentiality for schizophrenia, perhaps an essential one, though environmental factors play a substantial role" (p. 88). These and other twin studies provided a kind of statistical battering ram for forcing open the biological door in the study of schizophrenia and were for many years among the most powerful arguments for the organicity of the disease (today, evidence from neuroimaging is very compelling as well). Later twin-studies, using refined techniques, found the concordance for schizophrenia in identical twins somewhat lower than in the above studies. Yet, Irving Gottesman (1930–), a psychologist then at the University of Virginia, summarizing the literature in his 1991 book, Schizophrenia Genesis, nonetheless put the concordance in monozygotic twins at around 50%, in dyzygotic at only around 20%, in nephews and nieces of schizophrenic patients at 5%, and the risk in the general population at less than 1%. He concluded, "The facts about the risks of schizophrenia obtained from family studies of schizophrenics— their parents, siblings, children, and more distant relatives—all suggest that schizophrenia is familial. . . . Genetic factors are important, though not adequate to explain all the observations" (pp. 126–127).

   Penrose studies family genetics through careful interviewing (1938 and after). Lionel S. Penrose (1898–1972), a physician on staff at the Royal Eastern Counties’ Institution at Colchester—an asylum for mental retardation—studied the genetics of mental retardation (MR) by carefully interviewing the families of 1280 patients and securing other sources of information as well. In A Clinical and Genetic Study of 1280 Cases of Mental Defect (1938), he determined that 7% to 9% of the first-degree relatives of the patients had themselves some form of MR. (At Colchester, Penrose also discovered that one cause of MR, known as phenylketonuria, was inherited as an autosomal recessive trait. Identifying the genetics of this "error of metabolism" in an article in the Lancet in 1935—one of the few then known as causes of MR—represented a big advance for genetics.)

   In 1945, Penrose took up the chair of Galton Professor of Eugenics at University College London, established in 1911 with a bequest from Francis Galton. In 1963, after a long struggle owing to the wording of Galton’s will, he succeeded in changing the name of the chair to Galton Professorship of Human Genetics. (As editor, in 1954 he had similarly changed the title of the journal Annals of Eugenics to Annals of Human Genetics.)

   Adoption studies using a follow-up method as a means of separating genetic from environmental factors (from 1966). The issue of a "distorted family environment" as a possible source of illness continued to bedevil schizophrenia researchers. In 1966, Leonard L. Heston (1930–), then a resident in psychiatry at the University of Oregon Medical School, published a paper in the British Journal of Psychiatry on children of schizophrenic mothers who had been adopted away compared to controls. Five of the 47 children of the schizophrenic mothers were themselves schizophrenic; none of the control subjects, who were children selected at random from the same foundling home that cared for the children of the schizophrenic mothers, had become schizophrenic at follow-up. Heston concluded, "The results of this study support a genetic aetiology of schizophrenia" (p. 823). (For a psychiatry resident in Oregon, the choice of journal is an interesting one. Heston subsequently explained: "The article appeared in the British Journal of Psychiatry because I was doing a fellowship year in London at the time and my supervisor was Eliot Slater, the editor of the British Journal. It seemed the politic thing to do. However, I was pleased to have Dr. Slater on my side as I did not expect a friendly reception from American editors. I had submitted grants to NIMH and a few foundations. All were rejected, I thought quite disdainfully in some instances. So I knew that my findings would not be popular.")

   A year later, at a conference in Dorado, Puerto Rico, Seymour S. Kety (1915–2000), David Rosenthal (ca. 1919–1996), Paul H. Wender (1934–)—all at the National Institute of Mental Health—and Fini Schulsinger (1923–), a Copenhagen psychiatrist, reported the first results of an adoption study they had undertaken based on the adoption registers of Copenhagen, Denmark, a country having a recordkeeping system that permits the lifetime follow-up of individuals. They found that, of the 5483 adoptions in Copenhagen to unrelated adoptive parents from 1924 through 1947, 33 of the children had developed schizophrenia. How common was schizophrenia in the biological families of these children as opposed to those of controls? Of the 150 biological relatives of the schizophrenic children, 13 had a history of the illness, whereas in the adopted families of the 33 children, and among the controls, there was very little schizophrenia. The evidence pointed overwhelmingly to a genetic contribution to the illness. The authors concluded "that the roughly 10 percent prevalence of schizophrenia found in the families of naturally reared schizophrenics is a manifestation of genetically transmitted factors" (p. 359). The work was published in 1968 in the Journal of Psychiatric Research and created something of a sensation within psychiatry.

   First positive linkage to schizophrenia using DNA markers (1988). Was there a schizophrenia gene? The first link between forms of the illness and specific loci on the DNA was discovered on chromosome 5 by a team led by Robin Sherrington and reported in Nature in 1988. Yet, the finding of a specific gene was not confirmed. (See Schizophrenia: Recent Concepts [1988].) As this field has evolved, it appears that there are probably several DNA markers for schizophrenia, as indeed "schizophrenia" is likely to be a final common pathway for a number of biological conditions, some of them genetic in nature and having quite diverse DNA sources of susceptibility. (At this writing, it seems that "schizophrenia genes" as such probably do not exist, and that genetic influences affect mainly information processing within the brain.)