Luxenburger's 1939 Essay on "Schizophrenia and its Hereditary Circle".

In 1939, Hans Luxenburger published a detailed overview of the current status of schizophrenia genetics research, reaching six major conclusions. First, schizophrenia is clearly a hereditary disease. Second, however, schizophrenia is not the hereditary trait itself but rather the consequences of a slowly developing biological progress, the nature of which remains entirely unknown. Third, the full manifestation of the disorder requires certain environmental influences that must come into play. In around 30% of cases, the environment can inhibit hereditary factors so that the predisposition does not manifest in schizophrenia. Fourth, the mode of inheritance of schizophrenia remains unknown, although recessivity is more likely than dominance and monomerism is more likely than polymerism. Fifth, current evidence suggests that schizophrenia is likely etiologically homogenous. Sixth, schizophrenia is part of a hereditary circle that includes "normal" variants of the human personality (schizothymia), a pathological version of this dimension (schizoidia), and other schizophrenia-like delusional syndromes. Luxenburger is skeptical of efforts to clarify further Mendelian transmission models in the absence of pathophysiological markers because schizophrenia cannot serve as a typical phenotype for genetic analysis. By contrast, he strongly supports empirical work on hereditary prognosis, which does not depend on assumptions about any particular phenotype-genotype relationship.

Ryssia Wolfsohn's 1907 dissertation on "the heredity of dementia praecox".

In the 19th century, psychiatric genetic studies typically utilized a generic category of "insanity." This began to change after 1899, with the publication of Kraepelin's 6th edition containing, among other disorders, his mature concept of dementia praecox (DP). We here review an article published by Ryssia Wolfsohn in 1907 from her dissertation at the University of Zurich entitled "Die Heredität bei Dementia praecox" (The Heredity of Dementia Praecox). This work, performed under the supervision of E. Bleuler, was to our knowledge the first formal genetic study of the then new diagnosis of DP. She investigated 550 DP probands admitted to the Burghölzli hospital with known information about their "heredity burden." For most probands, she had information on parents, siblings, grandparents, and aunts/uncles. Of these patients, only 10% had no psychiatric illness in their families. In the remaining probands, she found rates of the four major categories of psychopathology she investigated: mental illness-56%, nervous disorders-19%, peculiar personalities 12% and alcoholism 13%. Her most novel analyses compared either total familial burden or burden of her four forms of mental disorders on her DP probands divided by subtype and outcome. In neither of these analyses, did she find significant differences.

Bruno Schulz's 1930 article "The Hereditary Relationships of Old-Age Paranoid Psychosis".

In the 1899 6th edition of his influential textbook, Kraepelin proposed a diagnostic category of "Old-Age Paranoid Psychosis." In this 1930 article, Bruno Schulz studied the morbid risk (MR) of several disorders and traits in the parents, siblings, offspring, and nieces/nephews of 51 probands with "Old-Age Paranoid Psychosis." His results permitted an evaluation of the validity of Kraepelin's category of Old-Age Paranoid Psychosis, in particular, whether it was a form of psychosis resulting from "senile changes" or late-onset schizophrenia. The MR of schizophrenia in these four groups of relatives varied from 0 to 2.4% with 3 of 4 somewhat higher than population expectations but much lower than parallel results in relatives of schizophrenics. By contrast, the rates of eccentricity in these relatives were uniformly elevated over population rates, sometimes approaching those seen in relatives of schizophrenics. Schulz concluded, from his study, that Old-Age Paranoid Psychosis was a distinct disorder not closely related to schizophrenia. However, he suggested that a family history and/or a premorbid trait of eccentricity increases the risk of developing a paranoid psychosis in old age, particularly when associated with physical or mental decline. He was uncertain about whether the trait of eccentricity he found in this study was very similar or distinct from that observed in excess in relatives of schizophrenics. This study was the first, to the best of our knowledge, to use a family study design explicitly to address a nosologic question-in this case the familial relationship between Old-Age Paranoid Psychosis and schizophrenia.

Bruno Schulz's 1936 book "Methodology of medical genetic research particularly with regard to psychiatry".

In 1936, Bruno Schulz published the first detailed, book-length review of the methodology of psychiatric genetic research, based on his experiences at the German Research Institute of Psychiatry. Emphasis is placed on proper selection of relatives and the ascertainment corrections required for Mendelian transmission models. Twin studies are considered as is the impact of reduced fertility on patterns of risk. For the field work, Schulz emphasizes the importance of trust-building, confidentiality, collateral informants, and the use of medical and other administrative records, all ideally stored in personal files. Several methods of age-correction are reviewed. Schulz provides detailed algebraic treatments of these and other problems, including tests for etiologic homogeneity, with worked examples. He emphasizes two fundamental concerns in psychiatric genetics research: (i) its inter-dependency with the optimal diagnostic boundaries, which are rarely known and (ii) the genetic homogeneity of clinical samples. Given these problems, he is pessimistic about finding Mendelian transmission patterns. He assesses the predominant 19th-century method of psychiatric genetic investigation-"hereditary burden"-to be crude and biased by family size. Although written at a time of consolidation of Nazi power in Germany, this book nowhere endorses their racial/eugenic policies and can be seen as subtly questioning them.

The examination of Kraepelin's diagnoses of dementia praecox and manic-depressive insanity in pedigrees: Studies of Schuppius in 1912 and Wittermann in 1913.

In the first two decades of the 20th century, a new approach to psychiatric genetics research emerged in Germany from three roots: (i) the wide-spread acceptance of Kraepelin's diagnostic system, (ii) increasing interest in pedigree research, and (iii) excitement about Mendelian models. We review two relevant papers, reporting analyses of, respectively, 62 and 81 pedigrees: S. Schuppius in 1912 and E. Wittermann in 1913. While most prior asylum based studies only reported a patient's "hereditary burden," they examined diagnoses of individual relatives at a particular place in a pedigree. Both authors focused on the segregation of dementia praecox (DP) and manic-depressive insanity (MDI). Schuppius reported that the two disorders frequently co-occurred in his pedigrees while Wittermann found them to be largely independent. Schuppius was skeptical of the feasibility of evaluating Mendelian models in humans. Wittermann, by contrast, with advice from Wilhelm Weinberg, applied algebraic models with proband correction to DP in his sibships with results consistent with autosomal recessive transmission. While he had less data, Wittermann suggested that MDI was likely an autosomal dominant disorder. Both authors were interested in other disorders or traits appearing in pedigrees dense with DP (e.g., idiocy) or MDI (e.g., highly excitable individuals).

Irma Weinberg's 1928 paper "on the problem of the determination of heredity prognosis: The risk in the cousins of schizophrenics".

Irma Weinberg, a German-Jewish Neuropsychiatrist/Physician, authored the fourth report from the German Research Institute for Psychiatry in Munich examining the risk for dementia praecox (DP) in particular relatives of DP probands, here first-cousins. She examined 977 cousins of 54 DP probands and found a best-estimate risk of 1.4%. She conducted within-study analyses, showing a much higher risk for DP in the siblings than cousins of DP probands. She studied DP-related personalities showing a familial link between these conditions and risk for DP. She demonstrated that the risk for DP in cousins was impacted substantially by the distribution, in ancestors, of psychosis and personality abnormalities. After completing work on this article, Weinberg worked in private practice in Frankfurt, emigrating to the Netherlands in 1934, where she worked at a Jewish psychiatric hospital. In 1943, German occupiers evacuated the hospital, transporting the patients and staff, either directly to Auschwitz or, like Weinberg, to the Westerbork transit camp. On September 4, 1944, Dr. Weinberg was transported to Theresienstadt and soon thereafter to Auschwitz, where she was murdered at the age of 53. Her history raises painful questions about the relationship between genetic studies of psychiatric illness in prewar Germany and the Holocaust.

The era of the Dawn of Mendelian research in the field of psychiatry: Rüdin's 1922 review paper "regarding the heredity of mental disturbances".

On September 27, 1922, Ernst Rüdin gave an address to the Annual Conference of the German Society of Genetics entitled "Regarding the Heredity of Mental Disturbances." Published in a 37-page article, Rüdin reviewed the progress in the field of Mendelian psychiatric genetics, then hardly more than a decade old. Topics included (a) the status of Mendelian analyses of dementia praecox and manic-depressive insanity which had expanded to include two and three locus and early polygenic models and sometimes included, respectively, schizoid and cyclothymic personalities; (b) a critique of theories for the explanation of co-occurrence of different psychiatric disorders within families; and (c) a sharp methodologic critique of Davenport and Rosanoff's contemporary work which emphasized Rüdin's commitment to careful, expert phenotyping, a primary focus on well-validated psychiatric disorders and not broad spectra of putatively inter-related conditions, and an emphasis on rigorous statistical modeling as seen in his continued collaboration with Wilhelm Weinberg.

Karl Grassmann's 1896 paper "critical overview of contemporary theories of the heredity of the psychoses".

Four years before the rediscovery of Mendel's work in 1900, Karl Grassmann published a detailed, scholarly review of the heredity of psychosis which we here review. A full translation is in the appendix. We emphasize seven major conclusions from this review. First, while recognizing the key importance of heredity in the etiology of psychosis. Grassmann was critical of many of the highly speculative extant theories. Second, he reviewed most of the major methodologic concerns in the literature from what kinds of heredity to investigate to the problems with the global use of insanity as a diagnostic category. Third, he discussed in detail genetic theories associated with Degeneration theory, maintaining considerable skepticism. Fourth, he recognized nongenetic contribution to familial transmission. Fifth, he reviewed evidence for both homogeneous and heterogeneous transmission of forms of mental illness in families, suggesting that both were important. Sixth, while he noted that mania, melancholia, and cyclothymia commonly replaced each other in families, Verrücktheit (delusional psychoses) rarely co-segregated in families with these mood disorders. Seventh, Grassmann, like other 19th century writers, saw relatives to be of value only in assessing the level of hereditary predisposition in patients and had limited appreciation of the need for controlled studies.

Bruno Schulz and his 1926 Article: "Regarding the Problem of Determining Hereditary Prognosis. The Affliction Prospects for Nephews and Nieces of Schizophrenics".

Authored by one of Rüdin's most productive colleagues, Bruno Schulz, the main goal of this article was to estimate risk for dementia praecox (DP) in nieces/nephews (n/n) of DP probands to address practical questions for genetic counseling. Schulz selected 76 primary probands from records of the genealogical department of the German Research Institute of Psychiatry who both had DP and had siblings-secondary probands-with children aged 20 years or greater. Those children had a morbid risk for DP of 1.4%, much lower than that found in the offspring of DP in Hoffmann's study. However, the secondary probands had much lower rates of DP than the unselected siblings of DP cases studied by Rüdin. So rates of DP in n/n of DP probands are likely lower than expected theoretically because the secondary probands are being indirectly selected for a lowered genetic risk for DP by having successfully reproduced. Schulz diagnosed eccentric and other disordered personalities in the secondary probands and their spouses and presented evidence that other disordered personalities but especially eccentric personalities in parents were related to the risk of both eccentricity and DP in their children, the n/n of the DP probands. Eugenic issues play a minor role in this article. Although generally supportive of eugenic goals, historical sources document that Schulz was opposed to the National Socialists and actively attempted to protect Jews and his patients from involuntary sterilization. This complicates attempts to judge the morality of the work of the Rüdin school as a single unit.

Rüdin's 1916 Monograph: On the Inheritance and Primary Origin of Dementia Praecox.

In 1916, Ernst Rüdin published the first modern family study in the history of psychiatric genetics, the major goal of which was to test whether the pattern of risk in the siblings of dementia praecox (DP) probands followed Mendelian expectations. He utilized systematic ascertainment of probands and multisourced diagnostic assessments of probands and relatives, applying the narrow Kraepelinian concept of DP. In a novel step, he collaborated closely with a statistical geneticist-Wilhelm Weinberg-and applied his sibling, proband, and age correction methods. In his key sample-701 sibships when neither parent had DP-the morbid risk for DP in siblings was 4.48%, much lower than 25% expected for a recessive disorder. Risk for DP was increased by alcoholism or other mental disorders in parents. Other non-DP psychoses were common in both siblings and parents of DP probands. Rüdin discussed several alternative genetic models for DP including a 2-locus recessive, incomplete penetrance, and an oligogenic model. The high rates of other psychoses and psychopathic personalities in relatives might arise, he suggested, because these disorders shared genetic risks with DP. Rüdin established that DP, when carefully studied, ran in families, did not have a simple Mendelian genetic transmission pattern, and appeared likely to be genetically related to other non-DP psychotic disorders and perhaps some kinds of psychopathic personalities. This study, the most important in Rüdin's career, should be viewed in the context of his later extensive support of and collaboration with Nazi eugenic policies.

The Beginnings of Scientific Psychiatric Twin Research: Luxenburger's 1928 "Preliminary Report on the Psychiatric Examination of a Series of Twins".

While reports of twin pairs concordant for insanity began to appear in the 19th century, the first modern psychiatric twin study that fulfilled Galton's 1875 promise of the value of the twin method was published by the German Psychiatrist and Geneticist Hans Luxenburger in 1928. Luxenburger introduced four major methodological advances: the use of representative sampling, proband-wise concordance, rigorous zygosity diagnoses, and age correction. He used a narrow Kraepelinian diagnostic approach diagnosis and ascertained twins hospitalized, on a specific day, in all large Bavarian asylums. We include a brief biography of Luxenburger, summarize the findings of his paper and provide a full English translation in the appendix. Luxenburger presents evidence that the frequency of twinning in those with severe mental illness were as expected and reports proband-wise concordance for probable and definite dementia praecox (MZ-76%, DZ-0%) and manic-depressive insanity (MZ-75%, DZ-0%). He also examined eccentricity and hyperthymic or hypothymic personality in the dementia praecox and manic-depressive pairs, respectively. Luxenburger's substantial contributions to the history of psychiatric genetics should be considered in the context of his intimate but ambivalent relationship with the racial-hygiene policy of the German National Socialists.

Bruno Schulz's 1933 Monograph: On the Hereditary Etiology of Schizophrenia.

In his 1933 article, Bruno Schulz reported a follow-up and reanalysis of the schizophrenic probands and their relatives first studied by Rüdin 20 years earlier that sought to clarify whether schizophrenia was a valid "unit-character" for Mendelian genetic analysis. He proposed a range of subgroupings of probands, particularly traditional subtyping, presence or absence of identifiable causal influences, and outcome. He then compared those subgroupings in several ways, most commonly by the risk for schizophrenia in their siblings and by the level of resemblance among proband-sibling affected pairs. Of his many findings, those of greatest interest included (1) probands with possible and probable physical causes, particularly those with head trauma, had substantially lower risk of illness in siblings, (2) probands with a hebephrenic subtype had a striking elevation of risk for schizophrenia in siblings, (3) probands with psychological causes had higher rates of good outcome, (4) proband-sibling pairs resembled one another for the classical schizophrenic subtypes, and (5) an absence of any cases of schizophrenia in siblings of a small group of schizophrenic probands with birth complications, convulsions, and skull deformities. Schulz used this sample in a fundamentally different way than Rüdin. Rather than seeking for Mendelian transmission patterns, Schulz used family data to evaluate hypothesis about clinical/etiological heterogeneity, thereby presaging many subsequent family studies of psychiatric disorders. While Schulz did not claim to have proved the etiologic heterogeneity of schizophrenia, he raised important questions, still unanswered, about whether schizophrenia is a legitimate "unit-character" appropriate for genetic analysis.

Hermann Hoffmann's 1921 Monograph: "The Offspring of Endogenous Psychoses: Genealogical-Characterological Examinations".

Five years after the publication of Rüdin's major sibling study, Hermann Hoffmann, working with Rüdin, performed the first systematic study of the risk for dementia praecox (DP) in offspring of DP probands. Field work was limited to 3 months. Hoffmann ascertained families with at least one parent with certain DP, after Kraepelin, with children the youngest of whom were at least 30 years old. These families contained 103 offspring 30 years or older of whom 7 had definite DP and two possible DP for an estimated risk of 6.8%-8.7%. Hoffmann assessed schizoidia in these children, reporting the quite high risk figure of 47.6%. Hoffmann explored a wide range of two and three locus recessive models in his modest sample. He finds Rüdin's two locus recessive model at the boundary of his results and then reviews three additional more complex models. The simplest is a three-locus recessive model which fits his data better. He also explores an oligogenic three locus model with risk classes of individuals with 1 to 6 risk alleles and an epistatic model where two loci form a di-recessive model for schizoidia, and the third locus is a dominant required for the expression of psychosis. Hoffman questioned whether DP was a "unit-character" appropriate for Mendelian analysis and advocated for a much larger study of offspring. His work should be appreciated in light of his enthusiastic endorsement of Nazi eugenic goals.

'Regarding the scientific viewpoint in psychiatry', lecture by Carl Wernicke (1880).

In 1880 Carl Wernicke gave this plenary lecture at an annual meeting of German physicians and natural scientists. He used principles from his 1874 aphasia monograph to build a neural model of mental illness. He proposed that the brain keeps a record of experiences in distinct areas of the sensory and motor cortices in the form of memory images, which allows for recognition of objects and the planning of motor acts. He conjectured that imperfections, partial defects and complete loss of such memory images lead, respectively, to mild, moderate and severe forms of psychopathology in sensory and motor realms. The lecture is an early presentation of Wernicke's system of psychiatry. Several of his concepts have remained relevant in contemporary neuroscience.

The place of Franz Kallmann's 1938 "the genetics of schizophrenia" in the history of psychiatric genetics.

This essay provides the historical context and key findings of one of the largest fieldwork-based family studies ever done in the history of psychiatric genetics conducted in Berlin by Franz Kallmann from 1929 to 1933. It included over 1,000 schizophrenic probands and 12,500 of their relatives including siblings, offspring, nieces/nephews and grandchildren. The work was analyzed in close collaboration with Rüdin, Schulz, and Luxenburger in Munich. Born of Jewish parents, Kallmann had to leave Germany in 1936, completing and publishing the monograph in the United States in 1938. This study included a number of methodologic advances over the classic 1916 sibling study of Rüdin: (a) joint analysis of multiple classes of relatives; (b) subdivision of schizophrenia into four subtypes; (c) a focus on schizoid personality [schizoidia]; (d) examination of the familial aggregation of schizophrenia; and (e) a more complex genetic model-with schizophrenia arising from a single-recessive gene with 70% penetrance and background polygenic influences, and schizoidia from heterozygotes. Kallmann found important differences in risk of relatives in nuclear versus peripheral subtypes and concluded that schizoidia was a part of schizophrenia disease complex while other psychopathies, feeblemindedness, and organic brain disorders were not. Kallmann was strongly invested in the eugenic implications of his results.

Julius Wagner von Jauregg, Otto Diem and research methods for assessing the contributions of hereditary burden to mental illness risk: 1902-1906.

After decades of methodological stasis in 19th century psychiatric genetics, when uncontrolled studies reported high rates of hereditary burden in hospitalized patients, Koller completed the first controlled study in 1895. We pick up this narrative 7 years later when the well-known Julius Wagner v. Jauregg published a biting critique of the then current psychiatric genetics' literature. In 1905, partially in response to Wagner v. Jauregg, Otto Diem attempted to replicate and extend Koller's study. Wagner v. Jauregg then wrote a follow-up to his earlier critique in 1906, commenting on Diem's investigation. Themes discussed in this point-counterpoint included the necessity of statistical methods to draw meaningful conclusions about the impact of hereditary burden on mental illness, the required sample size and proper selection of controls, the classes of relatives which should optimally be studied, the problems of obtaining accurate information on familial illnesses, the nature of the disorders in families which contribute to mental illness risk and the common unquestioned dogmatic belief that insanity is very often due to hereditary causes. Both Wagner v. Jauregg and Diem spoke out forcefully against the common assumption that hereditary burden operated in a deterministic fashion and emphasized the need to consider other causes of illness.

Philipp Jolly and his 1913 "the heredity of psychosis": Homogeneity versus heterogeneity of familial transmission and an early look at Mendelian models for manic-depressive illness and dementia praecox.

Philipp Jolly's 1913 extensive monograph "The Heredity of Psychoses" provides, in both his detailed literature review and new pedigree study, an extensive assessment of a key issue in the psychiatric genetics of his day: the degree to which the familial transmission of psychiatric disorders was specific (or homogeneous) versus nonspecific (or heterogeneous). Contrary to a number of earlier observations, Jolly concludes that heterogeneous transmission is rare. Multiple psychiatric disorders can occur in one family because members of a family may have elevated predispositions to more than one disorder rather than one predisposition which increases risk for a wide range of conditions. A notable exception to this, he notes, is within manic-depressive illness (MDI), where different forms of illness run together within families. Jolly is also among the earliest investigators to evaluate simple Mendelian models for MDI and dementia praecox (DP). While his methods were primitive and contained only "eye-ball" examinations rather than statistical modeling, Jolly demonstrated considerable conceptual sophistication in the early application of such models. He concludes that DP is likely a recessive disorder. MDI, he states, is either a recessive condition or demonstrates "gender-based dominant heredity" where heterozygote females are affected, and heterozygote males are not.

The turn to controls and the refinement of the concept of hereditary burden: The 1895 study of Jenny Koller.

Throughout the 19th century, many alienists reported the proportion of their patients who were "hereditarily burdened," meaning they had a positive family history for mental illness. The rates of such burden differed widely because different authors used divergent definition of illness and investigated different groups of relatives. Most importantly, no authors compared rates of burden with those seen in a nonpatient control group. The first such study in the history of psychiatric genetics was published in 1895, the doctoral dissertation of a Swiss physician Jenny Koller working under Auguste Forel. She obtained histories of a range of mental/neurologic disorders in the parents, aunts/uncles, grandparents and siblings of 370 hospitalized psychiatric patients and 370 controls. Rates of any hereditary burden were only modestly higher in cases (78%) than controls (59%). However, when examining individual syndromes, only major mental illness and eccentricities, but not apoplexy, nervous disorders or dementia, were more common in proband than control families. Furthermore, the rates of mental illness and eccentricities were substantially elevated in the first-degree relatives of cases versus controls but not in the second-degree relatives. Koller's study represented a major methodological advance in psychiatric genetics, helping to define which disorders coaggregated with major mental illness.