Studies on schizophrenia and psychopathology

Gottesman first studied the genetics of schizophrenia on a large scale using the Maudsley–Bethlem register of twin admissions for 16 years. Later he worked on psychiatric genetics and genomics. In his Twin Cities MMPI study, part of his Ph.D. thesis, Gottesman found high levels of inheritance in the scales related to schizophrenia, depression, anti-social personality disorder, and social introversion.^[3] Genes strongly influenced social introversion and aggressive tendencies. This led to further studies on personality traits of identical twins such as the Minnesota Study of Identical Twins Reared Apart.^[4]

Analyzing the results of the Maudsley–Bethlem study, Gottesman and Shields devised the multi-element, polygenic causation model for schizophrenia by modeling schizophrenia diagnoses using the recently introduced liability-threshold model. The book that summarized and expanded on the study, Schizophrenia and Genetics: A Twin Study Vantage Point, argued that schizophrenia is a product of several genes acting together, and introduced the techniques of precise analysis in the field of behavioral genetics.^[4]Gottesman and Shields introduced terms such as "reaction ranges/surface", "endophenotype" and "epigenetic puzzle" into the behavioral sciences.^[3] The threshold model hypothesized that both genetic and environmental risks combined to produce schizophrenia, and pushed an individual into a diagnosable condition when their influence grew strong enough. The reaction range concept is the idea that the genes and the environment control behavior, but with separate upper and lower limits on the strength of that control in each case, a concept now part of basic psychology.^[10] Before the study, the prevailing opinion was that schizophrenia originated from bad parental relationships.^[4] The researchers showed identical twins were more likely to either have or not have schizophrenia together, concluding the disorder was the "outcome of a genetically determined developmental predisposition".^[13]

The Maudsley–Bethlem study also hypothesized that schizophrenia was caused by a mixture of many small traits working together. These endophenotypes could be used for diagnosis.^[4] Endophenotypes have been interpreted as a link between genes and the final behavior, acted on by the environment and chance elements, with biochemical and epigenetic influences changing the genome but not being passed on to children. Molecular-biological studies in genetics have referred to endophenotypes to explain genetic causes of psychopathology.^[14] The researchers also examined how schizoids, those with mild, schizophrenia-like personality disorders, were linked to schizophrenics. Gottesman and Shields extended the term to classes of mild psychological disorders in twins and relatives of schizophrenics.^[15] The researchers had hypothesized that schizoida in a twin was how a schizophrenia carrier gene, one in a non-schizophrenic still passing on a genetic risk, expressed itself. The twin study did not confirm this.^[16]

In the Denmark study, the researchers evaluated the extent to which genes underpin psychopathology.^[3] Their twin studies of criminality found that a genetic disposition to poor self-control caused both identical twins to become felons, or to not become felons. They also studied identical twins who were discordant for schizophrenia, where one twin was schizophrenic and the other not, and found children of such twins had equal genetic vulnerability to the disease.^[4] A later study in the mid-1980s, resulting in a paper awarded the Kurt Schneider Prize, concluded that children of identical twins were at higher risk than those of fraternal twins, indicating the non-schizophrenic identical twin passed on a latent genetic disposition, even if it had not been expressed through schizoida.^[14] The Denmark study introduced the concepts of "unexpressed genotypes"—the latent genetic risk, and "epigenetic control"—the biochemical regulation of how genes work, into the new field of behavioral genetics.^[3]

Studies on delinquency and violence

In a 1989 review of the research on juvenile delinquency and violence, Lisabeth DiLalla and Gottesman found delinquency could be transitory or continuous, and genes contributed more to the continuous type.^[17] In 1991 the same authors published a critique of the then-prevalent idea of antisocial behavior being transmitted through generations by child abuse alone in antisocial families. They stated that a review by Cathy Spatz Widom and the studies she cited had missed an element: children maltreated in families might have been targets because their genes might have influenced them into committing antisocial acts and attracting such treatment from parents.^[18]

Gottesman was one of the presenters at the 1995 conference at the Aspen Institute in Maryland on how strongly genes controlled a person's leaning toward violence and crime. Gottesman presented results from studies on the influence of genes in criminality, stating that identical twins separated at birth were likely to show similar levels of criminal behavior. This concordance indicated that genes influenced such behavior. He did point out that behavioral patterns were strongly influenced by the environment and not set by genes alone. The conference, funded by the National Institutes of Health, was contentious, with detractors arguing that such studies would lead to minority groups, more likely to be criminals because they had lower social status or were poor, being targeted with gene therapy for violence. Protesters disrupted the conference and swarmed into the auditorium. Gottesman reasserted his belief that scientists should proceed with the research, not waiting for humanity to become ethical enough not to misuse it.^[19][20]

Work on IQ

In 1972, Gottesman was called before the United States Senate by senator Walter Mondale to discuss the then 15-point IQ gap separating African Americans and white Americans. Gottesman testified that genes influenced IQ, but only in conjunction with elements such as schooling, money, and nutritious food from childhood onwards.^[4] According to Eric Turkheimer, Gottesman "was certainly the most prominent behavior geneticist to refuse to sign" the editorial Mainstream Science on Intelligence.^[21] In 2003, he and colleagues published a study showing that heritability was higher for IQ differences within high socioeconomic status (SES) people than among low SES people, i.e., genes influenced differences between children's test scores more among high SES than among low SES children.^[22]

Humanistic views

Gottesman researched and published on the abuse of genetic research in Nazi Germany, and provided expert testimony in a Chinese human rights case involving schizophrenia in the family. His scholarly books on schizophrenia also highlighted the human costs of the disorder. In Schizophrenia Genesis: The Origins of Madness, he provided chapters in which patients describe their experiences of the disease, and those of their families.^[23] He opposed the Nazi-associated Pioneer Fund, which funded some of his colleagues.^[21] Gottesman emphasized that genetics influences patients' behavior in concert with the family, social, economic, and cultural contexts.^[10] Gottesman also highlighted random events as an important "third element" determining behavior and what unfolds as apparent destiny. In his writings, he reflected that the interaction between these elements is known only at the level of probabilities, and not as fixed and precise quantities.^[24]

Schizophrenia and Genetics: A Twin Study Vantage Point

Gottesman and Shields published Schizophrenia and Genetics to document their twin-study research at the Maudsley Hospital in London, the work that in part earned them the Hofheimer Prize for Research,^[25] the highest award for psychiatric research from the American Psychiatric Association.^[26] The study expanded on an earlier one by Eliot Slater at the same hospital, covering 24 identical and 33 fraternal twins, with at least one from every pair a schizophrenic being treated at the hospital between 1948 and 1964.^[25] This study was one of eleven such in the contemporary literature, and the book detailed the methodology and analytic detail differentiating it from the others.^[13]

Chapters on methodology comprise a third of the book's core. Identical and fraternal twins were classified using fingerprints and blood groups. Follow-up interviews were recorded to monitor the progress of their patients (the probands) and their twins, some schizophrenic and others not.^[27] Two psychological tests—the MMPI and the Object Sorting Test (Goldstein Scheerer Test of Concept Formation)—were used to measure mental traits and functioning. Case summaries were prepared by the Scandinavian psychiatrist Erick Essen-Moller, and these were sent, with data on identical-or-fraternal-twin status and diagnosis-of-schizophrenia removed, to six judges from the U.S., U.K. and Japan. The judges independently evaluated whether the patients were schizophrenic.^[28]

Results of studies comprise another third of the core of Schizophrenia and Genetics. The data showed that genes made a person likely to develop schizophrenia under environmental pressures. The study was not designed to find the genes responsible, but the authors hypothesized there would be several acting in tandem.Contextual elements responsible could not be identified, though some, such as an overly protective mother, birth order, natal weight, and social and economic elements were ruled out.^[27] Gottesman and Shields found roughly half of identical twins had a shared schizophrenic or non-schizophrenic status, but only one-eleventh of fraternal twins had such a shared diagnosis. MMPI scales coincided among identical twin pairs but not among fraternal twin pairs. The Object Sorting Test showed no useful relations.^[25] Those meeker than their twins were more liable to develop schizophrenia where their genes already put them at risk.^[27]

The book presents case histories of all the twin-pairs studied and the raw data from the analyses.^[25] Its last chapters put the results in the context of existing studies, and presented a new theory and model to explain the causes and continuance of the disorder.^[28] The environmental aspects the researchers checked drew on existing literature, and multiple judgments were pooled to both compare and mutually cancel differing criteria for diagnosing schizophrenia.^[13] The theory in the book was that many genes work together to dispose a person to the disorder under certain environmental pressures. The model provided no specific therapeutic insight, but was useful as a guideline for further study.^[27]

Schizophrenia: The Epigenetic Puzzle

Schizophrenia: The Epigenetic Puzzle outlined the approaches, conclusions and models Gottesman used in his study of schizophrenia. He co-wrote the book with James Shields, who died before it was published. The book introduces methods for diagnosing schizophrenia in a research setting, taking into account national differences in how the disorder was defined, debunked myths such as the mother transmitting schizophrenia, and introduced the concepts of the threshold model and the reaction range.^[29]

The book provided a tutorial on genetics to make the material self-contained.^[30] Family, adoption and twin studies were investigated to determine the ways vulnerability to the disorder changed with genetic similarity to the patient. Together they supported the presence of a genetic contribution to the cause and the progress of schizophrenia. Contextual elements such as birth problems and stressful incidents were also analyzed to help the authors build a combined model to explain the disorder.^[29] The researchers analyzed populations to determine the role of genes using simplified mathematical models of the influence of genes and the environment on each other, and with no biochemical signal of the disorder to guide them. Rue L. Cromwell, writing in PsycCRITIQUES, wrote that this approach lacked rigor.^[31] The role of genes was less emphasized in the results, with a heritability of 70%, than in earlier studies by Kallman. The researchers investigated neuroanatomy, and specifically the neurotransmitter dopamine, as a possible route by which genes influence the functioning of the brain to produce the symptoms of the disorder.^[29]

The authors investigated autism and psychiatric disorders among children, but found little relation to adult schizophrenia or genetic influence.^[29][31] They also covered the social implications of the disease, concluding that most schizophrenics were poor because the disorder eroded their resources and abilities. A chapter was devoted to social issues, violence, illnesses, death rates, sexual aspects, and the ability to father or bear children affecting schizophrenics. The authors provided data on the chance of relapse after an episode of the disorder.^[29] The book covered new methods and new models for studying schizophrenia. Because the disorder had no unanimously accepted diagnostic criteria, the researchers asked six clinicians and three colleagues to provide their analyses on the reports on 120 twins, and found an agreement of 86% among the clinicians. Averaging the criteria of the clinicians produced a set close to that of Manfred Bleuler, who had adapted it from Emil Kraepelin.^[29]

Schizophrenia Genesis: The Origins of Madness

Schizophrenia Genesis: The Origins of Madness, written in 1991, won the William James award from the American Psychological Association.^[32] It extensively reviewed how science has looked at schizophrenia. The book presented a vulnerability/diathesis–stress model to explain the causes of the disorder and a many-cause, many-gene model to explain how it is passed from parents to children.^[23] The book has been translated into Japanese and German.^[9] Schizophrenia Genesis was written for both the lay person and the clinical professional,^[33] and provides data, methods of interpreting the data, and an introduction to genetic analysis as used to analyze role of inheritance in behavior.^[23][34] The book also contains accounts of schizophrenics, with an artist depicting own suffering, saying, "I know ... it is craziness when every laugh is about me ... newspapers suddenly contain cures ... sparkles of light are demon eyes."^[35]

Schizophrenia Genesis starts with the history of schizophrenia. Gottesman takes the view that schizophrenia is a disease of the industrial world.^[36] because it is not mentioned in the Bible, by the ancient Greeks, the ancient physicians, or authors including Shakespeare. He saw it first mentioned by physicians in 1809 and by Balzac in a short story in 1832, showing minimally the disorder had by then been recognized as such.^[37] In 1896, Kraepelin defined its symptoms, and his student Ernst Rüdin began a genetic study of its transmission in 1916.^[33]} The book noted that schizophrenia existed across cultures and its rates had stayed steady for fifty years.^[35]

A chapter was devoted to criteria for determining schizophrenia, with Gottesman preferring those developed by Bleuler to those in the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders (version III-R), the International Classification of Diseases (ICD-9) and Kurt Schneider’s method. Diagnosis was based on the ways a person spoke and acted, and the standard measures were hallucinations, delusions, emotional apathy, jumbled thought, and sudden changes in a person. Gottesman mentioned a disparity in schizophrenia diagnosis after World War II across the Atlantic, when U.S. psychiatric diagnoses quadrupled those of British psychiatrists.^[37]

Family studies on schizophrenia were reviewed. That the disorder runs in families did not suggest it was genetically inherited, since cultural transmission occurs from parents to children. Twin and adoption studies were presented as the standard methods to disentangle contributions from genes and the environment.^[36] Gottesman used a computer-based method for calculating the odds of becoming schizophrenic based on the many causes.^[34] The book examines the problems caused by schizophrenia for relatives of patients and for society at large, larger-scale ones exemplified by the eugenics policies of states such as Nazi Germany. Two final chapters cover molecular biology and neuroanatomy briefly.^[36] Newer methods of behavioral genetics being researched at the time of publication, such as linkage analysis which used the likelihood of neighboring genes being inherited together, were not covered.^[33]