The study described in this book reflects the integration of developments

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1 This is a chapter excerpt from Guilford Publications. Genes, Environment, and Psychopathology: Understanding the Causes of Psychiatric and Substance Abuse Disorders By Kenneth S. Kendler and Carol A. Prescott. Copyright 2006 CHAPTER ONE The Scientific and Social Context of the Virginia Adult Twin Study of Psychiatric and Substance Use Disorders The study described in this book reflects the integration of developments in three research areas: biometrical genetics, psychiatric twin studies, and psychiatric epidemiology. We review these briefly and then describe how they were integrated into the Virginia Adult Twin Study of Psychiatric and Substance Use Disorders (VATSPSUD). This chapter concludes with some other introductory thoughts about our approach to the subject matter and substance of this book. BIOMETRICAL GENETICS In its early years, the field of human genetics included two distinct and sometimes antagonistic approaches to the study of genetic variation: biometrical genetics and Mendelian genetics. Biometrical genetics focused on quantitative traits ones that could be measured, quantified, and then put on a scale. Examples of such traits include height, blood pressure, and extroversion. In contrast, Mendelian genetics was concerned with qualitative traits, traits one either has or does not have. Examples of such traits include the 11

2 12 BACKGROUND color of peas in Mendel s famous experiments, human blood group, and classical human genetic disorders such as cystic fibrosis and Huntington s disease. When studying humans, biometrical geneticists began by examining correlations of quantitative traits in different classes of relatives, such as among siblings or between parents and offspring. Mendelian geneticists, by contrast, collected pedigrees and looked at specific patterns of transmission, such as dominant, recessive, or sex-linked. For the first 20 years of the 20th century, advocates of biometrical and Mendelian genetics fought vigorously over the validity of the two approaches. It was the brilliant statistician Ronald Fisher who showed, in his epic paper On the Correlation between Relatives on the Supposition of Mendelian Inheritance (Fisher, 1918), that these two approaches were compatible. The inheritance patterns of quantitative traits could be explained by assuming the existence of multiple genes, each of small effect, that combine in the manner expected given Mendelian inheritance. From the seminal work of Fisher and the earlier leader of the biometrical school, Karl Pearson, a large body of increasingly elegant biometrical genetics developed over the next 40 years. Although important work was done in the United States, the two world centers of statistical genetics during this time were both in the United Kingdom: Edinburgh and Birmingham. These centers examined the genetics of organisms such as fruit flies, plants, and livestock, which could be subject to experimentation. Driven in part by the practical needs of animal and plant breeders, these groups developed sophisticated statistical models for the different ways in which genes influence phenotypes (physical and behavioral outcomes) and are affected by different environmental conditions (Falconer, 1989; Lynch & Walsh, 1998; Mather & Jinks, 1982). PSYCHIATRIC TWIN STUDIES The first known description of the use of twins to study human differences was by Augustine of Hippo ( ; De civitate Dei, Bk. 5). He observed that the lives of a set of twins turn out differently, and he used this as a way to falsify the accepted belief that the alignment of the stars at the time of one s birth determined destiny. The more formal scientific use of twins to study the origins of individual differences in humans did not begin until the last quarter of the 19th century. The English polymath Francis Galton wrote a monograph, Hereditary Genius, which is probably the first systematic behavioral genetics study in humans. Galton published an essay in 1875 in Fraser s Magazine with the propitious title The History of Twins as a Criterion of the Relative Powers of Nature and Nurture (Galton, 1875). He was interested in using twins to evaluate the power of environmental experiences to make pairs similar or different. He did not then understand that twins could be divided into two groups: identical (monozygotic, or MZ) and fraternal (dizygotic, or DZ). This was not finally clarified until the 1920s.

3 The Scientific and Social Context of the VATSPSUD 13 The twin method as we now understand it consists of comparing the levels of similarity of MZ and DZ twin pairs. This method was described in 1924 by the American psychologist Curtis Merriman (1924) and the German dermatologist Hermann Siemens (1924). It did not take long for those working on the problems of psychiatric disorders to apply this new methodology. Four years later, Hans Luxenberger (1928) published the first systematic twin study of a psychiatric disorder. The following 50 years saw the completion and publication of more than a dozen major twin studies of psychiatric illness. In its infancy, psychiatric genetics under the leadership of Ernst Rüdin (whose critical contributions to the birth of this field were colored by his dealings, later in his life, with the Nazi party in Germany) was at the forefront of the methodological developments of the emerging field of human genetics (Zerbin-Rüdin & Kendler, 1996). From the mid-1930s until the 1970s, however, there was almost no contact between these two fields, and the methodological sophistication of psychiatric genetics suffered substantially. With rare exceptions, these traditional twin studies of psychopathology shared seven methodological limitations. First, they examined only severe forms of psychiatric illness, usually schizophrenia or bipolar disorder. Second, the twins were identified (ascertained) directly through hospitals or through registries that collected their information from hospitals. This meant that, in order to be included in these studies, twins had to be sufficiently ill to have been hospitalized. Third, the psychiatric diagnoses of both members of a twin pair were assigned by the same individual, typically on the basis of some kind of personal interview and/or a review of medical records. Fourth, psychiatric diagnoses were assigned by clinicians without the use of explicit diagnostic criteria such as those listed in the Diagnostic and Statistical Manual of Mental Disorders (DSM) of the American Psychiatric Association. Fifth, little effort was made to measure environmental risk factors, although some studies examined variables such as birth order, social class, age when the twins separated, or parental loss. Sixth, with a few notable exceptions (e.g., Kallmann, 1946; Kendler & Robinette, 1983), sample sizes were small and rarely included more than 100 twin pairs. Seventh, the statistical analyses of these studies were limited, usually consisting solely of determining whether the level of similarity (assessed as twin concordance, the proportion of pairs in which both twins are affected) was greater in MZ than in DZ pairs. As we describe in detail in Chapter 2, in the VATSPSUD we attempted to address all of these limitations. PSYCHIATRIC EPIDEMIOLOGY The discipline of psychiatric epidemiology examines the distribution of psychopathology within populations and the risk factors that influence that distribution. Dohrenwend (1995) has proposed a useful framework for understanding the historical evolution of psychiatric epidemiology from its origins

4 14 BACKGROUND at the beginning of the 20th century until today. The first generation of studies, conducted between 1900 and World War II, relied almost exclusively on reports from key informants and agency records for case detection. Rates of illness were low (averaging under 4% in these studies) and were particularly likely to underestimate conditions that did not lead to treatment or to contact with the criminal justice system. Second-generation studies, conducted between World War II and about 1980, relied largely on direct interviews with participants. Two different approaches to these assessments dominated during this period. In most European studies, a single psychiatrist or a small group of clinicians personally interviewed community residents. The interviews were free form and unstructured, mimicking the standard clinical assessment. On this basis, the clinicians would record their global psychiatric diagnoses. The second approach used a systematic approach to data collection that relied on brief questionnaires. The goal of using these instruments was not to obtain psychiatric diagnoses but to produce a scaled score that reflected broad concepts such as mental illness, emotional adjustment, or symptoms of stress. The third generation of psychiatric epidemiological studies began in the early 1980s with the development of structured and semistructured psychiatric interviews that were closely linked to systems of operationalized diagnostic criteria. These interviews share two major characteristics. First, each consists of a script of questions asked in a systematic order. Second, there are formal algorithms for combining items to determine whether or not a respondent meets criteria for a range of psychiatric diagnoses. The United States has seen two major third-generation studies of psychiatric epidemiology: the Epidemiologic Catchment Area Study, which interviewed more than 19,000 individuals at five study sites during the late 1970s (Robins & Regier, 1991) and the National Comorbidity Survey (Kessler et al., 1994), which studied more than 8,000 individuals from a national probability sample in the 1990s. In addition to improving the assessment of psychiatric illness, during the past 20 years clinical and epidemiological researchers in psychiatry have made important advances in the assessment of putative risk factors. Well-studied and validated instruments have been developed for use with general population samples to assess key variables such as stressful life events, social support, parent child relationships, and childhood sexual abuse. The use of structured interviews represented a substantial improvement over previous methods of assessment. However, this approach is not without its difficulties. Two are worth noting here (and others are described later in the book). First, the diagnostic criteria are largely based on the experience of clinicians working with patients in treatment settings; however, it remains to be established that the patterns of symptoms seen in individuals in treatment are the same as those for untreated individuals in the population. We know that severity of illness tends to be milder in community than in clinical cases, and there may be other important differences. A second limitation is that, although the reliability of structured assessments exceeds that of the unstruc-

5 The Scientific and Social Context of the VATSPSUD 15 tured interviews performed in earlier studies, their reliability is far from perfect. This is a particularly critical issue in genetic studies because unreliability of measurement imposes an upper limit on the estimated impact of genetic and environmental factors. A NEW PARADIGM FOR TWIN STUDIES Sometime in early 1984, a new paradigm for psychiatric twin studies began to emerge out of discussions among Kendler, Eaves, Martin, and Heath (see the Introduction). These discussions led eventually to the development of the VATSPSUD. The new paradigm drew on the traditions of biometrical genetics, psychiatric twin studies, and psychiatric epidemiology, merging the strengths and attempting to address the limitations of each. We decided that our study would have six key features. 1. It would be population based. Instead of selecting twins through treatment facilities (with all the expected biases such as selection for severity and comorbidity), we wanted to study a representative sample of twins from the general population. 2. Our conceptual and analytic approach would be based on the rigorous methods of biometrical genetics. Our goal was to test explicit hypotheses about the role of genetic and environmental risk factors in the etiology of psychiatric and substance use disorders and to obtain statistical estimates of their importance. 3. We wanted to collect a sample large enough to obtain these estimates. Most prior twin studies of psychiatric illness had too few participants to resolve the question of whether familial resemblance was due to genetic or shared environmental influences. Although large twin studies had been conducted of psychological traits and symptoms of depression and anxiety using mailed questionnaires (Eaves et al., 1989; Jardine, Martin, & Henderson, 1984), this would be the first large-scale interview-based twin study of psychiatric illness. 4. Because such large numbers of twins would have to be assessed, we needed to borrow the methods that had been developed in psychiatric epidemiology to assess accurately the history of psychiatric illness in large numbers of individuals. The old model for twin studies in which a single clinician spends a year or two driving around the countryside conducting interviews was no longer feasible. 5. We wanted to take the environment seriously. It has sometimes been said that for a real geneticist, environment is just something that gets in the way of gene expression. That was not our view. We did not want to prejudge the outcome of our results, and so we decided to spend at least as much of our assessment evaluating environmental risk factors as we did in the assessment of psychiatric and substance use disorders.

6 16 BACKGROUND 6. The study would be longitudinal. By interviewing participants more than once, it becomes much easier to move from correlational observations (in which A and B tend to occur together) to more causal conclusions (A truly increases the risk for B). As is seen later in this book, multiple waves of measurement allowed us to address interesting questions that would not have been possible if the twins had been interviewed only once. GENES At this point we need to say a bit about genes. Few concepts in biology have been so long debated (Carlson, 1966; Kendler, 2005a). The gene can be seen from a number of perspectives, particularly as the primary unit of evolution, a specific span of DNA, the source of information required for the production of a particular biological molecule, or a latent (or unobserved) entity that contributes to risk of illness. In this era of the sequencing of the human genome, the double helix has achieved the status of a cultural icon (Nelkin & Lindee, 1995). The results reported in this book are not based on directly measuring individual genes, as might be done with the now powerful methods of human molecular genetics. Instead, by using information we obtain from twins (the details of which are described in Chapter 3), we indirectly assess or infer the impact of all of an individual s genes on the risk for a particular trait or disorder. Why in the era of the human genome project would we pursue such an approach? Why did we not just measure everyone s genes and directly study the effects of each gene? Despite major advances in the science of human genetics, we are not even close to having the capacity to do anything like this. Indeed, only in the past few years have researchers begun to identify, in a way that can be replicated across laboratories, individual genes that influence the risk for psychiatric or substance use disorders. The human genome is extraordinarily complex, with some 20,000 25,000 different genes. Many of these genes are expressed in a variety of different forms in different tissues and at different times. The genome contains a wide range of new kinds of genetic elements (such as short-inhibitory RNA) that influence gene expression and function in ways we only dimly understand. Multiple control regions exist for many genes, often separated from the gene itself by very large distances. In addition to the problem of understanding the intricate biological aspects of genome function, understanding the conceptual and statistical issues surrounding the actions and interactions of these large numbers of genes and their effects on human behavior and disease is also an extraordinarily daunting task that currently lies far beyond our power. It may be possible years in the future to measure directly all the genes in the human genome and, more important, to know what is being measured and how to analyze it. But we are not there yet, nor are we even close. At the

7 The Scientific and Social Context of the VATSPSUD 17 end of this book, we return to the question of the relationship between twin studies and molecular genetics and show that these two scientific traditions are ultimately mutually complementary. What, then, does it mean to infer the action of genes from twins? Can that be a very scientific way of doing things? Doesn t science always require that we measure things directly? In fact, many scientific theories inferred the action of forces that could not be directly measured at the time the theory was developed. When Newton proposed his theory of gravitation, he inferred the action of this force from features of planetary motion. When the electron was first discovered by Thompson, it was not directly observed. Rather, its mass and electric charge were inferred from its behavior in a cathode ray tube. The initial theories about tectonic plates were proposed long before we had any idea of how the earth s crust could float over the earth s surface. So the method used in this book to assess an underlying process indirectly though patterns of results seen in nature has a long and distinguished history. THE SOCIAL AND POLITICAL CONTEXT OF THE VATSPSUD The question of the role of genetic factors in human behavior raises complex emotional, social, and political issues. Although we wish it were otherwise, medical genetic research has sometimes been applied to support particular political agendas and misused to justify the denial of human rights. This troubled history sometimes affects attitudes toward modern psychiatric genetics research and researchers. We address three related issues here. First, we saw our task in the design and implementation of the VATSPSUD to be that of basic scientists trying to understand how the world works. We did not begin this study with a strong agenda to demonstrate that psychiatric and substance use disorders are strongly influenced by genetic factors. Similarly, we did not begin with a strong bias for or against specific environmental theories about the origins of these disorders. Our goal was to conduct the best study we could, incorporating as many of the risk factors we could and letting the data speak for themselves. We are not naive in assuming that we have not shaped the results with our hypotheses. However, we have tried earnestly to be ecumenical in our approach. Second, we do not agree with many of the biases that exist about genes in the popular imagination. Genes are not destiny. It is a stunningly common misconception that genetic influence on a trait implies that the trait is inflexible and incapable of modification, whereas a role for environmental risk factors means great flexibility and ease of modification. This idea is just plain wrong. Many traits that genes influence can be easily modified. The effects of the single-gene disorder of phenylketonuria can be effectively reversed by a simple modification of diet. Millions of people in the United States are taking

8 18 BACKGROUND cholesterol-lowering drugs that are quite effective at reducing their genetically influenced levels of cholesterol. Depression, although genetically influenced, can be effectively treated by both pharmacological and psychotherapeutic means. In contrast, many environmental effects are relatively irreversible. Severe social deprivation, head trauma, serious malnutrition, and severe physical or sexual abuse can produce long-lasting and sometimes irreversible changes in an individual s emotional and cognitive functioning. There is no close relationship between the degree to which a trait is influenced by genetic and environmental factors and the malleability of that trait. Third, an even more sinister misconception held by some individuals is that researchers interested in genetic sources of individual differences in humans have dark, reactionary, and/or eugenic motives at heart. Genetic theories of human individual differences have been badly misused in the past. However, to tar an entire scientific field for the past misdeeds of racist or eugenic zealots is irrational. Were this logic to be applied widely in science, it would result in the cessation of many areas of research, to the detriment of mankind. We are both clinicians who have observed firsthand the suffering that psychiatric and substance use disorders inflict on our patients, friends, and family and those close to the sufferers. Our motive for conducting this effortful work over many years has been to use the best science we could to understand the etiology of psychiatric and substance use disorders so as to enable better prevention and treatment. There is no deeper political agenda at work here. OUR PHILOSOPHY OF SCIENCE A few words are also in order about the approach we have taken toward the science you will be reading about in this book. First, we believe there is an objective truth to be learned about the causes of human psychiatric and substance use disorders. We recognize that human beings are the most complex organisms we know about and that many factors make it difficult to obtain definitive results in human research. However, by conducting careful and thoughtful scientific research, we believe we can begin to untangle this complexity and contribute to the amelioration of these debilitating conditions. Second, the VATSPSUD is an example of observational and not experimental science. That is, in important ways our study bears more resemblance to other observational sciences such as geology and astronomy than it does to laboratory genetics. In laboratory studies, for example with rodents or fruit flies, the scientist can have complete control over both the genetic composition and the environment of individual organisms. By contrast, in observational sciences, all the scientist can do is observe and interpret the world as presented to him or her. In our study, neither genetic nor environmental risk factors were in any way under our control. All we could hope to do was to record carefully the relevant observations and attempt, through thoughtful interpre-

9 The Scientific and Social Context of the VATSPSUD 19 tation, to uncover etiological principles. Because we cannot do experiments, we can never be completely sure that we have ruled out the impact of hidden biases on our findings. We have tried to address the biases we are aware of, but our results are still vulnerable to those biases we do not know about. Third, because of the nonexperimental nature of our area of research, it is important to recognize that there is no such thing as a definitive study. No study in human behavioral and psychiatric genetics, including this one, is without significant flaws or limitations. Fourth, we are firm believers in an approach to scientific inquiry that has been called inference to the best explanation (Okasha, 2002). Scientists begin with the desire to test a particular hypothesis. They then attempt to collect as much information relevant to this question as possible, both in their own studies and in studies of others reported in the literature. Taking all these data, a scientist poses the following question: Can this entire set of data be best explained by my hypothesis, or are there hypotheses that would better explain these observations? Darwin s wonderful and epoch-making book The Origin of Species (1859) can be best understood as one long application of inference to the best explanation to arrive at the claim that natural selection provides the best available explanation for a wide variety of patterns observed in nature. This model, which suggests that science is a continuing, integrative, and cumulative process of refining explanatory models, is particularly appropriate for the subject matter of this book. It helps us emphasize that our goal is to provide the best possible explanation given current knowledge. We are not claiming to be in full possession of the truth. One final comment is in order. In the writing of this book, we faced a dilemma. On the one hand, it is important to set the results of our research in the context of other relevant investigations in the fields of psychiatry and substance abuse. On the other hand, this book deals with such a wide set of disorders and research questions that to do careful literature reviews in each relevant area would require us to write a textbook of psychiatric epidemiology and genetics with thousands of references and long, dry chapters. A compromise was needed. We have provided brief reviews of the relevant literature, often citing a few representative studies or a good review article. Readers who are interested in more details may consult the works cited or the original journal articles in which much of this work has appeared. The reason for the brevity of our references to other literature is not that we are unaware of the valuable contributions of our colleagues. Instead, it is that we value the clarity of the presentation that we provide to you, our reader. Copyright 2006 The Guilford Press. All rights reserved under International Copyright Convention. No part of this text may be reproduced, transmitted, downloaded, or stored in or introduced into any information storage or retrieval system, in any form or by any means, whether electronic or mechanical, now known or hereinafter invented, without the written permission of The Guilford Press. Guilford Publications 72 Spring Street New York, NY