The following is an attempt to elucidate current neurogenetic paradigms in order to have a deeper understanding of the complexities involved in the pathways from susceptibility genes to the complicated phenotypes of psychiatric disorders. In addition, it is my hope that the scientific weaknesses of neurogenetic reductionism will be more readily apparent. Bolton and Hill (1996) noted that intentionality (beliefs, goal-directed plans, fears, etc.) pervades biological systems to the molecular level. This is borne out in neuroscience research in which psychogenic stress was genotoxic in various body cells. Fishman and colleagues (1996) reporting in the International Journal of Neuroscience noted that in rats behavioral/ psychogenic stress can result in DNA damage and chromosome aberrations. They noted:”behavioral stress can induce genotoxic damage on at least two levels, chromosomal and molecular, and in at least two cell types, bone marrow and leukocytes” (p. 224).
Simply phrased, there is no single genetic switch that when turned on causes a specific psychiatric disorder. It is accepted by many neurogenetic researchers that that there is not sufficient information in the entire human genome to explain the information content of neuronal connections in the adult human brain,and that psychiatric disorders are complex adaptive systems that are multidimensional and mutifactorial in their origins and non-linearly interactive in their development.
The source of the information in this review of genetics is primarily contained in Kenneth Kendler’s (2005) “Psychiatric genetics: A methodological critique” which is to be found in Andreasen, N. C. (Ed.) (2005). “Research Advances in Genetics and Genomics: Implications for Psychiatry. Washington , DC : American Psychiatric Publishing, Inc”.
Four Genetic Paradigms
Paradigm I-Basic Genetic Epidemiology
The goal of basic genetic epidemiology is to quantify the degree which individual differences in risk (“liability”) to illness result from familial effects or genetic factors (as determined by twin or adoption studies). In twin studies, the task of basic genetic epidemiology is to estimate the proportion of liability in a given population due to genetic differences between individuals. This proportion is called heritability.
Paradigm II-Advanced Genetic Epidemiology
Once there is an indication of significant heritability, the goal of advanced genetic epidemiology is to explore and understand the nature and mode of action of these genetic factors. In both basic and advanced genetic epidemiological research paradigms, genetic risk factors are inferred, through the use of statistical methods, from the patterns of resemblance among particular classes of relatives such as monozygotic versus dyzygotic twins, and not directly measured.
Paradigm III-Gene Finding
The goal of gene finding methods is to determine the locations on the genome (“loci”) of genes variation, which influence liability to psychiatric disorders. Molecular methods are used for detecting the genetic variants (“markers”), but gene finding methods are statistical in nature. By observing the distribution of genetic markers within families or populations, these methods (linkage and/or association) infer the probability that a locus in the genomic region under investigation contributes to disease liability. Furthermore, the goal is to clarify the history of the pathogenetic variant or variants in the susceptibility gene by determining the background pieces of DNA (“haplotypes”) on which these variants are found.
Paradigm IV-Molecular Genetics
The goal of the molecular genetic paradigm in psychiatric genetics is to trace the biological processes by which the DNA variant identified with gene finding methods contributes to the disorder itself. The primary and most critical goal is to identify the change in gene function and/or expression resulting from the identified DNA variant. The more complex goal involves the use of a wide range of methods (molecular, pharmacological, neuroimaging, neuropsychological) to trace, at a biological level, the etiological pathways from the DNA variant to the abnormal neural/psychic functioning that characterizes the disorder.
Basic genetic epidemiology has the following critical limitations: -The goal of science is conceived to be the elucidation of causal processes. The basic genetic epidemiological paradigm is fundamentally descriptive in nature. The latter method quantifies the importance of genetic risk factors, it does not provide insight into causal or explanatory pathways.
-Heritability estimates apply to populations and not to individuals. The heritability of a disorder in an individual is undefined.
-In a defined population with a particular set of genes, the heritability of a disorder is not immutable and would be altered by the introduction of new sources of environmental risk. Therefore, the magnitude of heritability of a disorder is not solely a result of gene action, rather, it is a ratio of the variance in risk in a population due to genetic differences between individuals and the total variance of risk in that population. Heritability does not designate a characteristic of a disorder but only of a disorder in a given population at a specific time.
-The liability-threshold model that underlies most genetic epidemiological studies is biologically nonspecific and divorced from actual genetic processes.
The methodology of advanced genetic epidemiology offers only partial reductive explanations involving several adjacent levels of a complex causal chain. These causal explanations cannot reach the level of genetic/biological processes, e.g., DNA base-pair variation.
Although gene finding methods are based solidly on meiosis, e.g., gene recombination and segregation, and are more specific and informative than those of basic genetic epidemiology, they also have their limitations. As with heritability calculations, the statistical methods for gene localization do not directly reflect gene action, rather, they assess the ratio of genetic to total variance in liability. This means, for example, the evidence for linkage in a family would vary as a function of the strength and frequency of the environmental risk factors to which its members have been exposed. Susceptibility genes are difficult to localize, many tests have to be performed for detection to be realized.Positive results from gene finding methods are statistically less reliable than results from basic genetic epidemiological studies.
Molecular genetics raise the possibility of a reductive biological explanation that would describe the causal chain from molecular variation in DNA to the manifestations of psychiatric disorders. Molecular genetics, unlike the other genetic paradigms, are not fundamentally statistical in nature. However, there are significant practical problems which obstruct the elucidation of the very complex biological pathways from DNA variation to psychiatric disorders. Individual genetic variants which cause classic genetic diseases are usually easy to detect because they reflect alterations in coding for key amino acids or the destruction of well-defined regulatory sequences. The DNA variants which may predispose to complex psychiatric disorders may be very subtle in their effects and more difficult to detect. Molecular genetic studies of psychiatric illnesses need to be concerned about the details as to how disease risk emerges from interactions between genetically controlled biological processes and environmentally induced changes in brain function and structure, e.g., the neural effects of early abuse, neglect, isolation, etc.
Selective Review of Current Status of the Four Genetic Paradigms
Basic Genetic Epidemiology
Heritability estimates differ significantly between disorders, but a growing body of research implicates genetic factors as being important in all of the major psychiatric disorders. However, there is no way within this level of research to differentiate nongenomic from genomic pathways of heritability (e.g., epigenetics).
Advanced Genetic Epidemiology
A number of twin and adoption studies (e.g., Tienari et al in Finland ) have provided evidence for the importance of gene-environment interactions (demonstrating genetic control of sensitivity to the environment or environmental control of gene expression). Genetic risk factors may moderate the pathogenic effects of environmental risk factors. Genetic risk factors probably do not map very well onto DSM or ICD categories of mental/psychiatric disorders. environmental risk factors such as isolation and lack of social support, can be influenced by genetic factors. Genetic risk factors may influence susceptibility to psychiatric disorders in part
by altering the probability of exposure to certain environmental
stressors. Gender effects may also be important.
Gene Finding
Recent research reviews have documented what many suspected-a substantial proportion of positive results in gene association studies for complex psychiatric disorders, e.g., schizophrenia and bipolar disorder, do not survive the test of replication. Kendler (2005) notes what I think is a very important point: that whole genome linkage scans fail to corroborate the more robust findings of basic genetic epidemiological studies such as those comparing monozygotic and dyzogotic twin pairs. rather than assume it is a problem of needing further refinement and technological development in the former (although it may very well be this is the key factor), I believe that there are sources of error variance and bias permeating the twin research which researchers have failed to address, e.g., the neuropathological effects of prenatal stress, the role of a common blood supply for a majority of MZ twins (chorionic factor), the actual psychosocial experience of being an identical twin, etc. Kendler noted:
“Whole genome scans have been reported for many psychiatric and substance use disorders, including schizophrenia, bipolar disorder, alcoholism, autism, attention deficit hyperactivity disorder, bulimia, panic disorder, nicotine dependence, and major depression. a sufficient number of linkage studies of schizophrenia and bipolar illness have been conducted to show the rate of replication of positive regions across studies has been low. This pattern contrasts strikingly with the high level of consistency seen in the results of basic genetic epidemiological studies-for example, the results of twin and family studies of schizophrenia” (p.14).
Positional candidate gene strategies have recently appeared in which association methods are applied to genomic regions identified through linkage results. Variants in several genes, and their replication, have been observed to affect risk for schizophrenia using these methods.
Molecular Genetics
In the last year, we have seen the first viable effort to trace the biological pathways from potential susceptibility genes to psychiatric phenotypes Mice were developed in which neuregulin 1, a recently identified potential susceptibility gene for schizophrenia, was rendered nonfunctional (“knocked out”). These poor mice demonstrated reduced expression of N-methyl-D-aspartic acid receptors and abnormalities in prepulse inhibition (PPI)-a neuropsychological feature found in persons with schizophrenia (as I pointed out in previous papers PPI is associated with rats being raised in isolation).
Interrelationships Between the Four Paradigms
The crux of the problem is the relationship between genetic risk factors as defined by genetic epidemiological studies and susceptibility genes as defined by gene identification methods. The crucial question is as follows: do genetic risk factors reduce to susceptibility genes? This question can be addresses on two different levels with divergent answers. On a theoretical level, the results of twin and adoption studies should reflect the distal effects of genetic variation coded in DNA. From this perspective, genetic risk factors are nothing more than signals of susceptibility genes. however, at the practical level, the answer to the question is ambiguous in two important ways. First, it is reasonable to assume whether it will ever be possible, regardless of technological advances, to trace a clear and unambiguous complete set of causal links from DNA base-pair variation to complex psychiatric disorders such as schizophrenia or bipolar disorder. Kendler (2005) cogently, and to his credit, noted:
“...the problems of psychiatric illness, involving some of the most complex conceivable questions, including questions of consciousness, self-concept, and reality testing, may involve emergent properties that are not predictable from basic biological phenomena such as DNA variation” (p. 16).
Competing Paradigms
The hope of many geneticists is that instead of having to infer genetic risk factors from patterns of resemblance across relatives, as is done in genetic epidemiological research, it may become possible to measure directly all relevant variants within susceptibility genes and to combine this information with relevant environmental exposures to determine individual liability. However, if ever achievable, this is a long way off and therefore, the field of psychiatric genetics needs to work towards an integration of findings from many domains of scientific inquiry, including developmental psychobiology and psychopathology, and from my perspective, the findings which emerge from the long-term immersion involved in the psychotherapeutic/psychoanalytic situation.
Psychiatric Genetics and Reductive Models for Psychopathology
Kendler (2005) highlighted the broader discussion about the relative value of ‘hard’ reductive models in psychiatry and what he termed “explanatory pluralism.” He notes:
“With the remarkable advances in neuroscience and molecular biology, an increasingly common view within psychiatry, and especially biological psychiatry, is that the only valid etiologic models for psychiatric disorders are in basic biological or molecular terms. By contrast, advocates of explanatory pluralism would argue that our ignorance about the underlying causes of psychiatric illness is so profound that we are not in a position to be so selective about the origins of our knowledge. We should not reject, they would argue, partial etiologic explanations, even when they are expressed in nonbiological terms [I would understand attachments and interpersonal relationships as part of human biology]. They would see this kind of patchy reduction to be a much more realistic goal than a complete top-to-bottom hard reductive model” (pp. 19-20).
Brian Koehler PhD
New York University
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brian_koehler@psychoanalysis.net
