Genomics and psychiatric nosology: avoiding hype, maintaining hope

In recent years there have been important advances in our understanding of the genetic architecture of mental disorders1. An immediate question is the relevance of such advances for psychiatric nosology. In order to address this question, we can posit a classical, a critical, and an integrative position. These positions are not intended to refer to the work of any particular author in the field, but rather are outlined for heuristic purposes. A classical position takes a view that emphasizes biological essentialism and genetic determinism. In this view, mental disorders have a natural “essence”, this “essence” is closely tied to biology, and genes are key in determining behavioral variation. Given that mental disorders are heritable, it is only a matter of time before we fully delineate the genetic architecture and biological basis of such conditions. As sample sizes increase, for example, polygenic risk scores will account for increasing amounts of the variance. Those adopting a classical position may point to the genetics of height: we now know which genetic variants contribute to this trait – although food intake also exerts an important role – and we will increasingly be able to outline the biological pathways that account for it. Similarly, for mental disorders, different pathways may be delineated, also accounting for the frequent overlap of these disor- ders. Indeed, a large-scale analysis of shared heritability in men- tal disorders found an overlap between major depression and anxiety disorders, and between schizophrenia and bipolar disorder, pointing to an overlap in underlying causal mechanisms2. A critical position takes a view that biological essentialism and genetic determinism entail inappropriate reductionism and oversimplification, downplaying the complexity of both neurodevelopment and behavioral traits. In this view, the heritability of a mental disorder simply indicates an association between phenotype and genotype, but tells us little about the underlying mechanisms, which might involve genetic, shared environmental, or non-shared environmental factors3. With increases in sample sizes, we have learned that for some phenotypes (e.g., height) polygenic risk score accounts for a relatively large proportion of variance, but for others (e.g., IQ) it accounts for a relatively small proportion. Those adopting a critical position may emphasize that the heritability of a range of social constructs, such as educational attainment or divorce, tells us little about how genes and environments interact to lead to these outcomes, and, in the absence of such understanding, constructs such as polygenic risk scores are without value. Similarly, genome-wide association studies and gene-by-environment genome-wide interaction studies may be unable to delineate the biopsychosocial mechanisms that lead to mental disorders4. Even in the case of rare pathogenic mutations, it is notable that a single damaging variant can be associated with multiple different mental disorders. An integrative position attempts to draw on the strengths of the classical and critical positions. While natural kinds in physics and chemistry may be defined in terms of necessary and sufficient characteristics, in biology the complexity of organisms often constrains such an approach. Behavioral traits might be considered “soft natural kinds”, falling on spectrums of phenotypes, and accounted for by overlapping and distinctive biopsychosocial mechanisms. At one end of the spectrum of orderliness, for example, pathological obsessivity may be due to an acute brain lesion or even a rare damaging variant. At the other end of this spectrum, however, a student may choose to take a very orderly approach to his/her notes to ensure that his/her learning is on track. A pluralistic approach to explaining and understanding behavioral traits is, therefore, needed5. From an integrative perspective, both Alzheimer's disease and personality disorders are heritable, and involve the brain and its biology to some extent. But the biopsychosocial mechanisms that account for Alzheimer's disease and personality disorder are qualitatively different. Thus, while mental disorders are heritable, are biological, and involve the brain, they fall on spectrums of phenotypes, and involve a broad range of biopsychosocial difference-makers5. Biological/brain differences may be more defining of particular disorders (e.g., Alzheimer's disease often involves amyloid plaques), or far less so (as in personality disorders, for which any particular biomarker has low sensitivity and specificity). The classical position may be associated with considerable hype. Multiple genomic studies report the involvement of particular genes in specific mental disorders, and argue that this will imminently lead to targeted treatment. The critical position may, on the other hand, lead to too much pessimism about genomic research. Replacing neuroreductionism (brain mechanisms completely explain mental disorders) with cultural reductionism (societal mechanisms completely explain mental disorders) seems unwise. An integrative position allows for a balanced perspective on the relationship between genetics and nosology, avoiding hype and providing hope. To avoid hype, we should be aware of the “mechanism gap”, i.e., the significant challenge of identifying causal mechanisms that explain how genes impact biological pathways and how these in turn lead to spectrums of complex phenotypes4. Further, the “gloomy prospect”, that non-shared environmental influences are largely unpredictable and idiosyncratic, seems correct6. Finally, even with future advances in our understanding of causal mechanisms, genetics cannot solve the “line-drawing problem” of how best to differentiate mental disorder from normality, and mental disorders from one another. To maintain hope, we should be cognizant that, on occasion, understanding the involvement of a rare variant can lead to a new treatment. For example, rare variants of the PCSK9 protein were noted to cause familial hypercholesterolemia, and this led to use of PCSK9 inhibitors for the treatment of this condition. Further, genetic research has already made important contributions to understanding the structure of psychopathology: the genetic architecture of Alzheimer's disease clearly differs from that of personality traits. Finally, as we understand the genetic architecture of a range of dimensional traits and intermediate phenotypes, iterative progress in our understanding of mental disorders may occur7. A balanced perspective on the relationship of genetics to nosology might emphasize that genetics has been important in challenging an essentialist view of mental disorder, by supporting the dimensional nature of psychopathology, and emphasizing the overlapping mechanisms involved in mental disorders. Just as work on family history has contributed to the validation of mental disorders, so will work on their genetic architecture. However, in neither case will this contribution be definitive, and other validators may contradict family/genomic findings8. These issues are not peculiar to psychiatry: it is difficult to move from common variants to causal pathways in many conditions, and the substantial genetic overlap of different autoimmune disorders, for example, does not mean that these are no longer classified separately. Exemplifying a balanced stance, in an early paper on the relationship of genomics to nosology, K.S. Kendler concluded that “whereas psychiatric genetics has and will continue to provide important insights into the etiology of psychiatric and substance use disorders, it is not likely alone to provide deep answers to the complex and multifaceted problems facing psychiatric nosology”9. Although genomics has since made considerable advances, and will no doubt continue to do so, this conclusion is likely to remain valid for the foreseeable future. Notably, however, there are non-genetic ways of validating our nosology, and these should certainly be pursued. Similarly, there are many non-genetic risk and protective factors for mental disorder that deserve our attention.