This blog was inspired by discussions I have been having with Allen Frances and also partly in response to some blogs he was written about the role of genetics in psychiatry. He is, I think it's fair to say, highly skeptical that genetics will be of much use in psychiatry, as he discusses here. His jaded view stems partly from the relentless hype which accompanies a lot of announcements of large-scale genetics projects or of their results, and also from a perceived lack of progress of these efforts in explaining genetic risk for psychiatric disorders. With the rapid pace of developments in psychiatric genetics, it is worth taking a beat to consider what we know and to try and separate the hope from the hype.
Psychiatric disorders are highly heritable. Twin and adoption studies have demonstrated conclusively that differences in risk for these conditions are at least partly, and in many cases largely, due to genetic differences. Indeed, psychiatric disorders are far more heritable than conditions like heart disease or cancer. That is not to say that genetics explains all the risk, but certainly enough of it to make it worthwhile understanding the underlying biological mechanisms.
Genetic risk for mental illness overlaps clinical boundaries. Having a relative with a diagnosis of say, schizophrenia, increases an individual’s statistical risk not just of that disorder, but also of bipolar disorder, autism, depression, ADHD, epilepsy, intellectual disability and many others. Moreover, specific mutations often manifest in diverse clinical diagnoses across individuals. From an etiological perspective, the diagnostic categories in the DSM thus do not represent natural kinds.
Most of the genetic risk does not lie in common variants. This should not come as a surprise. Any genetic variant that increases risk of psychiatric disorders should be strongly selected against because such disorders greatly increase mortality and reduce fecundity (number of offspring). While genome-wide association studies have identified some, indeed many, common variants associated with risk for conditions like schizophrenia, or shared risk across disorders, these collectively explain very little (~7%) of the overall genetic risk. (Even techniques such as genome-wide complex trait analysis suggest only about 25% of genetic risk for schizophrenia is tagged by common variants. That is, if you take estimates from such techniques at face value, which I do not, for reasons I discuss here). Common variants likely contribute to modifying effects of genetic background but clearly do not explain disease risk by themselves. The oft-repeated line that disorders like schizophrenia are “due to the cumulative effects of many variants of small effect” is thus not supported – at least this is not a complete description of the genetic architecture.
Many cases are caused by rare mutations. It has been known for decades that some specific genetic syndromes, such as Fragile X syndrome or velocardiofacial syndrome (now called 22q11.2 deletion syndrome), convey very high risk of psychiatric disorders, such as autism or schizophrenia. It was thought by many that these conditions were somehow exceptional and not relevant to the remaining cases of idiopathic and non-syndromic cases, which were believed, on rather flimsy grounds, to have a very different genetic architecture. It turns out that, far from being exceptional, those long-known genetic disorders are perfect exemplars of the genetic architecture of psychiatric conditions. The development of chromosomal microarray technologies and whole-exome or whole-genome sequencing has led to the discovery of dozens, indeed now hundreds, of similar rare genetic disorders that predispose to very high risk of mental illness. More and more such disorders are being recognised as additional cases are sequenced. Clinical categories like autism or schizophrenia are, from an etiological point of view, umbrella terms encompassing hundreds of rare genetic disorders.
Sequencing can reveal rare mutations. Identifying such rare conditions will become easier as more and more cases and controls are sequenced, giving us greater power to discriminate pathogenic mutations from the background of rare mutations that we all carry. These efforts have only just begun but we are already seeing them yield results. Already 20-25% of cases of autism and ~10% of cases of schizophrenia can be ascribed to a primary genetic mutation – a huge increase in diagnostic yield from just a couple years ago.
Genetic causation is complex. Describing these as rare genetic disorders is not meant to imply simple genetic causation. All the known mutations can give rise to a wide variety of effects in different individuals and are often carried by clinically unaffected people. The pathogenic effects of particular mutations can be modified by other genetic variants that any individual may carry, whether common or rare. There is nothing unusual in this scenario, however – even the most classic Mendelian disorders, such as cystic fibrosis or Huntington’s disease, are subject to modifying effects from other genes. Specifically, we can expect that more severe cases, with earlier onset, will be more likely due to single genetic mutations, often arising de novo, while less severe cases, with later onset, will include a bigger contribution from inherited mutations and more interplay between multiple mutations in any given individual.
Non-genetic factors are also important. The variation in phenotype often observed between monozygotic twins also shows that non-genetic factors – such as stochastic processes of brain development or later experience – can have large effects on the phenotypic outcome associated with any given genotype. These observations place important limits on the ability to genetically predict disease risk in anything other than a probabilistic fashion.
Genetic diagnoses are still useful. Even with the complexities mentioned above, it will still often be possible to identify a primary causal mutation in individual patients. (See here for a more detailed discussion of inferences of genetic causality). Such diagnoses are immediately useful in many ways – they give a definitive etiological diagnosis that complements the often more fluid diagnoses based on symptoms; they allow clinicians to group patients and define new syndromes; they empower patients and their families to help drive such efforts; they inform on genetic risk to subsequent offspring; in some cases they may already give information on likely responsiveness to treatments. Just as importantly, they give biological entry points to dissect the underlying pathogenic mechanisms and hopefully develop new treatments.
Genetics is just the first step. There is a regrettable culture of hype around much of science these days, driven by the need to promise near-term translational impact to secure funding. This has certainly been the case in the field of psychiatric genetics. It is crucial to recognise, and, in my opinion, to state publicly, that identifying pathogenic mutations is just the first step in what will be a very long journey to develop new therapeutics.
The drug discovery model that has worked so well for disorders like cancer will simply not work for most of the rare disorders causing psychiatric illness. In cancer, the pathogenic effects of mutations arise at the cellular level – they directly affect the processes of proliferation and differentiation that drive the disease. Identifying a primary genetic mutation can thus directly implicate a particular biochemical pathway as a suitable drug target. Even when that is the case it is still a hugely difficult task to actually develop a new drug that works.
For psychiatric disorders, the difficulty of that task will be multiplied many-fold, because the answer will not come at the level of molecular biology or biochemistry. We must figure out how changes at those levels lead to alterations at the level of neural circuits and systems, which emerge only via cascading and indirect effects through the complex and dynamic processes of neural and cognitive development.
Predictions of new treatments in the short term should thus be tempered with a good dose of humility. Genetics will not suggest new pharmaceutical approaches by itself. What it will do is enable more insightful neuroscience by providing crucial entry points to elucidate the underlying pathobiology. This is especially true for high-risk mutations which can be modelled directly in cells or animals to elucidate the pathways by which mutation of specific genes lead ultimately to neural circuit and system dysfunction.
Genetics is thus the crucial first step on what will be a long journey to better understand the causes of mental illness. Indeed, not only do I think a genetic approach will be productive, I think it is the only thing that will be. Certainly nothing else has worked – psychiatry has made essentially no progress otherwise over the last sixty years or more. Maybe that’s a bit harsh, but we have certainly had no biological insights that have yielded new drugs with new mechanisms of action over that time-frame.
A key reason why is that we have had no way to dissect the cryptic heterogeneity of these disorders. Genetics not only illustrates that heterogeneity but provides the means to distinguish patients based on underlying etiology. This will entail a real paradigm shift in psychiatry – from treating all patients with similar symptoms as monolithic groups, to recognising that such symptoms can have very diverse causes and grouping patients instead on the basis of genetic etiology.
Thus, while I agree with Allen Frances that the attendant hype around genetics in psychiatry is misplaced and unhelpful, I am much more optimistic than he is that this approach will pay off. These are genetic disorders. Their inheritance may be complex but is not infinitely so or intractably so. We can and will make progress – but it will take a lot of subsequent research to turn that progress into new treatments.