What have we learned from psychiatric genetics? The view from 2022.
The hope is that elucidating the genetics of these conditions will reveal the underlying biology and provide a pathway to develop better diagnostics, new therapeutics, and ultimately a personalised approach to treatment. Given how much progress has been made in identifying genetic risk variants, it’s worth taking a moment to see what we’ve learned. In particular, I want to look at how our general conception of the genetics and biology of these conditions has changed over the past two decades.
First, the view from 2000
In the early 2000’s, the prevailing view was that the genetics of conditions like autism or schizophrenia was complex (though it wasn’t at all obvious in what way). It was known that there were rare genetic conditions that could result in the symptoms of psychiatric disorders – like Fragile X syndrome or Rett syndrome in the case of autism, or velocardiofacial syndrome in the case of schizophrenia. However, these were deemed to be exceptional cases – the main pool of “idiopathic” cases (the ones with no known genetic or organic cause at the time) were considered by many to reflect the “real” conditions of autism or schizophrenia. This reflects a history of using these diagnostic terms only for cases where an organic cause could not be found (like syphilis, in the case of psychosis, for example). It doesn’t, to my mind, make a lot of sense to apply that logic to genetic causes, and as we will see below, the dichotomy between rare, Mendelian conditions that result in these symptoms, and the supposedly common, idiopathic conditions is a mirage that has evaporated as our knowledge of high-risk genetic factors has increased.
When geneticists wanted to find the mutations causing a particular disease, their main methods prior to the 2000’s were cytogenetics and linkage analysis. Cytogenetics involves looking down the microscope at the actual physical chromosomes of people with an illness. In rare cases, an illness may be caused by a missing or an extra chromosome (as in Down syndrome) or by a deletion or duplication of a chunk of a chromosome (though it has to be pretty big to be visible down the microscope) or by a translocation (where bits of two chromosomes get swapped with each other, often disrupting some genes). There was one notable success story from this approach – the identification of a translocation in a large Scottish kindred that broke the DNA on chromosome 1 in the middle of a gene that was named DISC1 for “Disrupted in Schizophrenia-1” (though as it happens some carriers of the translocation were diagnosed with bipolar disorder or major depression). However, mutations in this gene are extremely rare, making it at best another rare genetic cause that could be considered as separate to the much larger pool with complex inheritance.
Linkage analysis had also been exhaustively pursued for conditions like schizophrenia, bipolar disorder, and depression in particular. The typical approach was to try and find families with multiple individuals with these conditions and use genetic markers to track inheritance of the different chromosomes to try and find regions that co-segregated with the disease and thus locate a place on a chromosome where a disease-causing mutation might be found. Those approaches were unsuccessful (in contrast to many other types of genetic conditions, like cystic fibrosis or haemophilia or inherited forms of blindness or deafness). It was very difficult to find large pedigrees where mental illness cleanly segregated over multiple generations. Pooling pedigrees to give more power for the statistical analyses didn’t help, suggesting that different families did not share mutations in the same gene. By this stage, it was thus already clear that these disorders would not have the simple kind of genetics observed in other, Mendelian conditions, which had clearly causal mutations in one or a smallish number of genes.
Enter genome-wide association studies, or GWAS. The theoretical idea underlying this approach is that common diseases may be at least partly caused by common genetic variants. This was quite a departure from the typical way of thinking about genetic disease. The idea is that perhaps multiple risk variants exist in a population but only cause actual disease when enough of them are inherited at once. This would explain why mental illnesses run in families, as some families might carry more of these common variants than others, and it would also explain why linkage analyses had failed – there was no single causal variant to be found in any given family. Early models posited on the order of 10-12 such risk variants in the population for a condition like schizophrenia. The independent segregation of these variants would generate a normal distribution of burden across the population, with only those inheriting more than some threshold actually developing disease. This model allowed the supposed underlying “liability” to be treated mathematically like a quantitative trait, like height (even if all we could see was the manifestation of illness or not).
GWAS took a while to get up to speed, as sample sizes in the thousands did not produce many positive findings. This suggested that there were no common variants that had even a moderate effect on disease risk or they would have been found. (This actually fits with evolutionary expectations – many psychiatric diseases are associated with reduced numbers of offspring, meaning any variants increasing risk significantly should be strongly selected against and thus would not be expected to become common in the population). It thus became clear that models with 10-12 risk variants were not realistic – there must be hundreds or thousands of such variants involved. As GWAS studies got bigger (and then much bigger) risk variants started to be discovered.
These are sites in the genome where the DNA letter is variable in the population – sometimes an “A”, sometimes a “T”, for example. If the frequency of one of these is slightly higher in people with a condition than without, then we say it is “associated” with increased risk of the condition. Usually, the increase in risk for any given common variant is tiny – on the order of 1.05 times the baseline. As more and more of these risk variants were found, the total amount of risk explained started to grow, though it remained low in absolute terms (on the order of 3-7% of the genetic variance in risk). Nevertheless, there was an expectation that eventually the remaining common variation making up this “polygenic” risk would be found, explaining the genetic risk for the majority of cases in the idiopathic pool.
In parallel, more rare variants with much higher risk began to be found. This began with the identification of so-called copy number variants (CNVs), which are deletions or duplications of small chunks of chromosomes. These were too small to be detected by traditional cytogenetics but they could be revealed by new molecular techniques. Some sites in the genome are particularly prone to the generation of these deletions and duplications, meaning they recur with an appreciable frequency in the population.
A couple striking observations were made from these studies. First, many such variants arise “de novo” – i.e., in the generation of sperm or eggs. De novo CNVs tended to be associated with much higher risk and severity of disease than inherited ones. (Consequently, they also tend to be almost immediately selected against as people who develop severe disease tend not to reproduce). And second, the same CNVs showed up in patients with diverse conditions, including schizophrenia, bipolar disorder, autism, intellectual disability, and even epilepsy. These rare mutations thus clearly increased risk for psychiatric and neurological conditions in a non-specific fashion, with some other factors required to explain what conditions actually emerged in any individual carriers. Indeed, the same CNVs are often found (at lower frequency) in clinically unaffected individuals in the general population.
CNVs are a class of rare mutations that happen to be particularly amenable to study because they recur at specific sites in the genome. But we all also carry many rare mutations that are just changes to individual letters of the genome that occur at random during copying of the DNA. These can also result in disease but are much harder to find. However, improvements in sequencing technologies soon enabled sequencing of the “exomes” (the bits of the genome coding for proteins) or the whole genomes of many individuals at an industrial scale. These studies are currently identifying more and more rare mutations (both de novo and inherited) that confer moderate to high risk of psychiatric illness. The idiopathic pool is thus shrinking all the time as more and more individuals are found to carry some high-risk mutation.
However, that does not make inheritance in such cases simple. The risk conferred by these mutations is moderate to high (anywhere from a 3- to 30-fold increase over baseline) but not enough to explain all the genomic risk. For example, we know that if one monozygotic (identical) twin has a condition like schizophrenia that the statistical risk to the other twin is about 50%. Carrying the same genome as someone with schizophrenia thus increases risk over baseline frequency (~1%) by over 50-fold – far more than that associated with any of the individual rare, high-risk mutations. This suggests that other factors in the genome must be increasing risk in the individuals who actually end up with disease.
More recent studies are helping to identify these risk factors and elucidate the nature of their interactions. Some patients carry single de novo mutations that confer very high risk and are probably sufficient to explain the occurrence of disease by themselves. Other patients carrying mutations conveying lower statistical risk have been found to be more likely to also carry a “second hit” somewhere else in the genome and/or to have a higher polygenic burden of common risk variants. This is consistent with a unifying model whereby the polygenic risk acts as a genetic background modifier of the effects of rare, high-risk mutations. There is thus no need or reason to suggest that there are separate pools of patients accounting for these conditions – some entirely caused by rare mutations and some entirely caused by polygenic burden. Both factors are likely at play in most, if not all patients.
Sex is also an important variable. Males show significantly higher rates of neurodevelopmental disorders (such as intellectual disability, autism and schizophrenia) than females, while the reverse is true for conditions like major depression. Females with the former conditions tend to have more severe mutations or a greater genomic burden than male patients. And, when inherited, such mutations are more likely inherited from the mother than the father. This is consistent with the idea that females are better able to buffer the effects of high-risk mutations than males. This greater genomic robustness may be due to the presence of two X chromosomes versus only one in males. Males are thus exposed to all genetic variation on the X, which can generally decrease the robustness of developmental processes and the ability to buffer mutations anywhere in the genome. This is likely the reason why males across many mammalian species are more variable for all kinds of traits. It is unlikely to be the whole explanation however, as it does not explain why the male vulnerability is much higher for conditions like autism and attention-deficit hyperactivity disorder, only slightly higher for schizophrenia, and lower for depression. There are thus likely more specific neural factors at play as well, reflecting differences in the organisation of male and female brains.
With that summary of the trajectories of research in the field, we can look at some take-home messages and implications for understanding the biology of these conditions and how this may inform treatment or the search for new therapies:
1. Diagnostic categories have overlapping etiology. Both common and rare variants tend to increase risk for psychiatric illness across many diagnostic categories. This doesn’t mean the categories are not distinct types of endpoints, but does show they can have common origins.
2. The dichotomy between rare and common disorders is an illusion – the idiopathic pool is likely composed of patients with one or several rare, high-risk mutations.
3. A substantial fraction of cases, especially of more severe, earlier-onset conditions, is caused by de novo mutation (explaining sporadic cases).
4. Mutations in any of hundreds of genes can confer significantly increased risk.
5. A balance between mutation and selection explains the prevalence and persistence of these conditions.
6. The distinction between simple and complex inheritance is really a continuum – even high-risk mutations are modified by genetic background (as is the case for traditional Mendelian conditions).
7. Genetic architecture is thus both heterogeneous and polygenic, involving both rare mutations in many different genes and a more diffuse polygenic background.
8. Polygenic risk is shared across disorders and may also manifest in various cognitive or personality traits, such as intelligence or neuroticism.
9. Sex is an additional contributor to risk, probably through general effects on neurodevelopmental robustness (lower in males) and some more specific effects through unknown neural mechanisms.
10. Overall burden is key, with an architecture of more high-risk single mutations at the clinically severe end and more combinatorial interactions at the less severe end.
11. Making definitive genetic diagnoses and prognoses will be challenging, as the clinical presentations associated with any given mutation can be highly variable.
12. The genes implicated by both rare and common variants are enriched for brain (especially fetal brain) expression, for expression in neurons (of many types), and for neurodevelopmental processes (very generally). This is an important reality check. If genes expressed in spleen or pancreas or skin were turning up, we would rightly be worried that the associations might be artifactual.
13. There is, however, no real convergence on specific biochemical pathways or cellular processes or cell types or brain regions.
14. The relationship between genotypes and phenotypes thus remains stubbornly obscure. There may, in fact, be no proximal relationship at all between the molecular and cellular functions of mutated genes and the symptoms of the disorders that may emerge.
15. Divergence of outcomes even in monozygotic twins, who obviously share all their genomic risk factors, illustrates the fact that what is inherited is not a disorder, but a more general risk for psychopathology.
16. Whether that risk manifests as actual disease, and which symptoms emerge, is probabilistic, reflecting additional non-genetic factors. Given the lack of evidence for systematic environmental risk factors, this diversity of outcomes may reflect intrinsic stochastic variation in the trajectories of brain development. Chance thus plays a substantial role in determining which outcome from a wide possible range is actually realised by the processes of development in an individual.
17. The types of symptom clusters we observe (as opposed to all the unobserved ways the brain could in theory exhibit pathology) likely reflect reactive or emergent processes in brain development and regimes of function.
In summary, mutations in any of hundreds of different genes, involved in all kinds of molecular and cellular processes, and modified strongly by genetic background, can indirectly and non-specifically lead to altered trajectories of brain development that sometimes result in atypical outcomes that can manifest in diverse modes of psychopathology.
This is, to say the least, frustrating. Unlike other conditions, like cancer or autoimmune disorders, identifying psychiatric risk genes did not directly reveal the underlying biology. This is, in my opinion, because psychiatric conditions do not reflect proximal molecular biological disturbances in the way these other cellular-level conditions do. The symptoms of psychiatric conditions affect the highest functions of perception, cognition, and behavioural control – those are underpinned by distributed neural circuits and systems, not the actions of specific molecules.
We won’t, therefore, be jumping straight from GWAS or whole-genome sequencing to “druggable targets” for therapeutic development. If we want to understand social isolation or hallucinations or mania, we will need to look to neuroscience, not to molecular genetics for proximal explanations. This is, however, where genetics can provide vital entry points for experimental follow-up, especially rare mutations of large effect that can be modelled in animals or other experimental systems.
But the answers will not lie in studying any such mutations in isolation – each of these will have some idiosyncratic, even arbitrary array of biochemical, cellular, developmental, and physiological effects, some proximal, others indirect, cascading and emergent. In my opinion, making real progress will require a much longer-term meta-project to understand trajectories of phenotypic convergence and divergence across many such mutations. These emerge from properties of the developing brain, which can only be understood as an evolving dynamical system.
The project of psychiatric genetics has thus been astoundingly successful, thanks to the dedication of thousands of researchers across the world and the willing involvement of hundreds of thousands of patients and their families. But it is clearly only the first step in what will be a much longer journey to understanding the nature of mental illness.