Schizophrenia and Genetics: End of the Road?

Genetics so far has offered few answers but has provided many clues

Schadenfreude over the supposed failure of the psychiatric genetics research program has flourished into a genre of its own. The latest installment in this genre comes from the psychiatrist E. Fuller Torrey with his article, “Did the human genome project affect research on Schizophrenia?” in Psychiatry Research. Here’s the abstract:

“The Human Genome Project was undertaken primarily to discover genetic causes and better treatments for human diseases. Schizophrenia was targeted since three of the project`s principal architects had a personal interest and also because, based on family, adoption, and twin studies, schizophrenia was widely believed to be a genetic disorder. Extensive studies using linkage analysis, candidate genes, genome wide association studies [GWAS], copy number variants, exome sequencing and other approaches have failed to identify causal genes. Instead, they identified almost 300 single nucleotide polymorphisms [SNPs] associated with altered risks of developing schizophrenia as well as some rare variants associated with increased risk in a small number of individuals. Risk genes play a role in the clinical expression of most diseases but do not cause the disease in the absence of other factors. Increasingly, observers question whether schizophrenia is strictly a genetic disorder. Beginning in 1996 NIMH began shifting its research resources from clinical studies to basic research based on the promise of the Human Genome Project. Consequently, three decades later NIMH's genetics investment has yielded almost nothing clinically useful for individuals currently affected. It is time to review NIMH’s schizophrenia research portfolio.”

The article detours into many other issues that are not touched on in the abstract. There is a fair bit about the history and politics of the Human Genome Project (HGP). I was not aware of the rivalry between Francis Collins and Craig Venter, so I found that interesting. The politics of how HGP actually got funded and implemented was also notable in the article. Unlike many popular critics of schizophrenia genetics who consider the failure to find causal genes to be evidence that schizophrenia doesn’t have a “biological” etiology and is primarily caused by psychosocial factors, Torrey argues instead for an infectious etiology. He believes that instead of genes, we should be investigating how infections (such as Toxoplasma gondii) can cause schizophrenia. It is generally accepted that infections, especially during pregnancy or early neurodevelopment, are an etiological risk factor, but few think that infectious processes are the central etiological mechanism.

Torrey is certainly right that three decades of genetics have neither led to the discovery of genes that cause schizophrenia nor have, so far, led to better treatments for schizophrenia. I believe Torrey is also correct that this casts doubt on the traditional idea that schizophrenia is primarily a “genetic disorder.” If there were genes that cause schizophrenia, we would’ve found them by now. Instead, what we have is a long list of 300 or so associations between schizophrenia and various genetic loci (and other genetic phenomena such as copy number variations), most of which are not specific to schizophrenia (they are also associated with other psychiatric disorders), most of which confer a tiny risk (with some rare alterations that confer a large risk), and collectively, they seem to account for a very small proportion of the variance in liability. The bulk of research evidence suggests that genetics plays a role in the etiology and that genetic alterations are causally relevant for some patients, but genetic factors appear to be neither necessary nor sufficient for the development of schizophrenia, which makes it difficult to justify schizophrenia as primarily a “genetic disorder” (or even primarily a disorder of gene-environment interactions).

So what remains of schizophrenia genetics? Are critics correct in saying that we have reached the end of the road?

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Many think that psychiatric genetics is at a dead end because they seem to be conceptually stuck in the 1990s¹. Two developments in particular have changed the way we think of psychiatric genetics.

One, the status of psychiatric categories such as “schizophrenia” and “depression” has been destabilized.

It is not simply the case that schizophrenia is etiologically heterogeneous, but rather that there is no clear neurobiological separation between schizophrenia and other DSM/ICD categories. The neurobiological mechanisms and processes are not specific to schizophrenia; they overlap with other DSM/ICD categories in complicated and messy ways. Furthermore, psychiatric symptoms appear to be dimensionally distributed in populations, such that psychiatric syndromes are better understood as extremes on continua. And categories such as schizophrenia likely represent the intersection of multiple continua.

Consider, for example, the psychosis superspectrum in HiTOP. A recent overview article on the etiology of the psychosis superspectrum by Katherine Jonas, et al. notes:

“The HiTOP psychosis superspectrum was developed to address shortcomings of traditional diagnoses for psychotic disorders and related conditions including low reliability, arbitrary boundaries between psychopathology and normality, high symptom co-occurrence, and heterogeneity within diagnostic categories. The psychosis superspectrum is a transdiagnostic dimensional model comprising two spectra—psychoticism and detachment—which are in turn broken down into fourteen narrow components, and two auxiliary domains—cognition and functional impairment. The structure of the spectra and their components are shown to parallel the genetic structure of psychosis and related traits. Psychoticism and detachment have distinct patterns of association with urbanicity, migrant and ethnic minority status, childhood adversity, and cannabis use.”

The section on genetic architecture offers more detail.

“The high genetic correlation between schizophrenia and bipolar disorder (r_g=0.68) outlines a psychoticism dimension in genomic structural equation models. Within the superspectrum, behavioral genetic methods identify a genetic factor underpinning psychoticism, and a distinct factor underlying detachment. Schizophrenia GWAS appear to capture genetic variance underlying both psychoticism and detachment, as the schizophrenia polygenic risk score, which quantifies common genetic risk associated with the schizophrenia diagnosis, has sometimes been associated with measures of psychoticism, and sometimes with measures of detachment. In aggregate, however, polygenic risk for schizophrenia has more often been associated with detachment in both people with psychotic disorders and in population samples.

Both behavioral and molecular genetic research identify strong genetic links between detachment and cognition. Behavioral genetic methods indicate that a large majority of the covariance between schizophrenia and cognition is driven by shared genetic risk factors. In molecular genetic approaches, shared genetic risk factors underlying the psychosis superspectrum and cognition are indicated by the significant genetic correlations between schizophrenia and intelligence. Genetic risk for schizophrenia has been shown to predict cognitive deficits in cases, nonpsychotic adults, and adolescents.” (for convenience of reading, I’ve removed references)

Robin Murray and Diego Quattrone (2022) write in Schizophrenia Research, “we no longer think it is useful to research schizophrenia as a discrete categorical diagnosis” and “now that we know that there is no “genuine” schizophrenia, much greater emphasis should be given to understanding the pathways from different risk factors to psychosis.” They note that schizophrenia appears to exist at the confluence of two major etiological continua: i) a predisposition towards psychopathology that is shared with bipolar disorder and that cuts across diagnostic categories; and ii) neurodevelopmental impairment.

Even in DSM terms, we can recognize positive symptoms, negative symptoms, and neurocognitive symptoms as separate domains. These domains are not specific to schizophrenia; our notion of schizophrenia arises from an intersection of these domains (that too in a polythetic manner, i.e. negative symptoms and neurocognitive symptoms are often observed but aren’t necessary for diagnosis) combined with a certain chronicity or recurrence of symptoms.

All this suggests that we won’t find causes for schizophrenia per se, but we can find mechanisms for different domains that cut across diagnostic categories and are on a continuum, with schizophrenia arising from the manner in which these domains intersect.

Second, the project of psychiatric genetics is no longer (or not simply) focused on identifying genes that cause schizophrenia (or other disorders), but on using findings from genetics to better understand mechanisms of psychopathology

Steven Hyman, former director of the National Institute of Mental Health, encapsulates the essence of this approach quite well in a recent article, “The Biology of Mental Disorders: Progress at Last” in Daedalus:

“In the search for biological insight, genetics serves as an unbiased “finding tool” for causal associations of a disease (or other trait) with biology, such as certain molecules, molecular pathways, cell types, or mechanisms.”

This shift has happened quietly, without much fanfare, and has resultantly been hard to notice for outsiders, especially with everyone loudly lamenting the failure to find causal genes. Torrey devotes a whole section of his article to “Dr. Hyman's nightmare,” referring to a 2018 interview in which Hyman complained of having a “nightmare that we will end up with [only] gene lists rather than mechanistic understandings that will propel therapeutics.”

But if Hyman’s nightmare has come true, he doesn’t seem to be aware of it. He writes in Daedalus:

“After decades of stasis, research on mental disorders has reached an inflection point. Unbiased large-scale genetics provides information that, if interpreted circumspectly and integrated with neurobiology, provides “finding tools” for causal biological mechanisms that can advance discovery of biomarkers, preventive interventions, and better treatments.”

So how do genetic associations shed light on the mechanisms of psychopathology? If an association is legitimate (that is, it is not a false positive or a result of confounding), it points towards pathways that are implicated in some manner in the pathophysiology. For example, many genetic associations for schizophrenia relate to the structure, development, and plasticity of synapses, indicating that disruptions in these pathways are relevant to the pathophysiology of schizophrenia. These disruptions could occur in some cases due to genetic variants, but they could also occur due to a wide variety of other causes. Both Torrey and Hyman note that the gene encoding complement factor 4a (c4a) is the most consistently implicated genetic finding to emerge from schizophrenia genetics, pointing towards the role of the complement cascade.

Hyman points out the importance of the convergence of common and rare variant associations:

“Many of the ultrarare variants discovered so far converge with small-effect common variants on the same biological processes. The importance of such convergence for biological experiments can be illustrated by the schizophrenia-associated gene grin2a, which encodes a subunit nmda glutamate receptor. Ultrarare lof variants affecting grin2a increase the risk of schizophrenia by approximately twenty-fold, whereas a common variant affecting grin2a increases the risk of schizophrenia by only 1.07-fold. The ultrarare variant leads to a marked reduction in the amount of receptor subunit protein in the nervous system. The common variant is found within the noncoding genome, like approximately 90 percent of gwas associations across all of biology. The best-known function of the noncoding genome is to regulate the expression of rnas and proteins. Thus, the common variant presumably regulates expression of the grin2a gene and has a far more modest effect on nmda receptors in the brain than the ultrarare lof variant.”

When we are approaching genetics to look for relevant pathways, a tiny effect size of the causal association doesn’t nullify the potential relevance. Hyman explains:

“When used as a tool to associate a trait with biology, the effect size of the allele on the ultimate phenotype does not matter. (As noted, however, effect size is important for the design of experiments, such as the construction of cellular or genetically engineered animal models.) Similarly, what makes a gene product a good drug target is not the effect size of the associated allele, but its overall role in biology. The importance of ldl cholesterol as a risk for coronary artery disease was initially learned epidemiologically from the Framingham heart study. Genetic studies that implicated the ldl cholesterol receptor in atherosclerotic heart disease served to focus attention on the cholesterol biosynthetic pathway. Once a pathway is shown to play a causal role, it can be exploited for biomarkers (such as serum ldl cholesterol levels) and therapeutic targets for drugs, antibodies, or other modalities. The rate-limiting enzyme in the cholesterol biosynthetic pathway, hmg-coa reductase, is the target of the highly effective statin drugs because of its biochemical role in the pathway. It does not matter that the gene that encodes hmg-coa reductase is linked to a common snp with a vanishingly small effect on overall risk of coronary artery disease. What matters is that convergent evidence from epidemiology and genetics identified a causal pathway that could be exploited for effective therapies.”

So what does this all mean for our mechanistic understanding of “schizophrenia”? Genetic associations support the idea of the involvement of complement pathways and synaptic pruning. Hyman writes:

“A key mechanism of synapse elimination involves the marking of weak synapses by complement proteins, leading to engulfment by microglia and other glial cell types… It is hypothesized that in association with other risk factors such as variations in synaptic proteins, as suggested by schizophrenia genetics, elevated levels of complement proteins might contribute to excessive and inappropriate synaptic pruning. Because normal brain maturation results in net synapse elimination, longitudinal studies of typically developing adolescents reveal reductions in cortical thickness. However, individuals who develop schizophrenia show more rapid and severe patterns of cortical thinning. Such findings from structural neuro-imaging, which have been corroborated by postmortem studies, converge on the conclusion that people affected by schizophrenia have greater net reductions in synapse numbers and the dendritic spines that bear them than unaffected individuals. The pattern of cognitive deficits observed in schizophrenia, such as prominent impairments of working memory and executive function, map to the pre-frontal cortex where cortical thinning is most severe. It is further hypothesized that psychosis is a downstream result of excessive synapse loss and synaptic dysfunction that leave the brain unable to process information and of abnormal reorganization of remaining synaptic networks.”

The end result is a hypothesized cascade that goes from complement activation, synapse elimination, and cortical thinning to cognitive impairments and aberrant information processing. It is a cascade that points away from genetic causes towards pathways that are disrupted in different individuals through a combination of a variety of different factors, which may include infection, inflammation, cannabis use, childhood trauma, adversity in later life, etc. In some people, genetic factors could still be important in the etiology if they had a lot of common variants linked to schizophrenia or if they had rare variants (or CNVs) with large effects. But this would be a subset of cases, and as noted previously, genetic alterations are neither necessary nor sufficient.

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I have skirted around one issue that Torrey focuses on, the matter of NIMH’s schizophrenia research portfolio. It is not something I am particularly qualified to comment on. My understanding is that the NIMH is interested in playing the “long game," with the goal of developing an understanding of the mechanisms and processes that lead to psychopathology, and that without such an understanding, “the alternative is clinical research based on hunches and guesswork” (Hyman, 2021). I completely understand the need for such an undertaking, and IMO, folks who think that we need to radically divert resources away from such an undertaking are mistaken. Yet I am also aware that there is a dire lack of research focused on addressing clinical questions that are relevant to the present moment. NIMH is not particularly interested in the question of how existing treatments could be used or combined most effectively (the RAISE early treatment program for first-episode psychosis is a notable exception), how their clinical use can be optimized, how different alternatives compare to each other, or how adverse effects can be evaluated and mitigated. There is also a desperate need for research that informs social policy and legislative efforts. Funding and support for such research have to come from somewhere, but where? The industry is interested in doing the bare minimum that gets them regulatory approval for new products; they are not interested in questions that arise in real-world clinical settings. SAMHSA (Substance Abuse and Mental Health Services Administration) seems to lack the resources needed to properly fund such efforts. In the absence of federal resources, researchers have to cobble together funds for small studies from university and foundation grants. So whether this is NIMH’s fault or not, it is certainly our collective failure. An important question is how people in positions of power can be motivated and convinced to support these efforts. The history of the Human Genome Project shows that such efforts do not materialize out of nowhere; they emerge out of sustained efforts to convince politicians and legislators of their value by people who understand how the system works. A golden age of clinical research in psychiatry is still possible, but not without the hard work of the right people in the right places.

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Follow-up post:

Contextualizing the Heritability of Schizophrenia

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1. To be honest, this is true of many proponents of psychiatric genetics as well.