Discoveries in the Genetics of Psychiatric Disorders

Psychiatry and Diagnosing Disorders, Not Diseases

What makes schizophrenia and autism spectrum disorders different from one another? Conceptually, both are thought to arise from early changes in brain development, and thus belong to the broader category of neurodevelopmental conditions [1]. Today, a particular neurodevelopmental or psychiatric diagnosis is defined by its specific symptomatology – the sum and constellation of an individual’s troubling behaviors and experiences. 

The tools that are used to differentiate such conditions and assign diagnoses are full of highly detailed and descriptive criteria [2,3]. Based on these criteria, various psychiatric and developmental disorders can be distinguished from one another at the clinical level. However, the idea that symptomology alone is sufficient to tell us what these disorders are, what is happening at the biological level, and how they should be treated, has been disputed since the very creation of the diagnoses [4]. Simply put, these diagnostic groups were created without knowledge of their underlying biology. So, it is still a lively matter of debate how exactly various disorders in psychiatry are different or related at fundamental levels. 

It was only in the past few decades that scientists have been able to study the biological origin of such neurodevelopmental disorders by examining their genetic contributions. This has been a rapidly advancing area of research and medicine. In certain cases, genetic diagnoses can now help understand and treat individuals with developmental conditions based on their specific genetic profile, in a more personalized and sophisticated fashion than symptom-based diagnoses alone could allow. Since an accurate and informative diagnosis is the cornerstone of good clinical decision making, it is important to acknowledge how advances in genetics are now enriching the diagnosis of neurodevelopmental and psychiatric disorders.

A Brief History of Diagnostic Codes

It was not until the late 1800’s that contemporary efforts began to develop comprehensive and standardized definitions for all mental disorders [5]. Diagnostic codes have been continually revised, and as a result, the definitions and grouping of disorders has been shifting and taking shape over the past century. As such, from a historical perspective, the disorders that are familiar today are quite young in their current form, and their definitions are more fluid than the highly ordered diagnostic criteria might suggest. In fact, it was not until the late 1970s that autism was officially recognized as being an independent diagnosis, severing it from a long history of being tied under the umbrella of childhood schizophrenia [6,7]. Since the 1970s, the prevalence of autism has then increased by an estimated 5- to 20-fold [8]. This change has corresponded, again, with changes that have occurred in diagnostic codes and the widening of the clinical definition which now applies to individuals that would not have fit into previous definitions of the disorder [9]. 

The practice of creating diagnostic groups for mental disorders by analyzing and clustering symptoms has been criticized for its vulnerability to subjective judgment. These criticisms make the practice easily comparable to early attempts by biologists to classify living species by assigning them to groups based on arbitrarily chosen features, such as their appearance, or diet, with no knowledge of their biological or evolutionary relatedness [10]. For the most part, the diagnostic groupings that exist in psychiatry today are similarly detached from biological insight.

Lessons from Genetics – Coming into Focus

One of the first solid genetic findings with relevance to neurodevelopment and psychiatric disease was the identification of the Fragile X syndrome mutation in 1969 [11]. Clinical descriptions of Fragile X syndrome date back to 1943, before the genetic mutation was even identified, and described an inherited syndrome associated with a broad array of developmental, cognitive, and psychiatric traits [12]. The affected individuals were described as experiencing intellectual deficits, difficulties with acquiring speech and language, hyperactivity, and psychotic symptoms. Additionally, several individuals were reported to even suffer from dementia. From the perspective of today’s diagnostic codes, this combination and variety of symptoms does not neatly fit into a single diagnostic category. Psychotic symptoms, such as delusions and hallucinations, are a hallmark of schizophrenia and typically emerge in late adolescence. Hyperactivity during childhood, on the other hand, is more closely aligned with attention deficit-hyperactivity disorder (ADHD). Difficulties in acquiring speech and language are a developmental disorder on their own. Essentially, these decades-old reports demonstrated that a single genetic cause could simultaneously increase the risk for multiple developmental, psychiatric, and neurodegenerative outcomes that cross and confuse symptom-based diagnostic boundaries.

This phenomenon suggests that separate disorders within psychiatry, that appear to be very different and are diagnosed as such, could involve common biological processes [13]. However, this possibility did not make a substantial impression in the field of psychiatry for several decades. Diagnostic groupings continued to take shape and act as fixed concepts, based around symptoms and clinical observations [4]. More recently, at the turn of the 20th century, advances in genetic technologies have begun to allow researchers to explore the genetic basis of brain disorders more thoroughly. These investigations took a “diagnosis-first” approach, as scientists studied each disorder separately. It was hoped that risk for a given disorder might be easily attributed to a small number of genetic mutations that would provide clear disease-specific biological insights [14]. 

Rather than having such simple and clear findings, the genetic basis for any given psychiatric disorder was found to be extremely complex and widely dispersed throughout the human genome [15]. This is the concept of polygenicity, in which many genes (the functional units of DNA) are involved in influencing complex traits. For example, schizophrenia has over one hundred different common DNA variations that influence the risk of developing the disorder, with each individual variation playing only a small role in overall risk [16]. Simultaneously, dozens of mutations have been discovered in the past decade that are much rarer but can more drastically increase the risk of neurodevelopmental and psychiatric outcomes [17]. This growing list of high-impact genetic disorders have notoriously non-specific effects, much like Fragile X syndrome, and are often associated with several different developmental and psychiatric disorders, as well as various medical conditions [18]. 

It will require much more research effort to fully untangle the complex role of genetics in neurodevelopment and psychiatry [19]. But after years of intense research and discovery, the essential question remains, what practical value has been gained so far? How can advances in genetics benefit diagnosis, treatment, and future research? 

The value of genetics in improving the diagnosis and treatment of neurodevelopmental disorders is the most established in pediatric medical settings, where genetic testing has been a part of routine care for over a decade [20]. Genetic disorders are now known to be common in these populations, with up to 30-50% of individuals having an identifiable genetic disorder [21]. 22q11.2 deletion syndrome is an example of one such genetic disorder. This occurs when a large segment of DNA that includes over 100 different genes is missing from one copy of chromosome 22 and is associated with an extensive set of health outcomes, including medical risks ranging from heart malformations to immunodeficiencies [22, 23]. Having a genetic diagnosis in this case provides a road map in which clinicians can use prior knowledge of the genetic variant to navigate what an individual’s health risks are, beyond what is immediately observable, to organize and coordinate their care more effectively. In fact, changes to clinical management take place in approximately 20% of cases following the identification of a genetic disorder [24]. Such changes are far reaching and can influence decisions regarding medical or surgical procedures, medication selection, or indicate the need for more proactive screening measures for anticipated medical developments [25, 24]. 

Although genetic testing has not yet been widely adopted into adult psychiatry, there are prospects that individuals in this population, especially those with schizophrenia, may benefit similarly as our knowledge of genetics grows [26]. Returning to the example of 22q11.2 deletion syndrome, up to 35% of individuals with this genetic disorder develop schizophrenia as they enter adulthood [27]. Recent studies have been focused on identifying what drug regimens and therapeutic practices might be the most effective at treating individuals with this genetic diagnosis and schizophrenia [28, 29]. Similarly, there are now data regarding how certain psychiatric medications may be prescribed more carefully in this group, as there could be a lower threshold for certain adverse reactions in these individuals [30]. Importantly, comprehensive guidelines have also been published that will help clinicians and caregivers best support individuals with 22q11.2 deletions in their everyday lives by considering their broader array of cognitive and behavioral impairments and specific vulnerabilities in areas ranging from interpersonal relations to finance management or employment [31]. 22q11.2 deletion syndrome is a bit of an exception in this regard, as this level of in-depth data does not exist to support the management of adults with many other genetic conditions in the context of psychiatric disturbance. 

Such rare genetic disorders have also been identified in individuals diagnosed with schizophrenia that experienced prolonged poor clinical response to conventional drug therapies [32,33,34]. Additionally, in adults with schizophrenia, such high-risk genetic disorders are more commonly found in individuals that have comorbid intellectual disabilities [35]. These findings suggest that, as a group, high-risk genetic conditions likely do play an important role in influencing the efficacy of standard therapeutic practices and can impact the level of cognitive functioning in adult psychiatric patients. Thus, there is a need to better understand these genetic conditions and their consequences throughout the lifespan to maximize support for affected individuals [36]. In one study by Bodkin et al., 2019, a novel drug treatment was used to remedy the specific biological effects of a genetic variation found in two adult family members with psychotic disorders [37]. This targeted treatment, although experimental, led to a more successful reduction of symptoms compared to standard treatments. Although such successful genetically informed interventions are not yet commonplace in adult psychiatry, this example represents the idealized personalized medicine approach that is often aspired for.

There are other cited benefits of genetic diagnoses besides tangible changes to patient healthcare. The emotional burden associated with having unexplained disabilities often affects patients, their loved ones, and caregivers, and has been reportedly relieved in many after having a clear biological explanation, which can put an end to what is commonly experienced as a “diagnostic odyssey” [38, 39]. 

Accepting the Complexity and Individuality of Developmental and Psychiatric Disorder

Providing an accurate diagnosis is an essential function of every medical discipline, and a functional diagnosis relates the observable ailment to the underlying disease and helps a clinician organize care [40]. Diagnosis in psychiatry, however, is of clinically derived disorders that are not directly tied to a specific underlying cause [41]. Although today’s diagnostic codes have, without a doubt, provided an organizing framework for the field, there is still plenty of room for improvement when it comes to addressing patients’ unique needs. There have been enormous research efforts attempting to objectify the diagnosis of psychiatric and developmental disorders by using emerging technologies, such as brain imaging, to identify biological signatures that relate to specific disease states [42]. Many of such efforts have rigidly set forth to identify markers that fit to conventional diagnostic boundaries – and thus agree with and validate existing diagnostic groupings – but have been unsuccessful at doing so. 

Recent discoveries in genetics have steadfastly underlined the complexity of neurodevelopmental and psychiatric disorders. Findings have suggested that different disorders may in some cases result from common or at least partially overlapping biological processes. At the same time, it is becoming realized that individuals’ genetic make-up, especially in the presence of known genetic disorders, are highly unique and in many cases can help direct their care. In these settings, the implementation of genetic testing has reinforced the notion that no two individuals are the same, and that individuals that appear to be similar based on symptomatology may be distinguishable in highly relevant ways based on their genetics. This is an exciting area of progress that has already brought new opportunities to improve care today, and with many more opportunities still ahead. It is likely that as more is learned, genetic information will play an evermore important role in guiding and supplementing classical psychiatric diagnoses.  

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