Genetic insights into psychiatric disorders

Psychiatric disorders such as schizophrenia, autism spectrum disorders (ASD) and major mood disorders are common, with 1 in 100 people affected by schizophrenia and a lifetime prevalence of 10% for major depressive disorder. They are highly debilitating to the patient and have a profound impact on the patient’s family, as well as society in general. For instance, schizophrenia is regarded as one of the most severe disorders when compared amongst any medical condition and costs the UK £11.8 billion a year. Major psychiatric disorders are characterised by a diverse range of clinically-diagnosed psychiatric phenotypes, from hallucinations and delusions in schizophrenia patients to impaired social interactions in ASD populations. In addition to these core symptoms, most psychiatric patients display considerable disruption in cognitive domains that are both poorly understood and under-researched.

Over the years, considerable and sustained scientific effort has been committed to uncovering the causes of these disorders. Numerous biological, genetic, developmental and environmental factors have been identified as important in psychiatric disorder causality. However, the findings are often poorly replicated and do not always fit into a clear unifying hypothesis or mechanism. The search for a pathogenic biomarkers including blood markers, behavioural/cognitive phenotypes or neuroimaging metrics have also been disappointing. Overall, progress has been slow and few major advances have been made.

In parallel, drug discovery has not advanced considerably since the early, serendipitous discovery of treatments such as the antipsychotic chlorpromazine for schizophrenia and lithium as a mood stabiliser for bipolar disorder. Psychiatric patients remain consigned to poor treatment options: up to a third of schizophrenia patients do not respond to antipsychotics and there is no effective treatment for ASD patients.

Genetic risk variants in psychiatric disorders

It is the field of psychiatric genetics, perhaps more than any other area of research, which is currently providing real aetiological and pathogenic insights into these complex disorders.

The highly heritable nature of schizophrenia (80%) and autism (60%) was established over half a century ago through historical twin and adoption studies. Now, with the advent of large-scale genomic studies, the role of common and rare genetic variation in the aetiology of psychiatric disorders is being exquisitely examined in psychiatric populations.

Genome-wide association studies have identified over a hundred common genetic variants (single-nucleotide polymorphisms, SNPs) that each contribute a small proportion of overall risk to schizophrenia, but together provide a polygenic risk for the disorder. Many of these genes are involved in glutamatergic neurotransmission, synaptic plasticity, calcium signalling and includes the biological target of antipsychotic medication, the dopamine D2 receptor.

At the same time, other genomic studies have highlighted the role of rare copy number variants (CNVs), which are large chromosomal deletions or duplications often spanning multiple genes. Studies have identified 11 recurrent CNVs, as well as newly occurring de novo CNVs, which confer high risk to schizophrenia. Similarly, 6 CNVs have been associated with ASD. Meanwhile, modern whole-exome sequencing techniques have provided the required resolution to observe the role of rare de novo SNPs and insertion and deletion variants (indels) in schizophrenia.

Clearly over the past decade, genomic studies have been highly successful at identifying risk variants, particularly in case of schizophrenia and ASD, and are now beginning to bear fruit in the study of other psychiatric populations such as bipolar disorder and major depressive disorder patients.

Beyond genetics: biological pathways

As we move towards a post-genomic era, there will be a pressing need for researchers to harness this increased genetic knowledge and characterise the biological consequence of genetic risk variants. Currently, confidence can be gained from the many genetic variants, in the form of SNPs and CNVs, which encode synaptic proteins that converge onto coherent pathways at the glutamatergic synapse.

Modified from Hall, Trent, Thomas, O'Donovan and Owen. Biol. Psychiatry (2015)
Modified from Hall, Trent, Thomas, O’Donovan and Owen.
Biol. Psychiatry (2015)

The neurobiological complex of the Fragile X Syndrome protein, FMRP, and its partner CYFIP1, and their regulation of ARC at the synapse, is one such biological pathway identified through multiple genomic studies. FMRP is a synaptic protein that works in concert with CYFIP1 at the synapse to regulate the interconnected processes of protein translation, synaptic plasticity and synaptic spine morphology, with clear consequences on memory and cognition. ARC in its own right is a well-established mediator of synaptic plasticity and is critical for memory formation and extinction.

Therefore, the continued study of CYFIP1-FMRP and ARC through animal and cellular models, should provide an intriguing entry point for researchers exploring genetic risk factors within the context of well-defined and plausible biological mechanisms.

Future of psychiatric genetics

Outstanding issues remain in the pursuit of understanding genetic risk in psychiatric disorders. Clearly, not all the genetic risk is accounted for and is likely due to the influence of other factors on genetic risk, such as the environment, and should be addressed by future epidemiological and epigenetic studies.

It is also clear that pleiotropy exists in genetic risk for psychiatric disorders, whereby the alteration of one gene can lead to multiple phenotypic traits. For instance, there is considerable sharing of the common risk variants associated with schizophrenia and bipolar disorder. The same appears to be true of rare CNVs associated with schizophrenia and ASD. Given that genetic risk variants appear to cross classical diagnostic boundaries, it challenges the very notion of categorical methods for diagnosing psychiatric disorders.

These findings point towards a future approach of genetic stratification of psychiatric population that will offer further aetiological insights and provide renewed optimism for improved therapeutic intervention.

2 thoughts on “Genetic insights into psychiatric disorders

  1. Your article is very interesting and gives hope for the future ( hopefully in my lifetime!) I have a 14 year old severely autistic son who is non verbal SLD, with severe OCD and bipolar. Even with these problems he has managed to learn to ride a 2 wheel bike, can swim like a fish and is loving , he learns visually by watching others. By far the worst and heartbreaking problem for him are the periods that can last weeks when he has high anxiety with no apparent triggers. Needless to say he is on medication sertraline and aripiprazole in a low dose, but these can cause side effects of anxiety that they are supposed to treat if in higher doses. Like many other parents I pray for a cure or at least something to help the comorbid conditions which must all be linked to a root cause.
    I truly believe genetics is the main cause, my mother had undiagnosed paranoid personality disorder she truly believed we were all in a conspiracy against her to the day she died, it was heartbreaking, she wouldn’t get help from a doctor because she wouldn’t believe she needed treatment, no doubt there are hundreds of families in the same situation today, why would someone with a psychological problem think they have a problem?
    There are mild autistic traits in myself and my husband, neither of us are comfortable in social situations or brilliant coversationalists.
    One other strange and interesting fact, my mother, myself and my son all have numerous congenitally missing teeth, I’ve heard this is quite common in autistic individuals!
    I’m just a parent and much of the scientific terminology was way above my head, but on behalf of my family and other parents of children suffering with cruel psychological problems, thank you to all the scientists who work so hard to unravel the mysteries of the brain!!

  2. there is no doubt in my mind that schizophrenia is genetic. My father diagnosed schizophrenic but poorly controlled committed suicide aged 40 my Son also diagnosed schizophrenic well controlled with clozapine recently died aged 29 his medication caused obesity and this is a direct cause of his death, so now two people closest to me lost to this horrendous illness. Other members of my family are suffering this condition also. I worry so much about genetics and future generations of my family

Leave a Reply

Your email address will not be published. Required fields are marked *