Genetics of Psychiatric Disorders

The stigma of mental disorders still puts proactive policy in terms of mental wellness promotion on the long finger in many countries. The conditioned approach of burying heads in sand is the norm. Surely the time is nigh for change with recent research beginning to elucidate the complex heritable components of disease?

Disorders of the mind are complex. The traditional view that the brain is a mysterious black box is being dispelled more and more each day as the wiring mechanisms of the brain are delineated.

• Discrimination is Clinical

The clinical expression of psychiatric disorders is distinctive, and yet there is often a great difficulty to diagnose disorders. There is much commonality between the major psychiatric disorders despite there being typical symptoms in specific disease classifications.

There is overlap in the clinical features of many of these conditions. Schizophrenia and bipolar disorder share many clinical features. There is some overlap between schizophrenia and autism. In early definitions of schizophrenia, autism features were included in the diagnosis.

Despite this clinical overlap, there are differences that make them clearly definitive diagnoses. There may be clear age of onset differences between some disorders; they may have different prevalence. They have different treatments and can have distinct outcomes.

• Gene versus Environment

The involvement of brain chemical defects is undeniable in many cases of mental disorder, but it is not clear how much such defects play a role. In many cases, there is an unclear distinction between core neuropsychiatric disorders genes and psychological conditions and reactions due to environmental exacerbators, such as stress.

• Genetic Tools

With new genetic tools, including genome wide analysis and relatively much cheaper methods of sequencing whole genomes and exons (bits of coding DNA), coming onstream novel candidate genes are being identified as potential causative agents in mental disease all the time. The result is not surprisingly that there is more complexity than expected.

• Risk Haplotypes

Mutations in specific genes that may cause damage have been found to be common to a number of psychiatric disorders. Clinical similarity is in part due to these shared causative genes or associated genes or risk haplotypes. This bears up with the genetic studies as certain risk haplotypes or groups of genes that link together have been shown to be inherited in families with mental disorders. DISC1 is a gene that has been shown to be linked to a variety of psychiatric disorders.

What is surprising from genetic studies is that the same gene can have a different role depending on its segregation with a specific disease or severity of disease. If it is knocked out or its function absent it may for example cause a severe brain disorder; if it is partially functional it may cause a mild autism.

• Role for Alleles

Allele variation throughout the coding and non-coding parts of the genome seems to be important. It can determine if there is schizophrenia of a milder or more severe type.

This makes treatment more complex as it may not just be mutation of a gene itself but involvement of other parts of the genome involved in regulation of that gene. Factors such as copy number and regulation of translation of a specific gene may come into play.

• What Fraction is Known?

The upshot is that there will be no one magic drug or fix on a population basis to fix a single defective gene causing a major psychiatric disorder. We may never be able to cure all schizophrenics or people with autism. Life is never that easy. The vast majority of autism and schizophrenia cases are not yet diagnosed by genetics. It has been suggested that we have only identified a fraction of the genes involved anyhow.

This does not mean that individual treatments will have a profound effect on an individual case by case. Some powerful medications have a significant impact on mental disease already, whereas others have little or no impact. Treatment choice remains a conundrum.

• Probing Early Development

Research into the normal early development of the brain will provide clues as to how diseases develop, but most research focuses on diseased individuals. Mutations of many genes involved in neuronal development can lead to psychiatric disorders but we need to know what is normal. Basic research should focus on how the wiring of the brain mediates functions and then we can determine what happens when those processes go wrong.

Although only a fraction of gene involvement can be explained so far, it seems that many of the candidate genes are involved in the brain plasticity. Plasticity includes mechanism of adaptation and rebuilding.

• Metabolic Comorbidity

Known metabolic risk markers have also been associated with psychiatric disorders. Certain gene mutations are associated with increased risk of cardiovascular disease and other metabolic conditions and these have been found in patients also with neurodevelopmental disorders including autism and schizophrenia. These metabolic risk factors include obesity, glucose abnormalities and raised lipid levels.

Diabetics do tend to have a more severe course of mood disorders, and more psychiatric hospital stays per lifetime. Perhaps it is burden of disease or it may be commonality of genetic cause, but diabetics with bipolar get more rapid cycling and has a more chronic condition rather than a more episodic course.

• Focus on Autism

Autism spectrum disorders (ASD) have a widely variable presentation. It is highly heritable as defined by twin studies. One twin has autism then a monozygotic twin has somewhere between 60 and 90% chance of having some form of ASD. Despite a particular genetic cause of autism is uncovered in 15% of those diagnosed with autism. So without marker genes and clear diagnosis and the wide spectrum of symptomatology it is most likely that much ASD remains a missed diagnosis.

Removal of funding for schools for support teachers for autism and behavioural disorders and monies for counselling services for the mentally ill will return Ireland to a prehistoric sort of management.

• Medieval Mental Management

Ireland remains in ignorant bliss of its negligence to the vast majority of these so-called ‘mentally disabled’ children who will become its future.

There is a dearth of affordable community counselling services for people with a range of problems from depression to bipolar disorder.

Psychiatric illness, although considered for so long to be a mental disability in Ireland, has a huge spectrum that affects a large proportion of the population. Some of these conditions are severe and others are mild.

Genetics may eventually provide some of the answers as to the causes of these disorders, but there is a continuum of symptoms that need to be tackled and not ignored to improve patient quality of life.

KEY POINTS

• There is symptom overlap between different psychiatric disorders and yet there are clear distinctive clinical diagnosis.
• The genetics of psychiatric disorders is complex and only a small proportion of genes involved have been elucidated.
• Some genes are involved in seemingly diverse psychiatric disorders and may also be involved in certain metabolic conditions.

Conor Caffrey is a medical and science writer who has recently been diagnosed with bipolar 2.  This article is after several presentations on the genetics of psychiatric disorders at the recent Wiring the Brain Conference held in Powerscourt, County Wicklow.

Related articles

• Identifying The Genes Responsible For Autism Disorders Is Critical For Diagnosis And Treatment (medicalnewstoday.com)
• Asperger’s and Autism (realintent.org)
• Some autism behaviors linked to altered gene (sciencedaily.com)