Schizophrenia

Schizophrenia is a chronic mental illness characterised by disturbances in thinking, perception, emotion and behaviour. It is caused by a combination of genetic and environmental factors with a high degree of heredity.

To date, 12 copy number variants (CNVs) have been identified as risk factors for schizophrenia, greatly increasing the risk of developing the disorder, in some cases more than ten-fold. At least 2.5% of people with schizophrenia carry such a CNV and the diagnostic yield is likely to be higher for those with a positive family history, intellectual disability, other neurodevelopmental conditions, treatment-resistance and early-onset symptoms.

Genomic testing should be considered when there is clinical suspicion of an underlying CNV. Detecting a genomic risk variant for schizophrenia gives rise to opportunities for early intervention, health surveillance and screening for associated conditions. This promotes engagement with services and empowers patients with information on risks to relatives, facilitating choice and decision-making.

Schizophrenia is diagnosed according to international diagnostic classification systems, including ICD-11 and DSM-5. It is characterised by the following symptoms:

• delusions;
• hallucinations;
• disorganised thinking;
• experiences of influence, passivity or control;
• negative symptoms such as affective flattening, alogia, paucity of speech, avolition, asociality and anhedonia;
• grossly disorganised behaviour that impedes goal-directed behaviour; and
• psychomotor disturbances.

Genetic epidemiology studies indicate that schizophrenia is highly heritable (65%–80%). The inheritance is not Mendelian: the genetic architecture is complex, with multiple genes interacting together with environmental factors to increase risk.

Some genetic risk factors are relatively common, with only a small individual effect size. Others, such as CNVs, are rare but have been found to greatly increase risk.

To date, 12 CNVs have been associated with schizophrenia and it is likely that many more will be identified as patient sample sizes increase in psychiatric genomic research. These CNVs contain multiple genes, increasing the risk of a range of neurodevelopmental, psychiatric and physical health symptoms. Associated conditions can include intellectual disability, autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), anxiety disorders, epilepsy and congenital malformations, depending on the specific CNV.

CNVs vary in their frequency in the population and their odds ratios for schizophrenia (between about 2 and 60). For example, 22q11.2 deletion is the most common microdeletion syndrome and increases risk of a variety of health problems, including a 25–30-fold increase in the risk of schizophrenia.

The currently known pathogenic CNVs are listed below:

• 1q21.1 deletion;
• 1q21.1 duplication;
• 2p16.3 exonic deletion;
• 3q29 deletion;
• 7q11.23 duplication;
• 15q11.2 deletion;
• 15q13.3 deletion;
• 15q11-13 duplication;
• 16p11.2 duplication;
• 16p12.1 deletion;
• 16p13.11 duplication; and
• 22q11.2 deletion.

History, examination and investigation should be carried out to identify other potential causes of psychotic symptoms; for example, brain tumour, encephalitis, substance use and prescribed medication (such as corticosteroids). Genomic testing should be considered for those with early-onset schizophrenia, treatment resistance, personal history of neurodevelopmental conditions or congenital anomalies, and those with a family history of the above, or a family history of a pathogenic CNV.

For information about arranging genomic testing, see ‘Presentation: Adult with schizophrenia’.

CNVs may occur as new variants in an individual (de novo), or can be inherited from a parent. If a CNV has been inherited, both parents and siblings of the index patient will have a 50% chance of also having inherited the CNV and the associated risks.

Whether a CNV is inherited or occurs de novo, offspring of affected patients will also have a 50% chance of inheriting it. Thus, the identification of a pathogenic CNV can have implications for both the patient and their wider family. Genomic counselling about the risks and implications of testing, and the interpretation of results, is therefore an important component of good clinical care.

There is currently little evidence to guide the management of schizophrenia in specific CNV carriers, so current treatment options are broadly similar to those without a pathogenic CNV. There are reports that some pathogenic CNV carriers have an increased propensity to treatment resistance and medication side effects. Some CNVs are also associated with an increased risk of physical health problems; for example, cardiac anomalies and immune deficiencies. Where appropriate, screening should be carried out for any associated health conditions, giving rise to an opportunity for preventative medicine.

For clinicians

• Royal College of Psychiatrists: The role of genetic testing in mental health settings (CR237)

References:

• Kendall KM, Duffin D, Doherty J and others. ‘The translation of psychiatric genetic findings to the clinic‘. Schizophrenia Research 2024: volume 267, pages 470–472. DOI: 10.1016/j.schres.2023.10.024
• Kirov G, Rees E and Walters J. ‘What a psychiatrist needs to know about copy number variants‘. BJPsych Advances 2015: volume 21, issue 3, pages 157–163. DOI: 10.1192/apt.bp.113.012039
• Rees E, Walters JTR, Georgieva L and others. ‘Analysis of copy number variations at 15 schizophrenia-associated loci’. British Journal of Psychiatry 2014, volume 204, issue 2, pages 108–114. DOI: 10.1192/bjp.bp.113.131052

For patients

• MaxAppeal (charity offering information and support to those affected by 22q11.2 deletion)
• NHS: Psychosis
• Unique (charity for anyone affected by a rare chromosome disorder, copy number variant or single gene disorder associated with a neurodevelopmental disorder)