THE GENETICS OF SCHIZOPHRENIA: A REVIEW
Ruky Agbahovbe UCD School of Medicine and Medical Science, University College Dublin, Belfield, Dublin 4, Ireland
Schizophrenia is a complex, chronic psychiatric disorder characterised by positive symptoms (hallucinations and delusions), negative symptoms (avolition and withdrawal), and cognitive dysfunction (deficits in executive function, attention and memory)1. The diagnosis of schizophrenia is almost entirely clinical, as no objective measurements currently exist. The early onset of this disease, coupled with its chronicity, make it a significantly disabling condition for many patients and their families. The heterogeneous nature of schizophrenia has resulted in a lack of consensus regarding schizophrenia’s aetiology and pathophysiology.
Schizophrenia has an estimated prevalence of 5 per 1000 in the population. Similarly, the incidence of schizophrenia is approximately 0.20 per thousand per year2. Juxtaposition of the prevalence and incidence in any given geographical region demonstrates the prevalence is typically greater than ten times the annual incidence, which further highlights the chronic nature of this disorder. The age of onset comparing men and women is variable, although men often present earlier. The peak incidence for males and females is between 15-24 years, with females exhibiting a second peak between the ages of 55-64 years. Overall, males are suggested to have a 30-40% higher lifetime risk of developing schizophrenia3.
Despite over 100 years of post-mortem inspection of brains from individuals diagnosed with schizophrenia, the exact mechanism underlying its pathophysiology remains poorly understood. Such studies have shown a notable absence of gross malformations, anomalies or pathological stigmata that are seen in many congenital neurological disorders or neurodegenerative diseases4. In recent years, neuroinflammation has been proposed as a possible pathogenic mechanism and has amassed scientific opinions as seen in other psychiatric conditions such as major depressive disorder4.
Biological studies over the last twenty years have focused on neurochemical observations and theories. For the most part, schizophrenia is thought to be characterised by abnormalities in neurotransmission. An excess or deficiency of neurotransmitters, including dopamine, glutamate and gamma-aminobutyric acid (GABA) have been implicated in the pathogenesis5. Of these, it is suggested an excess of the neurotransmitter dopamine plays the most significant role. Abnormal activity at dopamine receptor sites, particularly the D2receptor, is associated with the symptoms of schizophrenia6. The use of levodopa (L-DOPA; dihydroxyphenylalanine) for the treatment of Parkinson’s disease (caused by death of dopamine secreting neurons in the basal ganglia) has been demonstrated to cause schizophrenia-like side effects such as auditory and visual hallucinations and irritability7.
Multiple risk factors have been implicated in the development of schizophrenia. Interesting, it has been known that individuals with schizophrenia are often born in the winter months8. Possible explanations for this small increased relative risk include the correlation of the second trimester of pregnancy and the seasonal influenza8. Antenatal infection as a risk factor is consistent with the neurodevelopmental theory of schizophrenia. Furthermore, there is consistent evidence that those with antibodies to the parasite Toxoplasma gondii, neonatal meningitis and antenatal infection of the rubella virus have a higher prevalence of schizophrenia in later life9-11. Furthermore, it has also been suggested that these seasonal effects could infer genetic vulnerability. Birth complications such as malnutrition, extreme prematurity and hypoxia-ischaemia have also been linked to the development of schizophrenia later in life12. Evidence, although small, consistently indicates that individuals with schizophrenia have an unusual resistance to autoimmune diseases, namely rheumatoid arthritis, thyroid disorders and coeliac disease13. Perhaps the physiological consequences are protective, or it could mean that one gene raises the risk for one disorder, while protecting from the other. The role of advanced parental age in relation to an increased risk of schizophrenia has achieved a considerable amount of attention14. Population-based epidemiological studies have found that the relative risk of schizophrenia increases in each 5-year group of paternal age, with a maximum relative risk of 2.96 in those aged 55 and over compared to those aged 20-24 years14. Current research supports the hypothesis that advancing paternal age-related increased risk of schizophrenia is only significant in those without a family history, which alludes to the possibility of the aggregation of de novo mutations in sperm with advancing age14.
A family history of schizophrenia appears to be the most significant risk factor. Twin and adoption studies are strongly suggestive that inheritance accounts for most cases of familial aggregation of schizophrenia8. However, little is known about the contribution of this inheritance to the occurrence of schizophrenia in the general population and the broad inheritance pattern. The elucidation of the genetic architecture of the disorder will help us gain a greater understanding of the underlying neurophysiological mechanisms.
As mentioned, evidence of the heritability of schizophrenia has mainly been provided by twin studies and family linkage studies. Concordance rates of illness in monozygotic and dizygotic twins have been found to be about 40-50%, while the estimated genetic heritability of schizophrenia is approximately 80%15. Based on current knowledge, schizophrenia is a polygenic disorder caused by variations in many genes that in combination, contribute to the risk of developing schizophrenia. Initial cytogenetic investigations of large chromosomal deletions, duplications and translocations were followed by linkage studies to assess polymorphic co-segregation with disease in families16. The first linkage study of schizophrenia and chromosome 5 was published in Nature in 198817. Candidate gene association studies have identified possible putative risk genes. However, these linkage and candidate gene studies are often questioned due to inconsistencies in replication and lack of evidential power.
A new era of schizophrenia research emerged with the advent of genome-wide association studies (GWAS). The GWAS approach has evolved over the last decade and has become a powerful tool for identifying and assessing genetic risk factors for common complex diseases, as well as rare Mendelian diseases. Over thirty schizophrenia GWASs have been conducted and these studies have collectively highlighted specific genetic loci associated with schizophrenia. The modern unit of genetic variation is the single nucleotide polymorphism (SNP). A SNP is a single base-pair change in the DNA sequence that occurs with a high frequency in the genome. In genetic studies, SNPs are utilised as markers for a genomic region and are the most abundant form of genetic variation in the genome. The majority have little impact on biological systems but some may have functional consequences. The most recently published large-scale schizophrenia GWAS of 37,000 individuals with schizophrenia by the international Psychiatric Genomics Consortium (PGC) identified over 100 loci containing SNPs with genome wide significance for schizophrenia association18. There are an estimated 600 SNPs that have rather minor effects individually but cumulatively explain a great portion of a person’s genetic predisposition to developing schizophrenia18. It is postulated that these risk SNPs alter gene regulation and affect transcription and other downstream events such as abundance and expression of the gene18. At present, it is not known whether different schizophrenia risk genes are associated with different subtypes or clinical features of the disorder.
The PGC analysis has identified several candidate genes that have reached genome-wide significance. These include the dopamine D2 receptor (DRD2) and several glutamate receptors (GRIN2A, GRIA1, GRM3)18. Furthermore, the gene ZNF804A (zing finger protein 804A) has become the first prototypical “schizophrenia gene”18. The SNP rs1344706 within ZNF804A shows strong evidence for genome-wide association to schizophrenia (p=2.5 x 10-11)19. The PGC meta-analysis has also found additional SNPs within this gene that are also significant. ZNF804A mRNA is expressed throughout the course of an individual’s life, peaking antenatally with localisation of the protein to cortical pyramidal neurons20. Several research groups have investigated the functions of rs1344706 and ZNF804A utilising neuroimaging and have observed that although rs1344706 does not influence brain volumes, it may affect neural connectivity and cortical functioning20.
The GWAS era has also resulted in the study of copy number variants (CNVs) which has elucidated our understanding of the impact of rare structural variants for schizophrenia. In an additional combined meta-analysis by the PGC of 21,000 schizophrenia cases and 38,000 controls, CNVs were found at eight different loci – 1q21.1, 2p16.3, 3q28, 7q11.2, 15q11.3, 15q13.3, 16p11.2 and 22q11.221. Although rare, these CNVs show greater effects on schizophrenia risk than do the common variants (SNPs). Notably, many of the schizophrenia-associated CNVs are also associated with autism spectrum disorder, intellectual disability, attention-deficit-hyperactivity disorder and epilepsy21. This pleiotropy may suggest that schizophrenia may indeed be a developmental “extension” of other, more traditional, neurodevelopmental disorders. This theory is consistent with the finding that the CNV most often found in patients (1 in 100 patients with schizophrenia) is the 22q11.2 deletion that is responsible for DiGeorge syndrome. Thus, the relative risk for schizophrenia in a patient with 22q11.2 deletion syndrome is about 20- to 25-times the lifetime general population risk of 1%22. However, since these CNVs are so rare, the percentage of schizophrenia cases for which CNVs are likely pathogenic is 2% or less of the entire clinical population22.
Many questions in the discovery of schizophrenia-associated gene variants remain unanswered. It may be that there are classes of genomic variants that account for schizophrenia heritability that cannot yet be identified by genomic methods and platforms that are currently available. Although large-scale GWAS have identified common and rare genetic variants (SNPs and CNVs) associated with schizophrenia, this statistical association has not yet elucidated any disease mechanism or pathophysiology. Functional characterisation of the schizophrenia risk loci and bioinformatic analyses of animal models and human neural tissue may be highly informative. Thus far, pathway analysis of genome-wide loci has failed to identify a single, statistically significant biological pathway. This is partly because many of the schizophrenia-associated risk variants reside in non-coding regions (introns) of the genome and only presumably confer risk by affecting gene expression depending on their location in a critical regulatory region (for example a promoter or enhancer element) or whether they have epigenetic significance (sites of histone or chromatin modification via methylation-induced gene silencing)23. Several studies have shown that epigenetic mechanisms during early brain development are also implicated in schizophrenia risk. A survey of 450,000 genome-wide CpG sites in fetal cortical brain tissue exposed a 4-fold enrichment of GWAS schizophrenia risk loci associated with differential DNA methylation24.
Genetic research has provided insights into schizophrenia, with identification of risk loci and genes and the contribution or rare variants in genetic predisposition. The next generation of genetic studies commences with the development of new analytical and bioinformatic tools. Soon, key gene networks and biochemical pathways will be identified that will support the discovery of the underlying mechanisms of schizophrenia. These findings will be important in influencing pharmaco-therapeutic research strategies and diagnostics. With these discoveries comes the grievous realisation that the genetic basis of schizophrenia is even more complex, in many ways, than initially anticipated. Identifying specific genetic loci and causative genes for schizophrenia is a huge achievement, yet it is merely the start of a long process towards meaningful biological understanding.
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