Schizophrenia is a neurodevelopmental disorder with no precise or single cause. Schizophrenia is thought to arise from multiple mechanisms and complex gene–environment interactions with vulnerability factors. Risk factors of schizophrenia have been identified and include genetic factors, environmental factors such as experiences in life and exposures in a person's environment, and also the function of a person's brain as it develops. The interactions of these risk factors are intricate, as numerous and diverse medical insults from conception to adulthood can be involved. Many theories have been proposed including the combination of genetic and environmental factors may lead to deficits in the neural circuits that affect sensory input and cognitive functions.
A genetic predisposition on its own, without superimposed environmental risk factors, is not thought to give rise to schizophrenia. Environmental risk factors are many, and include pregnancy complications, prenatal stress and nutrition, and adverse childhood experiences. An environmental risk factor may act alone or in combination with others.
Schizophrenia typically develops between the ages of 16–30 (generally males aged 16–25 years and females 25–30 years); about 75 percent of people living with the illness developed it in these age-ranges. Childhood schizophrenia (very early onset schizophrenia) develops before the age of 13 years and is quite rare. On average there is a somewhat earlier onset for men than women, with the possible influence of the female sex hormone estrogen being one hypothesis and socio-cultural influences another. Estrogen seems to have a dampening effect on dopamine receptors.
Gene-environment interaction Evidence suggests that it is the interaction between genes and the environment that may be associated with the development of schizophrenia. This is a complex process involving multiple environmental factors that have influence on a range of developmental periods that interact with a genetic susceptibility. It has been suggested that apart from gene-environment interactions, environment-environment interactions also be taken into account as each environmental risk factor on its own is not enough to promote the development of schizophrenia.
A meta-analysis was performed to determine the association between schizophrenia and oxidative DNA damage measured by 8-hydroxy-2'-8-deoxyguanosine (8-OHdG) or 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG). Levels of 8-OHdG and 8-oxodG are widely used as measures of oxidative stress in mental illnesses including schizophrenia. It was determined from this meta-analysis that oxidative DNA damage was significantly increased in schizophrenia.
Genetics Schizophrenia is thought to have a heritable component in some people, but many people who appear to carry schizophrenia-associated genes may not develop the disease. Research has shown that schizophrenia is a polygenic disorder and that genetic vulnerability to schizophrenia is highly multifactorial, caused by the interactions of several genes with environmental risk factors. Twin studies have shown that an identical twin has ~50% risk of also developing the disorder.
Family studies indicate that the closer a person's genetic relatedness to a person with schizophrenia, the greater the likelihood of developing the disorder. Paternal age may be a factor in schizophrenia because of the increased likelihood of mutations in the chromosomes of cells that produce sperm. In contrast, women's oocytes divide twenty-three times before the time of birth. The chance of a copying error in DNA replication during cell division increases with the number of cell divisions, and an increase in copying errors may cause an accumulation of mutations that are responsible for an increased incidence of schizophrenia. The average concordance rates are higher for identical twins than for fraternal twins and evidence also suggests that the prenatal and perinatal environments may also affect concordance rates in identical twins.
Genetic candidates Although twin studies and family studies have indicated a large degree of heritability for schizophrenia, the exact genetic causes remain unclear. However, some large-scale studies have begun to unravel the genetic underpinnings for the disease. Important segregation should be made between lower risk, common variants (identified by candidate studies or genome-wide association studies) and high risk, rare variants (which could be caused by de novo mutations) and copy-number variations (CNVs).
Candidate gene studies A 2003 review of linkage studies also listed seven genes as likely to increase risk for a later diagnosis of the disorder. Two reviews suggested that the evidence was strongest for two genes known as dysbindin (DTNBP1) and neuregulin (NRG1), and that a number of other genes (such as COMT, RGS4, PPP3CC, ZDHHC8, DISC1, and AKT1) showed some early promising results. Knockout studies in Drosophila show that reduced expression of dysbindin reduced glutamatergic synaptic transmission, resulting in impaired memory. Variations near the gene FXYD6 have also been associated with schizophrenia in the UK but not in Japan. In 2008, rs7341475 single nucleotide polymorphism (SNP) of the reelin gene was associated with an increased risk of schizophrenia in women, but not in men. This female-specific association was replicated in several populations. Studies have found evidence that the protein phosphatase 3 known as calcineurin might be involved in susceptibility to schizophrenia.
The largest most comprehensive genetic study of its kind, involving tests of several hundred single-nucleotide polymorphisms (SNPs) in nearly 1,900 individuals with schizophrenia or schizoaffective disorder and 2,000 comparison subjects, reported in 2008 that there was no evidence of any significant association between the disorders and any of 14 previously identified candidate genes (RGS4, DISC1, DTNBP1, STX7, TAAR6, PPP3CC, NRG1, DRD2, HTR2A, DAOA, AKT1, CHRNA7, COMT, and ARVCF). The statistical distributions suggested nothing more than chance variation. The authors concluded that the findings make it unlikely that common SNPs in these genes account for a substantial proportion of the genetic risk for schizophrenia, although small effects could not be ruled out.
The perhaps largest analysis of genetic associations in schizophrenia is with the SzGene database at the Schizophrenia Research Forum. One 2008 meta-analysis examined genetic variants in 16 genes and found nominally significant effects.
A 2009 study was able to create mice matching symptoms of schizophrenia by the deletion of only one gene set, those of the neuregulin post-synaptic receptor. The result showed that although the mice mostly developed normally, on further brain development, glutamate receptors broke down. This theory supports the glutamate hypothesis of schizophrenia. Another study in 2009 by Simon Fraser University researchers identifies a link between autism and schizophrenia: "The SFU group found that variations in four sets of genes are related to both autism and schizophrenia. People normally have two copies of each gene, but in those people with autism some genome locations have only single copies, and in those with schizophrenia extra copies are present at the same locations."
Genome-wide association studies
To increase sample size for a better powered detection of common variants with small effects, data from genome-wide association studies (GWAS) is continuing to be clustered in large international consortia. The Psychiatric Genomics Consortium (PGC) attempts to aggregate GWAS data on schizophrenia to detect associations of common variants with small effect on disease risk.
In 2011, this collaboration identified by meta-analysis of genome-wide association studies that 129 single-nucleotide polymorphism (SNP) significantly associated with schizophrenia were located in major histocompatibility complex region of the genome.
In 2013 this dataset was expanded to identify in total 13 candidate loci for the disease, and also implicated calcium signaling as an important factor in the disease.
In 2014 this collaboration expanded to an even larger meta-analysis, the largest to date, on GWAS data (36,989 cases and 113,075 controls) in Nature, indicating 108 schizophrenia-associated genetic loci, of which 83 have not been previously described. Together, these candidate genes pointed to an importance of neurotransmission and immunology as important factors in the disease.
Distinct symptomatic subtypes of schizophrenia groups showed to have a different pattern of SNP variations, reflecting the heterogeneous nature of the disease.
A 2016 study implicated the C4A gene in schizophrenia risk. C4A was found to play a role in synaptic pruning, and increased C4A expression leads to reduced dendritic spines and a higher schizophrenia risk.
Copy number variations Other research has suggested that a greater than average number of structural variations such as rare deletions or duplications of tiny DNA sequences within genes (known as copy number variations) are linked to increased risk for schizophrenia, especially in "sporadic" cases not linked to family history of schizophrenia, and that the genetic factors and developmental pathways can thus be different in different individuals. A genome wide survey of 3,391 individuals with schizophrenia found CNVs in less than 1% of cases. Within them, deletions in regions related to psychosis were observed, as well as deletions on chromosome 15q13.3 and 1q21.1.
CNVs occur due to non-allelic homologous recombination mediated by low copy repeats (sequentially similar regions). This results in deletions and duplications of dosage sensitive genes. It has been speculated that CNVs underlie a significant proportion of normal human variation, including differences in cognitive, behavioral, and psychological features, and that CNVs in at least three loci can result in increased risk for schizophrenia in a few individuals. One such CNV is found in DiGeorge syndrome, which carries a 25-30% lifetime risk of schizophrenia. Epigenetics may also play a role in schizophrenia, with the expression of Protocadherin 11 X-linked/Protocadherin 11 Y-linked playing a possible role in schizophrenia.
A 2008 investigation of 2,977 schizophrenia patients and 33,746 controls from seven European populations examined CNVs in neurexins, and found that exon-affecting deletions in the NRXN1 gene conferred risk of schizophrenia.
An updated meta-analysis on CNVs for schizophrenia published in 2015 expanded the number of CNVs indicated in the disease, which was also the first genetic evidence for the involvement of GABAergic neurotransmission. This study further supported genetic involvement for excitatory neurotransmission.
Overlap with other disorders Several studies have suggested a genetic overlap and possible genetic correlation between schizophrenia and other psychiatric disorders including autism spectrum disorder, attention deficit hyperactivity disorder, bipolar disorder, and major depressive disorder. One genome-wide association study analyzed single-nucleotide polymorphism (SNP) data for the five disorders; four gene areas overlapped with the five disorders, two of which regulate calcium balance in the brain.
Environment Environmental risk factors include prenatal stress, pregnancy and birth complications, and adverse childhood experiences, among others. Many are associated with prenatal development, prenatal stress and nutrition, pregnancy and childbirth. Later ones include adverse childhood experiences and substance use disorders.
Prenatal development