Dr. Opler is adjunct assistant professor in the Department of Psychiatry at New York University (NYU) and assistant professor of clinical neuroscience in the Department of Psychiatry at Columbia University in New York City. Dr. Perrin is assistant professor in the Departments of Psychiatry and Environmental Medicine at NYU. Dr. Kleinhaus is a Schizophrenia Research Fellow in the Department of Psychiatry at Columbia University. Dr. Malaspina is professor in and chairman of the Department of Psychiatry at NYU.
Disclosure: Drs. Opler, Perrin, and Kleinhaus report no affiliation with or financial interest in any organization that may pose a conflict of interest. Dr. Malaspina receives grant support from the National Institute of Mental Health.
Please direct all correspondence to: Mark G. A. Opler, PhD, Department of Psychiatry, New York University, 550 1st Avenue, MHB – 3rd Floor, New York, NY 10016; Tel: 646-234-3607; Fax: 646-758-8169; E-mail: firstname.lastname@example.org.
Schizophrenia is a brain disorder with a complex etiology believed to have both genetic and environmental risk factors. Although the precise pathology of the disease and the mechanisms that cause the emergence of symptoms remain elusive, understanding the causes of schizophrenia and its risk factors have evolved considerably over the past decade. The discussion has shifted from the reductionist “genes versus environment” debate to a more integrative approach, ie, the functions of susceptibility genes, epigenetics and paternal age, and toxic exposures throughout early development. This article discusses evidence for three major categories of risk factors, including genetic contributions, the role of paternal age and potential mechanisms by which it exerts its influence on risk, and new findings on the role of environmental exposures.
Conventional wisdom holds that schizophrenia is a disorder of “unknown etiology,” and for many years, almost every review on the subject of causality began with some variation on that theme. However, as the end of the first decade of the 21st century approaches, the picture has begun to change. Several findings have now been confirmed (eg, nutritional deprivation) and a widely replicated risk factor, ie, advanced paternal age, has strongly implicated new mechanisms such as epigenetics. This article discusses current findings on the etiology of schizophrenia and related psychotic disorders. Divided into three sections, this article evaluates genes, particularly the evidence for genetic associations and the function of suspected susceptibility of genes; advanced paternal age and potential mechanisms by which it exerts its influence on pathology; and selected environmental exposures, including chemical exposures and nutritional deprivation during early development.
Twin, Family, and Adoption Studies
At the beginning of the 20th century, it was strongly suspected that some cases of schizophrenia were genetic in origin.1 This supposition was based on numerous twin studies performed in the intervening years that found monozygotic twins consistently had a higher concordance rate for schizophrenia than dizygotic twins.1 Among more recent studies, the concordance rate in monozygotic twins ranges from 44% to 79%, and among dizygotic twins the concordance rate ranges from 4% to 17%.2 Heritability estimates range from 71% to 85%.2
In an analysis of 40 family studies, Gottesman3 found that the grand average risk of being diagnosed with schizophrenia among relatives of cases was 2% for third-degree relatives, 4% to 6% for second-degree relatives, 9% to 13% for children and siblings, and approximately 46% for monozygotic twins. Adoption studies provided further support for a genetic contribution to schizophrenia risk. Adopted offspring of mothers diagnosed with a schizophrenia spectrum disorder (SSD) were at higher risk of SSD than the control adoptees (relative risk 4.67, 95% CI=2.24–9.77, P<.001),4 and there was a higher prevalence of SSD in the biologic relatives of an adoptee with SSD than in the adoptive relatives (14.4% versus 3%, P<.0001).5
Based on twin, family, and adoption studies there is clearly a strong genetic component to the risk of schizophrenia as well as an environmental and probable epigenetic component. Epigenetic processes can cause heritable changes in the genome. Although they do not involve changes in deoxyribonucleic acid (DNA) sequence, they can nonetheless alter gene expression. A common variant or polymorphism in a susceptibility gene may not in and of itself increase the risk of schizophrenia. However, in combination with other polymorphisms in other genes, it may increase the risk for rare variants. Furthermore, the increased risk associated with a particular polymorphism may only be relevant in conjunction with an environmental exposure. In the absence of an environmental exposure the polymorphism may have no effect on risk of schizophrenia.
In addition to polymorphisms, gene copy number and structural changes in chromosomes may play a role in schizophrenia. A recent study by Walsh and colleagues6 looked at rare structural variants through microarray comparative genomic hybridization. This study reported that rare deletions and duplications were significantly more common in schizophrenia cases than controls (15% versus 5%, P=.0008). In cases, rare structural variants were seen more frequently in pathways involving neurodevelopment, including neuregulin signaling, extracellular signal-regulated kinase/mitogen-activated protein kinase signaling, axonal guidance signaling, and glutamate signaling, among others. Further, the microdeletions and or duplications in 11 out of 24 genes were involved in the pathways referred to above. In controls, disrupted genes were not found to be predominantly in neurodevelopmental pathways or any other pathway.
The search for variants in genes detected in linkage studies or most recently through genome-wide scans have detected genes such as neuregulin (NRG1), dysbindin (DTNBP1), and disrupted in schizophrenia (DISC1). Studying these and other genes is a continuing process as is the study of the biologic import of their proteins. NRG1, DTNBP1, and DISC1 have generated a great deal of interest as putative susceptibility genes in schizophrenia.
NRG1, which is located on chromosome 8p, was identified as a potential candidate gene for schizophrenia by a study in Iceland that reported a haplotype on NRG1 was present two times as frequently among cases compared to controls.7 These results were later confirmed in a Scottish study (Table 1).7-14 Expressed isoforms of NRG1 are associated with a multitude of biologic processes, some of which include neuronal migration and specification; neuron-glial signaling; glial development and differentiation; synapse formation; myelination; and regulation of NMDA, γ-aminobutyric acid-A, and nicotinic receptors.15
Many studies,15 but not all, have reported positive findings between different single nucleotide polymorphisms (SNPs) and haplotypes of NRG1 and schizophrenia. A meta-analysis performed in 2006,9 however, reported that though there was no association between the most frequently studied SNP, SNP8NRG221533, there was an association between NRG1 and schizophrenia based on a haplotype analysis. An update study10 published in 2008 found that the previous association between NRG1 and schizophrenia using haplotype analysis was attenuated compared to the 2006 study. Another meta-analysis11 showed an association for four SNPs and two microsatellite markers and risk of schizophrenia, though the results differed somewhat by ethnicity. Haplotype analysis also showed a significant association among Europeans. However, the largest single study to date12 found no link between NRG1, SNPs, and schizophrenia (Table 1).7-14
DTNBP1 is located on chromosome 6p22.3 and its overexpression is linked to increased basal glutamate levels.16 It is believed to be protective of neuronal viability via P13-kinase-Akt signaling.17 In a postmortem brain study, there was 20% to 40% reduction in DTNBP1 messenger ribonucleic acid expression in patients with schizophrenia compared to controls (F=4.69, df=1, 18 P=.04). There was decreased expression in dentate granule cells (t=-1.90, P=.04) and dentate polymorph cells (t= -2.32, P=.02) and in CA3 (t=-1.99, P=.03) but not CA1 (t=-1.33, P>.05) regions of the hippocampus among those with schizophrenia compared to controls.17 It is hypothesized that lower levels of DTNPB1 may alter synaptic connectivity and glutamate signaling,17 possibly impacting the risk of schizophrenia.
Research in healthy individuals suggests that DTNPB1 genotype affects prefrontal brain function18 and general cognitive ability in schizophrenia patients and controls.19 In 11 out of 14 samples there was a significant association between SNPs in DTNPB1 and schizophrenia.20 The results of more recent studies are presented in Table 2.12-14,21-23
A balanced translocation in t1:11 (q43, q21) was found in large Scottish family which occurred in 16/34 members with a psychiatric diagnosis and 5/43 without.24 This translocation results in damaged DISC1 on chromosome 1.23 It has been suggested that DISC1 is a “hub” protein interacting with many different proteins. For example, DISC1 and phosphodiesterase 4B (PDE4B) together regulate cyclic adenosine monophosphate signaling.25 DISC1 and fasciculation and elongation protein 1 are thought to act in concert with one another in axon guidance and outgrowth. In the mouse, DISC1 is developmentally regulated and is particularly associated with peaks prenatally, postnatally, and during puberty. DISC1 interacts with other proteins critical to neurodevelopment25 and has been implicated in centrosomal-based functioning and kinesin-mediated intracellular transport.26 Thus, alterations in DISC1 expression during early development due to events such as SNPs and rare mutations could be one of the factors that increase the risk of schizophrenia years later. Some,27-29 but not all, studies12 have been largely supportive of DISC1 as a susceptibility gene for schizophrenia (Table 3).12-14,27-29
The genetic contribution to schizophrenia is clearly complex and involves more genes than those discussed here. Genome-wide scans are currently ongoing and their results, ie, the genes they identify, are eagerly anticipated. The next step is identifying SNPs and haplotypes in the genes that the genome-wide scans detect and determining their effect on protein product and expression. This will be challenging research as the risk associated with variants in a detected gene may affect the risk associated with variants in other genes in a particular pathway. In addition, copy number and structural changes in genes may also play a role. Complicating the research further is that schizophrenia is a heterogeneous disorder and the pathways to schizophrenia diagnosis likely differ among individuals. Finally, these pathways plausibly include not only genetic but environmental and epigenetic components as well.
There is conclusive evidence that advancing paternal age is associated with an increased risk of schizophrenia. In 2001, Malaspina and colleagues30 published the first analysis of data from a large prospective cohort that showed the strong relationship between paternal age and risk of schizophrenia. It established that the findings were not confounded by maternal age, family history, or other socio-demographic factors such as birth order, social class, and birth weight. Offspring of fathers 45–49 years of age and ≥50 years of age had twice and three times the risk for schizophrenia, respectively, as the children of men <25 years of age.30 The observations in Malaspina and colleagues’ landmark study have been confirmed multiple times in the literature.31-33 Maternal age has not been associated with the risk of schizophrenia after accounting for effects of paternal age.30,32 It was considered whether the link between a father’s age and the risk of schizophrenia was due to psychiatric problems in parents delaying childbearing. Offspring of older fathers would then be more likely to inherit these psychiatric disorders, and paternal age would be only a mediator in the causal pathway to disease. However, effects of paternal age are not attenuated by family history of psychiatric illness.31
Paternal age is associated with other negative reproductive outcomes. Spontaneous abortion, autism, adolescent intelligence quotient, and the need for special education have each been related to paternal age independently of maternal age.34-37 Older men have an increased risk of fathering offspring with achondroplasia, Apert’s syndrome,38 and breast cancer, presenting before the child reaches 40 years of age.39 There is also convincing evidence that as men age they experience a statistically significant decline in fertility, independent of women’s age, coital frequency, and lifestyle effects.40
Genetic and Epigenetic Mechanisms
It is hypothesized that increased rates of genetic mutation in the sperm of older fathers may constitute an underlying mechanism for the link of advancing paternal age with an increased risk of schizophrenia as well as other negative reproductive outcomes.41 Current opinion is that replication errors are a major cause of such mutations as a consequence of the ongoing division of spermatogonial stem cells throughout a man’s reproductive life.42 An increase in point mutations has been linked with advancing paternal age43 as has the number of repeated DNA sequences and the rate of chromosomal breakage.44,45 The 22q11 deletion syndrome is associated with congenital anomalies, neurocognitive deficits, and increased risk of schizophrenia.46,47
Epigenetic changes might also contribute to increased risk.48 Epigenetic processes (eg, DNA methylation) change gene expression without changing gene sequence. In schizophrenia, parental imprinting is thought to be an important epigenetic process.48 In parental imprinting, either the maternal or paternal allele is silenced, leaving the other to be expressed. It is possible that changes in epigenetic regulation of gene expression occur over time in rapidly dividing spermatogonia cells due to either the effects of aging or the cumulative exposure to environmental insults over time in the father.48 Imprinted genes function in the growth of the central nervous system and might increase the risk of schizophrenia through direct effects on the expression of genes related to its pathology.48
The link between paternal age and schizophrenia might also be considered in relation to observations in achondroplasia. Offspring of older fathers have an increased risk of achondroplasia. It is theorized that age-related lesions may have occurred in sperm that disable DNA repair by oocyte components in the newly formed zygote; this disabling of DNA repair then results in disease in offspring.49 The most common mutation observed in sperm of fathers who have offspring with achondroplasia is also the most common mutation following oxidative damage to DNA, and lesions responsible for the initiation of aberrant DNA repair in the oocyte are oxidative in nature.49 Human spermatozoa are capable of generating Reactive Oxygen Species (ROS), and this activity is of physiologic significance in promoting sperm capacitation.50 If the process is disrupted, endogenous ROS generated by human spermatozoa can damage sperm function and DNA integrity.49 It is conceivable that paternal age-related mutations in regulation of ROS in sperm might also contribute to other negative outcomes associated with advanced paternal age.51
Schizophrenia is a disease with a complex genetic background, and environmental factors contribute to risk. Environmental exposures during fetal and childhood development could interact with genetic mutations or changes in epigenetic regulation. While social status does not account for paternal age effect in schizophrenia,30 older fathers may create different home environments during pregnancy or different rearing environments for their children in ways that are not easily measured. These environments could contribute to the increased risk for schizophrenia in the offspring of older fathers.
Paternal age is an important risk factor for schizophrenia in offspring. There is increasing evidence that epigenetic errors as well as gene mutations may contribute substantially to this effect, while gene environment interactions may also be involved in the association.52-54 The mechanisms responsible for its strong association with the risk for schizophrenia warrant further study.
The role of in utero and pre-conceptual exposures in the etiology of schizophrenia has expanded considerably in the past decade. Recent investigations using prospective cohorts identified prior to birth have assessed the impact of known or suspected neurodevelopmental disruptors. Several ascertain prenatal exposure through laboratory measures, eg, analysis of archived maternal biologic samples collected prior to birth. Various hypotheses have been advanced and numerous studies have produced suggestive results.
Maternal Nutritional Deprivation
The role of maternal nutrition has been associated with the risk of schizophrenia. Both lack of specific micronutrients and general nutritional deprivation have been previously implicated as risk factors for broad developmental disruption and for schizophrenia specifically. In one landmark study of prenatal nutritional deprivation known as the Dutch Famine Study,55 neurodevelopmental outcomes following severe caloric restriction were measured. Rates of schizophrenia were approximately doubled for individuals conceived under conditions of nutrient deprivation during early gestation.56 This finding has been re-examined and replicated by St. Clair and colleagues.57
Maternal Body Mass Index
Recently, high maternal body mass index (BMI) has become a focus of concern as the number of women of reproductive age with above average or high BMI has increased in industrialized societies.58 It has been studied in a prospective birth cohort, the Prenatal Determinants of Schizophrenia (PDS) study. The PDS is a cohort of 12,097 pregnancies in California that occurred between 1959 and 1967.59 Over the 40 years of follow up, 71 cases of schizophrenia spectrum disorder were identified by standardized procedures, including in-person diagnostic interviews. The PDS study used measures of prepregnant maternal BMI that were categorized to low (<19.9), average (20.0–26.9), above average (27.0–29.9), and high (≥30.0). As compared with average maternal prepregnant BMI, high BMI was significantly associated with schizophrenia and spectrum disorders in the adult offspring (relative risk=2.9; 95% CI=1.3–6.6).60
Influenza and Markers of Infection
Previous work describing associations between prenatal exposure to a variety of viral agents has been considered for some time and extensively reviewed elsewhere.61-63 Studies by Brown and colleagues64 demonstrate that first trimester exposure to influenza (determined serologically) was associated with a seven-fold increase in risk of schizophrenia spectrum disorder, while second and third trimester exposure showed no increase in risk. Additional analyses examined exposure during the first and second halves of pregnancy defined as 0–142 days (in effect, 40–142 days post-last menstrual period [LMP]) and from 143 days post-LMP until termination of pregnancy, respectively. Exposure in the first half of pregnancy conferred a threefold increase in risk, while no increase was seen following exposure during the second half of pregnancy or when second trimester exposure was considered.64
In-utero Lead Exposure
The first study65 on prenatal lead exposure and schizophrenia was conducted as a case-control study, nested within a prospective birth cohort—the previously mentioned PDS. Maternal serum samples were analyzed for δ-aminolevulinic acid (ALA), which is a biologic marker of Pb exposure using high pressure liquid chromatography with fluorescence detection. Validity studies were conducted and showed that serum δ-ALA levels >9.05 ng/mL were predictive of Pb exposure; δ-ALA levels >9.05 ng/mL were associated with a non-significant increase in risk of schizophrenia (odds ratio=1.54, 95% CI=0.86–2.86). This study provided preliminary evidence that prenatal exposure to Pb may be a risk factor for schizophrenia spectrum disorders in later life, but was restricted by sample size. A second analysis incorporating data from the New England Cohort of the National Collaborative Perinatal Project is consistent with earlier findings and the results will be forthcoming (M Opler, PhD, unpublished data, April 2008).
Parental Tetrachloroethylene Exposure
In an effort to expand research from lead into other parental chemical exposures and schizophrenia, tetrachloroethylene (PCE) exposure was examined. PCE (also referred to as perchloroethylene and tetrachloroethene, or PERC), is a common organic solvent, frequently appearing as a ground water contaminant.66 Dry cleaners are occupationally exposed to PCE since it has been used as a cleaning agent since the 1950s.67
The Jerusalem Perinatal Study of Schizophrenia,30,68,69 is a cohort study of 88,829 individuals born in Jerusalem, Israel, from 1964–1976 and followed to January 1, 1998; at this point, they were 21–33 years of age. Demographic data on parents, including their occupations, were linked to data on schizophrenia in offspring obtained from national registries. Six-hundred thirty-seven offspring were diagnosed with schizophrenia or related conditions. An estimate of the relative risk of schizophrenia in offspring of parents who were dry cleaners was calculated, taking into account confounders such as parental age, social class, duration of marriage, residence (urban or rural), religion, ethnicity, parental immigration status, birth order, sex, birth weight, and month of birth. The cohort available for study included 88,060 offspring, 637 with schizophrenia-related diagnoses, and 144 with one or more parents who were dry cleaners. Of these, four were diagnosed with schizophrenia over the 21–33 years of follow-up. The offspring of dry cleaners had a significantly increased risk of schizophrenia compared to offspring of parents in all other occupations (relative risk 3.4, 95% CI=1.3–9.2). This relationship was unexplained by parental age, social class, duration of marriage, urban versus rural residence, religion, ethnicity, or immigration status, or by the offspring’s birth order, sex, birth weight, and month of birth.
These results suggest that pre-conceptual, prenatal, or childhood exposures to PCE could play a meaningful role in the risk for schizophrenia, particularly in populations with occupational or environmental exposures. Similar to findings on lead exposure described above, the role of paternal exposure cannot be confirmed or refuted on the basis of this study. However, the results provide a further rationale for conducting basic and clinical research studies to investigate parental chemical exposure.
This article illustrates the diverse nature of the findings on the etiology of schizophrenia, including genetic, environmental, and epigenetic. One important question that has yet to be addressed is whether or not these multiple risk factors contribute via a single common pathway that leads to a single disease, or rather, if they act via multiple pathways, causing similar but separate disorders. It has been known for many decades that schizophrenia is highly variable in clinical presentation and in the relative efficacy of treatments across patients. The multiple pathways to schizophrenia that have been reviewed here may be reflected in neurobiologic differences, in the heterogeneous clinical presentation of the disease, and in differential responses to treatment. New research efforts must now be undertaken to determine if the heterogeneity of schizophrenia can be organized in terms of etiology. Communicating research findings between disciplines and incorporating both systematic and serendipitous clinical observations will be crucial as clinicians learn to apply this growing body of knowledge to improving the effectiveness of their treatments and reduce the incidence of new cases worldwide. PP
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