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: mark.opler@med.nyu.edu.




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


Susceptibility Genes

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.


Parental Age

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.


Environmental Exposures

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



1.    Gottesman II, Shields J. Genetical puzzle pieces: twin studies. In: Gottesman II, Shields J. Schizophrenia: the Epigenetic Puzzle. Cambridge, UK: Press Syndicate of the University of Cambridge; 1982:101-126.
2.    Shih RA, Belmonte PL, Zandi PP. A review of the evidence from family, twin, and adoption studies for a genetic contribution to adult psychiatric disorders. Int Rev Psychiatry. 2004;16(4):260-283.
3.    Gottesman II. Schizophrenia: the Origins of Madness. New York, NY: W.H. Freeman and Company; 1991.
4.    Tienari P, Wynne LC, Läksy K, et al. Genetic boundaries of the schizophrenia spectrum: evidence from the Finnish Adoptive Family Study of Schizophrenia. Am J Psychiatry. 2003;160(9):1587-1594.
5.    Kendler KS, Gruenberg AM, Kinney DK. Independent diagnoses of adoptees and relatives as defined by DSM-III in the provincial and national samples of the Danish Adoption Study of Schizophrenia. Arch Gen Psychiatry. 1994;51(6):456-468.
6.    Walsh T, McClellan JM, McCarthy SE, et al. Rare structural variants disrupt multiple genes in neurodevelopmental pathways in schizophrenia. Science. 2008. In press.
7.    Stefansson H, Sigurdsson E, Steinthorsdottir V, et al. Neuregulin 1 and susceptibility to schizophrenia. Am J Hum Genet. 2002;71(4):877-892.
8.    Stefansson H, Sarginson J, Kong A, et al. Association of neuregulin 1 with schizophrenia confirmed in a Scottish population. Am J Hum Genet. 2003;72(1):83-87.
9.    Munafò MR, Thiselton DL, Clark TG, Flint J. Association of the NRG1 gene and schizophrenia: a meta-analysis. Mol Psychiatry. 2006;11(6):539-546.
10.    Munafo MR, Attwood AS, Flint J. Neuregulin 1 genotype and schizophrenia. Schizophr Bull. 2008;34(1):9-12.
11.    Li D, Collier DA, He L. Meta-analysis shows strong positive association of the neuregulin 1 (NRG1) gene with schizophrenia. Hum Mol Genet. 2006;15(12):1995-2002.
12.    Sanders AR, Duan J, Levinson DF, et al. No significant association of 14 candidate genes with schizophrenia in a large European ancestry sample: implications for psychiatric genetics. Am J Psychiatry. 2008;165(4):497-506.
13.    Suarez BK, Duan J, Sanders AR, et al. Genomewide linkage scan of 409 European-ancestry and African American families with schizophrenia: suggestive evidence of linkage at 8p23.3-p21.2 and 11p13.1-q14.1 in the combined sample. Am J Hum Genet. 2006;78(2):315-333.
14.    Cloninger CR, Kaufmann CA, Faraone SV, et al. Genome-wide search for schizophrenia susceptibility loci: the NIMH Genetics Initiative and Millennium Consortium. Am J Med Genet. 1998;81(4):275-281.
15.    Harrison PJ, Law AJ. Neuregulin 1 and schizophrenia: genetics, gene expression, and neurobiology. Biol Psychiatry. 2006;60(2):132-140.
16.    Numakawa T, Yagasaki Y, Ishimoto T, et al. Evidence of novel neuronal functions of dysbindin, a susceptibility gene for schizophrenia. Hum Mol Genet. 2004;13(21):2699-2708.
17.    Weickert CS, Rothmond DA, Hyde TM, Kleinman JE, Straub RE, et al. Reduced DTNBP1 (dysbindin-1) mRNA in the hippocampal formation of schizophrenia patients. Schizophr Res. 2008;98(1-3):105-110.
18.    Fallgatter AJ, Herrmann MJ, Hohoff C, et al. DTNBP1 (dysbindin) gene variants modulate prefrontal brain function in healthy individuals. Neuropsychopharmacology. 2006;31(9):2002-2010.
19.    Burdick KE, Lencz T, Funke B, et al. Genetic variation in DTNBP1 influences general cognitive ability. Hum Mol Genet. 2006;15(10):1563-1568.
20.    Williams NM, O’Donovan MC, Owen MJ. Is the dysbindin gene (DTNBP1) a susceptibility gene for schizophrenia? Schizophr Bull. 2005;31(4):800-805.
21.    Joo EJ, Lee KY, Jeong SH, Ahn YM, Koo YJ, Kim YS. The dysbindin gene (DTNBP1) and schizophrenia: no support for an association in the Korean population. Neurosci Lett. 2006;407(2):101-106.
22.    Vilella E, Costas J, Sanjuan J, et al. Association of schizophrenia with DTNBP1 but not with DAO, DAOA, NRG1 and RGS4 nor their genetic interaction. J Psychiatr Res. 2007;42(4):278-288.
23.    Millar JK, Christie S, Anderson S, et al. Genomic structure and localisation within a linkage hotspot of Disrupted In Schizophrenia 1, a gene disrupted by a translocation segregating with schizophrenia. Mol Psychiatry. 2001;6(2):173-178.
24.    St Clair D, Blackwood D, Muir W, et al. Association within a family of a balanced autosomal translocation with major mental illness. Lancet. 1990;336(8706):13-16.
25.    Mackie S, Millar JK, Porteous DJ. Role of DISC1 in neural development and schizophrenia. Curr Opin Neurobiol. 2007;17(1):95-102.
26.    Chubb JE, Bradshaw NJ, Soares DC, Porteous DJ, Millar JK. The DISC locus in psychiatric illness. Mol Psychiatry. 2008;13(1):36-64.
27.    Zhang F, Sarginson J, Crombie C, Walker N, St Clair D, Shaw D. Genetic association between schizophrenia and the DISC1 gene in the Scottish population. Am J Med Genet B Neuropsychiatr Genet. 2006;141(2):155-159.
28.    Hodgkinson CA, Goldman D, Jaeger J, et al. Disrupted in schizophrenia 1 (DISC1): association with schizophrenia, schizoaffective disorder, and bipolar disorder. Am J Hum Genet. 2004;75(5):862-872.
29.    Cannon TD, Hennah W, van Erp TG, et al. Association of DISC1/TRAX haplotypes with schizophrenia, reduced prefrontal gray matter, and impaired short- and long-term memory. Arch Gen Psychiatry. 2005;62(11):1205-1213.
30.    Malaspina D, Harlap S, Fennig S, et al. Advancing paternal age and the risk of schizophrenia. Arch Gen Psychiatry. 2001;58(4):361-367.
31.    El-Saadi O, Pedersen CB, McNeil TF, et al. Paternal and maternal age as risk factors for psychosis: findings from Denmark, Sweden, and Australia. Schizophr Res. 2004;67(2-3):227-236.
32.    Byrne M, Agerbo E, Ewald H, Eaton WW, Mortensen PB. Parental age and risk of schizophrenia: a case-control study. Arch Gen Psychiatry. 2003;60(7):673-678.
33.    Dalman C, Allebeck P. Paternal age and schizophrenia: further support for an association. Am J Psychiatry. 2002;159(9):1591-1592.
34.    Kleinhaus K, Perrin M, Friedlander Y, Paltiel O, Malaspina D, Harlap S. Paternal age and spontaneous abortion. Obstet Gynecol. 2006;108(2):369-377.
35.    Reichenberg A, Gross R, Weiser M, et al. Advancing paternal age and autism. Arch Gen Psychiatry. 2006;63(9):1026-1032.
36.    Malaspina D, Reichenberg A, Weiser M, et al. Paternal age and intelligence: implications for age-related genomic changes in male germ cells. Psychiatr Genet. 2005;15(2):117-125.
37.    Mannerkoski MK, Aberg LE, Autti TH, Hoikkala M, Sarna S, Heiskala HJ. Newborns at risk for special education placement: a population-based study. Eur J Paediatr Neurol. 2007;11(4):223-231.
38.    Kuhnert B, Nieschlag E. Reproductive functions of the ageing male. Hum Reprod Update. 2004;10(4):327-339.
39.    Weiss-Salz I, Harlap S, Friedlander Y, et al. Ethnic ancestry and increased paternal age are risk factors for breast cancer before the age of 40 years. Eur J Cancer Prev. 2007;16(6):549-554.
40.    Hassan MA, Killick SR. Effect of male age on fertility: evidence for the decline in male fertility with increasing age. Fertil Steril. 2003;79(suppl 3):1520-1527.
41.    Jung A, Schuppe HC, Schill WB. Are children of older fathers at risk for genetic disorders? Andrologia. 2003;35(4):191-199.
42.    Drake JW, Charlesworth B, Charlesworth D, Crow JF. Rates of spontaneous mutation. Genetics. 1998;148(4):1667-1686.
43.    Crow JF. Spontaneous mutation in man. Mutat Res. 1999;437(1):5-9.
44.    Andreassen R, Lundsted J, Olaisen B. Mutation at minisatellite locus DYF155S1: allele length mutation rate is affected by age of progenitor. Electrophoresis. 2002;23(15):2377-2383.
45.    Singh NP, Muller CH, Berger RE. Effects of age on DNA double-strand breaks and apoptosis in human sperm. Fertil Steril. 2003;80(6):1420-1430.
46.    Weksberg R, et al. Molecular characterization of deletion breakpoints in adults with 22q11 deletion syndrome. Hum Genet. 2007;120(6):837-845.
47.    Liu H, et al. Genetic variation at the 22q11 PRODH2/DGCR6 locus presents an unusual pattern and increases susceptibility to schizophrenia. Proc Natl Acad Sci USA. 2002;99(6):3717-3722.
48.    Perrin MC, Brown AS, Malaspina D. Aberrant epigenetic regulation could explain the relationship of paternal age to schizophrenia. Schizophr Bull. 2007;33(6):1270-1273.
49.    Baker MA, Aitken RJ. Reactive oxygen species in spermatozoa: methods for monitoring and significance for the origins of genetic disease and infertility. Reprod Biol Endocrinol. 2005;3:67.
50.    Rivlin J, Mendel J, Rubinstein S, Etkovitz N, Breitbart H. Role of hydrogen peroxide in sperm capacitation and acrosome reaction. Biol Reprod. 2004;70(2):518-522.
51.    Tarin JJ, Brines J, Cano A. Long-term effects of delayed parenthood. Hum Reprod. 1998;13(9):2371-2376.
52.    Mill J, Tang T, Kaminsky Z, et al. Epigenomic profiling reveals DNA-methylation changes associated with major psychosis. Am J Hum Genet. 2008;82(3):696-711.
53.    Nicodemus KK, Marenco S, Batten AJ, et al. Serious obstetric complications interact with hypoxia-regulated/vascular-expression genes to influence schizophrenia risk. Mol Psychiatry. 2008. In press.
54.    Lambert SM, Masson P, Fisch H. The male biological clock. World J Urol. 2006;24(6):611-617.
55.    Susser E, Hoek HW, Brown A. Neurodevelopmental disorders after prenatal famine: the story of the Dutch Famine Study. Am J Epidemiol. 1998;147(3):213-216.
56.    Susser E, Neugebauer R, Hoek HW, et al. Schizophrenia after prenatal famine. Further evidence. Arch Gen Psychiatry. 1996;53(1):25-31.
57.    St Clair D, Xu M, Wang P, et al. Rates of adult schizophrenia following prenatal exposure to the Chinese famine of 1959-1961. JAMA. 2005;294(5):557-562.
58.    Kuczmarski RJ, Carroll MD, Flegal KM, Troiano RP. Varying body mass index cutoff points to describe overweight prevalence among U.S. adults: NHANES III (1988 to 1994). Obes Res. 1997;5(6):542-548.
59.    Susser ES, Schaefer CA, Brown AS, Begg MD, Wyatt RJ. The design of the prenatal determinants of schizophrenia study. Schizophr Bull. 2000;26(2):257-273.
60.    Schaefer CA, Brown AS, Wyatt RJ, et al. Maternal prepregnant body mass and risk of schizophrenia in adult offspring. Schizophr Bull. 2000;26(2):275-286.
61.    Brown AS. Prenatal infection as a risk factor for schizophrenia. Schizophr Bull. 2006;32(2):200-202.
62.    Crow TJ. Maternal viral infection hypothesis. Br J Psychiatry. 1992;161:570-572.
63.    Cannon M, Clarke MC. Risk for schizophrenia–broadening the concepts, pushing back the boundaries. Schizophr Res. 2005;79(1):5-13.
64.    Brown AS, Begg MD, Gravenstein S, et al. Serologic evidence of prenatal influenza in the etiology of schizophrenia. Arch Gen Psychiatry. 2004;61(8):774-780.
65.    Opler MGA, Brown AS, Graziano J, et al. Prenatal lead exposure, delta-aminolevulinic acid, and schizophrenia. Environ Health Perspect. 2004;112(5):548-552.
66.    Agency for Toxic Substances and Disease Registry  (ATSDR). Toxicological Profile for Tetrachloroethylene (PERC). Atlanta, GA: U.S. Department of Health and Human Services, Public Health Service; 1997.
67.    Mundt KA, Birk T, Burch MT. Critical review of the epidemiological literature on occupational exposure to perchloroethylene and cancer. Int Arch Occup Environ Health. 2003;76(7):473-491.
68.    Harlap S, Davies AM, Grover NB, Prywes R. The Jerusalem perinatal study: the first decade 1964-1973. Isr J Med Sci. 1977;13(11):1073-1091.
69.    Paltiel O, Friedlander Y, Tiram E, Barchana M, Xue X, Harlap S. Cancer after pre-eclampsia: follow up of the Jerusalem perinatal study cohort. BMJ. 2004;328(7445):919.