Paternal Factors and Schizophrenia Risk: De Novo Mutations and Imprinting

by Dolores Malaspina Downloaded from https://academic.oup.com/schizophreniabulletin/article/27/3/379/1835092 by guest on 23 September 2021

Abstract (Impagnatiello et al. 1998; Kao et al. 1998), but there is no consensus that any particular gene plays a meaning- There is a strong genetic component for schizophrenia ful role in the etiology of schizophrenia (Hyman 2000). risk, but it is unclear how the illness is maintained in Some of the obstacles in genetic research in schiz- the population given the significantly reduced fertility ophrenia are those of any complex disorder, and include of those with the disorder. One possibility is that new incomplete penetrance, polygenic interaction (epista- mutations occur in schizophrenia vulnerability genes. sis), diagnostic instability, and variable expressivity. If so, then those with schizophrenia may have older Schizophrenia also does not show a clear Mendelian fathers, because advancing paternal age is the major inheritance pattern, although segregation analyses have source of new mutations in humans. This review variably supported dominant, recessive, additive, sex- describes several neurodevelopmental disorders that linked, and oligogenic inheritance (Book 1953; Slater have been associated with de novo mutations in the 1958; Garrone 1962; Elston and Campbell 1970; Slater paternal germ line and reviews data linking increased and Cowie 1971; Karlsson 1972; Stewart et al. 1980; schizophrenia risk with older fathers. Several genetic Risch 1990a, 1990fc; reviewed by Kendler and Diehl mechanisms that could explain this association are 1993). Furthermore, both nonallelic (Kaufmann et al. proposed, including paternal germ line mutations, 1998) and etiologic heterogeneity (Malaspina et al. trinucleotide repeat expansions, and alterations in 1999, 2000; Tsuang 2000) are likely for schizophrenia, genetic imprinting in one or several genes involved in with various exposures and gene-environment interac- neurodevelopment. Animal models may be useful in tions presumed to result in a common phenotype. exploring these and other explanations for the pater- Another part of the genetic puzzle of schizophrenia nal age effect and they may provide a novel approach is how the disorder is maintained in the population for gene identification. Finally, it is proposed that envi- despite the reproductive disadvantage of affected indi- ronmental exposures of the father, as well as those of viduals (Fananas et al. 1995; McGrath et al. 1999). One the mother and developing fetus, may be relevant to way to explain its persistence would be if schizophrenia the etiology of schizophrenia. genes were constantly being replenished through new Keywords: Development, signaling, schizophrenia, mutations. genetics, teratogenesis, neuronal circuits. Schizophrenia Bulletin, 27(3):379-393,2001. New Mutations

It was more than a century ago that Kraepelin (1899) first In addition to sustaining schizophrenia in the popula- observed the hereditary nature of schizophrenia vulnera- tion, de novo mutations could account for some of the bility, which has now been confirmed by scores of family, inconsistencies in segregation and linkage studies. New twin, and adoption studies. But now, well into the dawn of mutations might also explain why there is a greater the molecular genetic revolution, and despite the over- recurrence risk for schizophrenia in the children and whelming evidence that schizophrenia is a genetic disor- siblings of schizophrenia probands (-10%) than in their der, the nature of the underlying genetic diathesis remains parents (-5%) (Gottesman 1991). As early as the 1950s, unclear. Genetic linkage and association studies have pro- duced several interesting leads (Berrettini 2000; Pulver Send reprint requests to Dr. D. Malaspina, New York State Psychiatric 2000) and scientists have demonstrated that particular Institute, 1051 Riverside Drive, New York, NY 10032; e-mail: gene disruptions can alter neurodevelopment [email protected].

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both Book (1953) and Lewis (1958) suggested a role for either maternal or paternal age (Martin et al. 1995). It has new mutations in the etiology of schizophrenia, but the long been known that a few autosomal dominant diseases idea was discounted because human mutation rates were are related to paternal age, but recent findings show that it considered to be too low to account for the prevalence of is related to some complex genetic disorders as well, schizophrenia (Huxley et al. 1964; Penrose 1968). To the including prostate cancer (Zhang et al. 1999), nervous contrary, recent data show that mutations are common in system cancer (Hemminiki et al. 1999), and several birth humans; we may acquire 100 mutations per individual per defects (Macintosh et al. 1995). generation, including several deleterious mutations, one or two of which may persist in the gene pool (Crow 1999; New Mutations and Neurodevelopment. There has Downloaded from https://academic.oup.com/schizophreniabulletin/article/27/3/379/1835092 by guest on 23 September 2021 Eyre-Walker et al. 1999). The noted geneticist, James F. been a recent surge in the discovery of genes that are criti- Crow, has written extensively on the nature and outcome cal for brain development, many of which have been iden- of human mutations and has proposed that a high sponta- tified from specific mutations that cause pediatric neuro- neous mutation rate could present a genetic risk for the logical disorders (Tanaka and Gleeson 2000). De novo future human population (Crow 1997, 1999). mutations arise in a number of these genes in proportion to paternal age, including those that cause several of the craniosynostosis syndromes. These syndromes are among New Mutations and Human Genetic the most common causes of craniofacial anomalies (Hehr Disease and Muenke 1999; Singer et al. 1999), and they may be particularly pertinent to schizophrenia. Waddington et al. Association With Paternal Age. The major source of (1999), for example, has highlighted in utero cranial facial new mutations in human populations is from advancing dysmorphogenesis as an important element in the paternal age (see Crow 1999). Weinberg (1912) had sug- etiopathology of schizophrenia. Many craniosynostosis gested that aging parental germ cells may be prone to syndromes arise from mutations in the fibroblast growth mutation after observing that achondroplasia was more factor receptor gene pathways (Schell et al. 1995; Vajo et common in last-born siblings. In 1955, Penrose demon- al. 2000). These syndromes commonly include midfacial strated that later paternal age, but not maternal age, was hypoplasia, prognathism, and a high-arched palate as well predictive of de novo mutations. He proposed that muta- as developmental delay, mental retardation, and hydro- tions arose by DNA copy errors that accumulate over the cephalus. These disorders can present a widely variable many replication cycles that occur in the male germ line. phenotype, even within families, consistent with epistasis Spermatogonial cells replicate every 16 days, approximat- or other modifying in utero exposures. Several of these ing 200 divisions by age 20, and 660 by age 40 (see syndromes are described in table 1. Drake et al. 1998). By contrast, oocytes undergo only 24 Other sporadic neurodevelopmental disorders arising cell divisions, of which all but the last occur before a from de novo mutations include the Klippel-Trenaunay- woman's birth. In addition, as men age, mutations may Weber syndrome (Lorda-Sanchez et al. 1998), which increase because spermatogenesis occurs in the presence includes hemimegalencephaly or holoprosencephaly of declining testosterone, lower levels of DNA proofread- (Odent et al. 1998), and results from a developmental ing and repair enzymes (Tarin et al. 1998), and reduced defect causing forebrain cleavage failure. Another example antioxidant enzyme activity, along with the limitations in is the CHARGE syndrome (Tellier et al. 1998), which vascular supply and reduced cellular efficiency that includes central nervous system malformations and mental accompany aging in other tissues. New genetic diseases retardation and is attributed to a polytopic developmental arising from mutations are likely to minimally affect 1 of field defect of the neural tube and the neural crest cells. every 200 offspring of men older than 40 years (Friedman Achondroplasia can similarly include craniosynostosis and 1981). nonprogressive ventricular dilation consistent with arrested Although a correlation between disease risk and hydrocephalus, as well as corpus callosum hypoplasia paternal age suggests a role for de novo mutations, a (Rousseau et al. 1994; Tolarova et al. 1997; Thompson et paternal origin of the new mutations can only be con- al. 1999). Idiopathic torsion dystonia (Fletcher et al. 1990), firmed with molecular methods if disease loci are known. mental retardation of unknown etiology (Zhang et al. The mutations most clearly associated with paternal aging 1992), and Alzheimer's disease (Whalley et al. 1995; are those involving substitutions at a single base (Crow Bertram et al. 1998) are among the other conditions related 1997), whereas small deletions and inversions are more to paternal age and neurodevelopment, as are the conditions often inherited from the mother (Sapienza 1996) and are described in table 2. Of interest with respect to schizophre- independent of maternal age. Other de novo rearrange- nia are some cases of cerebral palsy—previously consid- ments of chromosomes, such as translocations, large ered to result from birth asphyxia—that are related to pater- inversions, or aneuploidies, may be variably related to nal age and gene mutations (Fletcher et al. 1996).

380 Table 1. Some craniosvnostoses associated with de novo mutations in fibroblast qrowth factor receptor qenes 2P Syndrome Nervous System Phenotype Genotype n EL Apert Syndrome Developmental disorder including craniosynostosis, with 10q25-q26. One of two substitutions, both C-»G (Moloney et al. 1996; displacement of the frontal and parietal bone centers, in the fibroblast growth factor receptor 2 gene Tolarovaetal.1997; midfacial hypoplasia, facial asymmetry, depressed nasal (FGFR2) > 98% de novo in association with Yu et al. 2000) ridge, and mental retardation. Can include hydrocephalus paternal age. Approximately 5% of craniosynostoses. and hearing difficulties. to o Pfeiffer Syndrome Type 1 is an autosomal dominant condition including 8p11.2,10q25-26. Mutation of FGFR2 or (Plompetal. 1998; craniofacial abnormalities, coronal craniostosis, and FGFR1 genes. Approximately 70% of cases I Robin et al. 1998; midface hypoplasia. Type 2 (always de novo) includes a are sporadic. Glaser et al. 2000) cloverleaf skull, deafness, and midface hypoplasia. Severe cases have significant cognitive impairment. 5 Crouzon Syndrome Includes craniosynostosis, hypertelorism, midface hypoplasia, 10q24 heterogeneous FGFR2 mutations. Birth (Glaser et al. 2000; and exophthalmos. Premature closure of some cranial sutures prevalence is 16/million with approximately Yuetal. 2000) affects brain growth. Includes cognitive difficulties and retardation. 30%-60% of cases from de novo events. Thanatophoric Dysplasia Characterized by multiple severe bone abnormalities. Includes All cases are de novo and often do not survive. (Orioli etal. 1995; prominent forehead, hypertelorism, depressed nasal bridge, Result from missense mutations in the FGFR3. Yu et al. 2000) and a cloverleaf skull. Surviving cases show dramatic growth failure, hydrocephalus, and severe developmental delay.

Table 2. Some neurodevelopmentai conditions associated with de novo mutations and paternal aqe Disease Nervous System Phenotype Genotype Nonsyndromic Developmental failure of forebrain cleavage. Brain malformations 2p21, 7q36,18p11-3, 21q22-3. Sonic Holoprosencephaly are typically associated with facial anomalies ranging from hedgehog is the disease-causing gene. (Odent et al. 1998) cyclopia to hypotelorism. Approximately 70% of cases arise de novo. Pelizaeus-Merzbacher Disease Developmental myelination defect. Includes decreased mature Xq21-q22. Proteolipoprotein (PLP) gene (Mimault et al. 1999) oligodendrocytes, severe hypotonia, and nystagmus. Pro- duplication. Affects the major myelin proteins gressive spastic paraplegia and abnormal movements develop. and PLP and its isoform, DM20. De novo Impaired early motor development; intellect is generally less duplications arise in the maternal grandfather, affected. but point mutations occur in both parents. Neurofibromatosis type 1 Developmental disorder of muscles, bones, 17q11.2. Half of the patients inherit the disease 1 (Evans etal. 1992; skin (cafe au lait spots) and multiple tumors from a parent, but 50% of cases are from a de i North 1993; Bunin in the central and peripheral nervous system. novo mutation, and more than 90% of these 5' etal. 1997; Also can include delayed developmental milestones, mutations occur in the paternal germ line. Co Yin et al. 2000) learning disability, attention deficit disorder, and deficits in visual-motor coordination and language. <§= Retinoblastoma Retinal cancer from the loss of a pair of tumor-suppressor 13q14 deletion. Typically de novo, more than (Der Kinderen et al. 1990; genes. It can include a variable degree of mental retardation. 80% arise in the paternal germ line. Z Dryja etal. 1997) Approximately 90% penetrance. p Cerebral palsy (CP) Aberrant control of movement or posture arising from cortical 9p12-q12, also X-linked and recessive types y (Fletcher etal. 1992; migration abnormality or hypoxia-ischemia. Intellectual, vision, possible.

McHale et al. 2000) and speech impairments possible. Downloaded from https://academic.oup.com/schizophreniabulletin/article/27/3/379/1835092 by guest on 23 September 2021 September 23 on guest by https://academic.oup.com/schizophreniabulletin/article/27/3/379/1835092 from Downloaded Schizophrenia Bulletin, Vol. 27, No. 3, 2001 D. Malaspina

Paternal Age and Risk for Schizophrenia. If schizo- ment of the patients. The ideal study design for examin- phrenia could be caused by de novo mutations, then it ing parental birth ages and schizophrenia risk is a should also be associated with paternal age. Indeed there prospective birth cohort study, in which an entire popula- were early reports of advanced paternal age in schizophre- tion of affected and unaffected individuals is identified nia, including those of Johanson (1958), Gregory (1959), before illness onset; however, given the relative rareness Farina (1963), Schooler (1964), and Bojanovsky and of schizophrenia in the population and the decades-long Gerylovova (1967), although Granville-Grossman (1966) duration between birth and disease onset, it is necessary found no differences between patients and their siblings. to have a large population size, long study duration, and An association with advanced maternal birth age is also careful sociodemographic assessments to address this Downloaded from https://academic.oup.com/schizophreniabulletin/article/27/3/379/1835092 by guest on 23 September 2021 reported (Shur 1982; Halmo et al. 1992), but analyses that question. A recent study by Malaspina et al. (in press) also included paternal age data found that they accounted met these requirements, examining the association of for the maternal age effects (Hare and Moran 1979; schizophrenia and parental age in an 89,722-member Kinnell 1983). Bertranpetit and Fananas (1983) critiqued population birth cohort. This analysis revealed a robust these latter two studies for failing to use appropriate case- association of paternal age and schizophrenia risk, with control methods, particularly for lack of stratification of each decade of the father's age further multiplying the the control population. They found no significant parental relative risk for schizophrenia by approximately 50 per- age differences between patients and controls using cent in controlled analyses, and no corresponding effect (unspecified) sociodemographic variables to select the of maternal age (figure 1). An association of an increas- controls. In general, the data showing later paternal age in ing schizophrenia risk with advancing paternal age was schizophrenia received little attention. Although similar subsequently replicated in a second birth cohort by contemporaneous findings in other medical conditions Brown et al. (submitted). implicated a role for de novo mutations in disease etiol- ogy, such results in schizophrenia were considered to be Figure 1. An estimated relationship between artifacts of methodological errors or, if valid, as resulting paternal age and schizophrenia risk from delayed marriage and childbearing by psychiatri- cally vulnerable parents or other confounds. Late birth order, which could be a proxy for advancing paternal age, has also been described in schizophrenia. This finding prompted speculation about factors that might augment schizophrenia vulnerability, although a genetic explanation for the association was excluded. Schooler (1964) and others presumed that genes affecting schizophrenia risk would have an equal chance of distribution to those in each birth rank. Instead they presumed that the birth order effect resulted from environmental causes, ranging from intrauterine fatigue to economic factors, although a psy- chological explanation centering on the mother-child relationship unfortunately became the prevailing Rsq - 0.9268 10 20 30 40 50 60 hypothesis several decades ago (Neill 1990; Hartwell 1996). The basis for this largely nonmedical approach paternal age (years) to etiopathology was related to the perception that schizophrenia was more of a functional disorder than an It can be argued that the relationship between pater- organic illness. More recently, Sham et al. (1993) nal age and schizophrenia risk is an artifact of delayed reported a significantly increased risk of schizophrenia parental childbearing, perhaps because of social inadequa- among subjects who had several older siblings. They cies in psychiatrically vulnerable parents. However, if considered this late birth order effect to be the conse- parental psychiatric vulnerability delays childbearing, quence of maternal viral infections, which were trans- then paternal age should be later in familial schizophrenia mitted to the pregnant mother by her older school-aged cases than in sporadic cases. This possibility was exam- children. ined in a series of schizophrenia research patients The major methodological limitation of these studies (Malaspina et al., submitted) that showed, to the contrary, was the choice of the appropriate comparison groups, that paternal age was significantly older for the sporadic considering the many biases inherent in the ascertain- cases. Taken together, these findings are consistent with a

382 Paternal Factors and Schizophrenia Risk Schizophrenia Bulletin, Vol. 27, No. 3, 2001 significant role for new mutations in schizophrenia vul- fathers in whom the mutation arose would be unaffected nerability. and the mutated gene would be absent from their somatic cells, further confounding genetic studies that did not allow for this possibility in allele sharing and linkage Genetic Mechanisms That Could studies. Associate Schizophrenia With Advancing Paternal Age Mutations May Occur in Any One of a Number of

There are several potential scenarios whereby mutational Genes Involved in Neurodevelopment. Thousands of Downloaded from https://academic.oup.com/schizophreniabulletin/article/27/3/379/1835092 by guest on 23 September 2021 events might increase schizophrenia vulnerability. These genes are estimated to play a role in neurodevelopment; mechanisms include mutations in either a single major therefore, it is possible that mutations in many genes schizophrenia gene or in any of several genes involved in could cause schizophrenia as a final common pheno- neurodevelopment, such as point mutations, trinucleotide type. Mutations arising in the male germ line would be repeat expansions, or by impairments in epigenetic modi- amplified in clones of spermatozoa over the repeated fications in imprinted genes. cell divisions that occur with paternal aging. Although a full discussion of the agents that augment mutations in A Mutation "Hot Spot" in a Schizophrenia Gene. spermatogenesis is beyond the scope of this article, it is Because the type of new mutation that most frequently worth mentioning that they are, by and large, the same arises in the paternal gametes is a single base pair change, ones that induce mutations in somatic cells, including it is possible that a mutation, which enhances schizophre- DNA repair enzyme insufficiency, free radicals, oxida- nia risk, occurs in a specific "schizophrenia gene." This is tive damage, radiation, nutritional deficiency, the case in achondroplastic dwarfism (Tolarova et al. chemotherapy, and high temperature (Cummins et al. 1997; Wilkin et al. 1998), where more than 90 percent of 1994; Robbins 1996; see Cohen 1986). Cigarette smok- the cases are sporadic and, in more than 97 percent of ing has also been linked to genetic damage in spermato- people afflicted, the de novo mutation occurs at a "hot zoa, and free radical-induced mutations are theorized to spot" in a single codon leading to a missense mutation in be a common cause of male infertility; both of these the fibroblast growth factor 3 gene (Orioli et al. 1995; Yu exposures have been implicated in the etiology of child- et al. 2000). hood cancer (Aitken 1999; Shen and Ong 2000; Zenzes Such de novo mutations for schizophrenia would 2000). need to occur in a dominant or partially dominant gene if Despite the high fidelity of DNA replication, a inheritance of a single mutated allele confers an increased small number of new mutations are generated at every risk for the disease. Autosomal dominant models for cell division and are fixed by repair enzymes. The schizophrenia have been supported by some early segre- amount of new mutations tolerated by an organism is a gation analyses. Book (1953) was able to account for the trade-off between the cellular energy expenditures by observed frequencies of schizophrenia in a geographical DNA proofreading and repair and the loss of offspring isolate with a dominant gene (with gene frequency 0.07) viability from mutations. Because most mutations having a homozygous penetrance of 100 percent and a decrease fitness, evolution will sustain genomes with limited heterozygous penetrance (20%). Similarly, Slater efficient DNA repair enzymes. However, there has (1958) and Slater and Cowie (1971) reanalyzed the earlier likely been little evolutionary pressure to maintain high family data collected by Kallmann and by Zerbin-Rudin DNA replication accuracy in older men (Drake et al. and found fair agreement for a partially dominant gene 1998). Of note, the offspring of very young fathers also with frequency 0.015 and a heterozygous penetrance of have an elevated risk for de novo genetic disorders, 26 percent; Gregory (1960) obtained similar results. which may result from the immaturity of spermatids or Overall, dominant gene models were largely discounted from low activity of DNA repair or antioxidant because the reduced fertility of schizophrenia patients enzymes. This leads to a "U-shaped curve" for paternal would select against a dominant gene. But if a dominant age and the offspring's risk for several genetic condi- gene is being continually introduced into the population tions, including type 1 diabetes mellitus (Tai et al. through new mutations, then its prevalence will not be 1998), cardiac ventricular and atrial septal deficits dependent on reproductive fitness. Such a major locus (Olshan et al. 1994), and neural tube defects (Mclntosh may have been undetected in genetic studies if those with et al. 1995). the de novo mutation have an even lower fecundity than other schizophrenia probands. Then they would appear to Trinucleotide Repeat Expansions. Increased schizo- have a sporadic (environmentally induced) disorder. The phrenia risk could also be a consequence of progressive

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DNA trinucleotide expansions in one or several genes that maternally expressed genes. Genes are silenced by DNA participate in neurodevelopment. This effect would be methylation—which may preclude transcription factor more marked as paternal age advances because the possi- binding—and by alterations in chromatin structure. The bility for further trinucleotide expansion occurs at each inherited methylation pattern is maintained in somatic cell DNA replication. This molecular mechanism, discovered divisions, but is erased in the primordial germ cells and by Richards and Sutherland in 1992, underlies the clinical reestablished late in gametogenesis. The monoallelic pat- phenomenon of anticipation, which is the greater risk of tern of gene expression is maintained in offspring of the illness or increasing disease severity in subsequent gener- same sex and is reversed when genes are transmitted

ations. Repeat expansions have been demonstrated in a through individuals of the opposite sex. Imprinted genes Downloaded from https://academic.oup.com/schizophreniabulletin/article/27/3/379/1835092 by guest on 23 September 2021 number of neuropsychiatric disorders, including myotonic do not conform to Mendelian principles because only one dystrophy, fragile X syndrome, spinocerebellar ataxias allele from the prior generation is expressed, even though (Takano et al. 1996), and Huntington's disease (Orr 1994). an equivalent amount of genetic material, other than sex The sex of the transmitting parent is frequently a major chromosomes, is inherited from both parents. factor influencing anticipation (Telenius et al. 1993), with Paternal age-related factors might have a detrimental many disorders showing greater trinucleotide repeat effect on genetic imprinting because paternal genes are expansion with paternal inheritance (Wellington et al. imprinted during spermatogenesis. Environmental expo- 1997). For example, early-onset Huntington's disease is sures, in addition to genetic mechanisms, can cause epige- usually inherited paternally and offspring have a signifi- netic changes in imprinted genes (Jirtle et al. 2000), and cantly younger age of illness onset than their father spermatozoan DNA may be especially susceptible to nox- (Ridley et al. 1988). The DNA in individual spermatozoa ious exposures because of the ongoing replication during of an affected individual shows high variability in spermatogenesis and the unstable nature of genetic Huntington trinucleotide repeat lengths (MacDonald imprinting. Many of the mutations associated with 1993; Leeflang 1999), suggesting that repeat expansions advancing paternal age are at CpG nucleotides, which are could be related to chance molecular events during the methylation sites (Sapienza 1994) consistent with many cell divisions that occur during spermatogenesis. imprinted gene involvement. For schizophrenia, too, the onset appears to be earlier Although our understanding of genetic imprinting is in successive generations of multiply affected pedigrees, nascent, there are several characteristics of imprinted genes consistent with anticipation (Gorwood et al. 1995; that make them reasonable candidates for schizophrenia Petronis and Kennedy 1995; Heiden et al. 1999) or possi- vulnerability. First, imprinted genes play a key role in brain bly resulting from biases in methodology and ascertain- development, leading to lasting changes in cognition and ment. Clinically, anticipation has reported to be stronger behavior (Keveme et al. 1996; Isles and Wilkinson 2000). for paternal than for maternal transmission of schizophre- Paternal and maternal genes both are necessary for embryo- nia in some (Gorwood et al. 1997; Johnson et al. 1997; genesis (Surani et al. 1990), playing greater parts, respec- Husted et al. 1998), but not all, studies (Imamura et al. tively, in placental and embryo development (Kato et al. 1998). Furthermore, Mclnnis et al. (1999) reported the 1999). The influence of paternal genes in the placenta may presence of anticipation for aunt:niece/nephew pairs, but represent a mechanism for the father to ensure that his off- not for uncle:niece/nephew pairs. Parent of origin effects spring derive adequate resources from the maternal in utero are consistent with both anticipation and with genetic environment, even if it may be in the best interest of the imprinting (see following). mother to limit these resources (Iwasa 1998). Only some studies have found longer trinucleotide Second, there appears to be a neuroanatomic localiza- repeats in schizophrenia patients (Morris et al. 1995; tion pattern for the expression of certain imprinted genes O'Donovan et al. 1996; Bowen et al. 2000). It is further in mice that the paternal or maternal allele expression pat- unclear which genes have these expansions and whether terns correspond, respectively, to limbic and neocortical such genes play a meaningful role in the pathogenesis of regions (Allen et al. 1995; Keverne et al. 1996). The con- schizophrenia (O'Donovan and Owen 1999; Vincent et al. ceptualization of schizophrenia symptoms as deriving 2000). from an imbalance or modulatory disturbance between these regions (Weinberger et al. 1992) might be pertinent to these expression differences. In addition, genes for sev- Impairments in Imprinting. Imprinting is a form of eral neurotransmitters implicated in schizophrenia may be gene regulation in which gene expression depends on imprinted, including those for the serotonin 2A receptor, whether the allele was inherited from the male or female the dopamine 3 receptor, and several GABA A receptors parent in the prior generation. Imprinted genes that are (Meguro et al. 1997; Petronis 2000). only expressed if paternally inherited are reciprocally Third, imprinted genes and schizophrenia are both silenced at the maternal allele, and the contrary is true for associated with language development and social func-

384 Paternal Factors and Schizophrenia Risk Schizophrenia Bulletin, Vol. 27, No. 3, 2001 tioning. A role for imprinted genes in determining lan- mother (both before and during the pregnancy) and the in guage and social capacity was shown in an elegant set of utero environment, as well as on the developing fetus and studies by Skuse et al. (1997) in patients with Turner syn- neonate. drome, a sporadic female disorder in which all or part of either the maternal or paternal X chromosome is missing. Paternal Occupation. Recent data suggest that environ- Turner syndrome females who inherited their father's X mental exposures of the male parent could also be perti- chromosome had relatively better social adjustment, supe- nent to schizophrenia risk. Paternal exposures have rior verbal skills, and higher executive functioning than already been related to several congenital conditions, typi- those who had inherited the maternal X chromosome, cally by using occupation to index probable environmen- Downloaded from https://academic.oup.com/schizophreniabulletin/article/27/3/379/1835092 by guest on 23 September 2021 who, in turn, had relatively better spatial skills. Bishop et tal factors. Olshan et al. (1991) found that paternal occu- al. (2000) suggests that imprinted X chromosome genes pations in forestry and logging, printing, and janitorial influence the neurodevelopment of the brain lateralization service were related to birth defects, the latter two occu- observable for different neuropsychological tasks. The pations being associated with central nervous system sexual dimorphism in the expression of schizophrenia, anomalies. An elevated risk of Wilms tumor has been with males showing an earlier onset, more severe course, demonstrated in offspring whose fathers were auto and a greater disability, could also involve imprinting of mechanics, automobile body repairmen, and welders in the X chromosome. Human sexual dimorphisms may be the preconception period (Olshan et al. 1990). partially determined by imprinted genes on the X chromo- Occupational hydrocarbon exposure is elevated among some, according to Skuse (1999). Only normal female fathers of Prader-Willi syndrome patients (Cassidy et al. offspring receive a paternal X chromosome and normal 1989) and Blatter (1991) showed that spina bifida was male offspring only receive a maternal X chromosome. related to paternal exposures to welding fumes, UV radia- Because the paternal X chromosome genes are associated tion, cleaning agents, and high levels of pesticides, but not with superior social communication skills, their absence with organic solvent exposures. Whalley et al. (1995) in male offspring may account for their increased vulnera- found that both paternal age and occupation as a coal bility for developmental disorders involving social behav- miner made significant contributions to the risk for ior and language, such as schizophrenia. Alzheimer's disease. Finally, parent of origin effects have been linked with several other neuropsychiatric disorders, including autism Season of Birth Effects. There is a well-documented (Cook et al. 1997; Schroer et al. 1998), bipolar affective excess of winter and early spring births for those with disorder (McMahon et al. 1995), epilepsy (Gurrieri et al. schizophrenia—on the order of 8 to 10 percent (Torrey et 1999), and Tourette syndrome (Lichter et al. 1995; Eapen al. 1977; Bradbury and Miller 1985)—that may preferen- et al. 1997). In schizophrenia, parent of origin effects tially comprise sporadic patients (O'Callaghan et al. include greater negative symptoms, a worse course, and 1991). These data suggest that some seasonally varying greater sibling concordance in those who have inherited factor bearing a relationship to the time of birth may influ- schizophrenia paternally (Crow 1989; Asherson et al. ence the subsequent development of schizophrenia. 1994; Ohara et al. 1997). Schizophrenia has also shown Infections are often seasonably variable, and there are genetic linkage to chromosome 15ql3-ql4 (Freedman good data that maternal infections are related to schizo- 1997), a region near many imprinted genes, including phrenia vulnerability (Mednick et al. 1988; Adams et al. those for Angelman and Prader-Willi syndromes (Mann 1993; McGrath and Castle 1995; Takei et al. 1996). and Bautolomei 1999). Moreover, Prader-Willi syndrome, However other environmental factors are also season- in which the paternal gene is deleted, is frequently charac- ally variable, including ambient temperature in many cli- terized by a schizophrenia-like psychosis (Clarke 1998). mates. Because heat increases exposure of spermatozoa to mutagenic metabolites (Setchell 1998), a physiological adaptation to high temperatures is necessary. The scrotal Male Germline Mutations May location of the testes and the countercurrent heat Participate in Other Risk Pathways for exchange between the spermatic artery and vein keep the Schizophrenia testicular temperature 4 to 7 degrees cooler than the rest of the body. Heat exposure in the period before concep- It is anticipated that vulnerability genes may be inherited tion could theoretically increase de novo mutations or from either parent, but little consideration has been given alter the epigenetic modification of imprinted genes, par- to the influence of paternal health on schizophrenia risk, ticularly because late spermatids and mature spermatozoa other than for a few postnatal psychosocial variables. do not have repair enzymes (Tarin et al. 1998). The effects Studies of deleterious exposures have centered on the of elevated external temperature on sperm may persist for

385 Schizophrenia Bulletin, Vol. 27, No. 3, 2001 D. Malaspina

3 months after exposure (Rachootin and Olsen 1983). postpubescent fathers or older fathers have less sponta- Somewhat akin to this idea, T. Crow (1987) previously neous activity and worse learning capacity than offspring theorized that heat-related mutagenesis during the warmer of mature fathers, leading to a U-shaped curve for learn- summer months could affect "an integrated virogene" in ing and paternal age (Auroux et al. 1998; 1999). spermatozoa that might account for the winter-spring birth Although spontaneous mutation rates in mice and excess in schizophrenia. humans are not comparable (Sankaranarayanan et al. 1998) and the genes that are involved in rodent cognition Birth Events. Adverse birth events and hypoxia are con- may be dissimilar to any human genes involved in schiz- Downloaded from https://academic.oup.com/schizophreniabulletin/article/27/3/379/1835092 by guest on 23 September 2021 sidered to contribute to schizophrenia risk (McNeil 1988; ophrenia risk, the rodent data minimally suggest that ani- Parnas et al. 1982; Magrath et al. 1995), although Jones et mal models of the advancing paternal age might be use- al. (1998) reported that the characteristics of the offspring ful in identifying genes involved in learning and, (low birth weight and early birth), not of the delivery, optimally, might be useful in identifying schizophrenia were related to later schizophrenia. Because genetic vulnerability genes. imprinting by paternal genes contributes to the develop- ment and maintenance of the placenta, placental insuffi- ciency and hypoxia could be a proximal cause of schizo- Conclusion phrenia from mutations or epigenetic events arising in paternal genes. For example, the paternal insulin-like This article has reviewed data that support an association growth factor II receptor allele facilitates the use of between schizophrenia risk and advancing paternal age. maternal resources by the fetus whereas the maternal gene As such, schizophrenia may be one of a number of neu- acts to limit these resources (Haig et al. 1997). An unop- rodevelopmental disorders caused by de novo mutations posed maternal allele could limit the growth of the fetus, in the male germ line. This mutation mechanism may con- leading to low birth weight. Studies in mice show that tribute a significant proportion of schizophrenia risk imprinted genes may even influence the future maternal within a population in proportion to the demographics of behavior of female offspring onto their young (Lefebvre paternal childbearing age. Furthermore, this risk may 1998; Li et al. 1999). have implications for public health and for the primary prevention of schizophrenia. Gene environment interaction in schizophrenia is Implications for Translational Studies most often considered to result from interplay between fetal genes and the in utero environment. This perspec- Schizophrenia Phenotype. A phenotype for the sub- tive of this review suggests that we should expand our type of schizophrenia that is related to paternal age is epidemiological viewpoint to include the effects of suggested from the results of birth-order studies. Farina environmental exposures on spermatozoan DNA. (1963) reported that schizophrenia patients with many Animal studies offer an opportunity to test more com- older siblings were less likely to recover than were plex models and, optimally, to generate unexpected can- other patients, and Schooler (1961) found that schizo- didate genes for schizophrenia or other human cognitive phrenia patients who were last-born siblings were more disorders. Our understanding of de novo mutations and likely to have catatonia and were more socially isolated. schizophrenia risk may provide a new paradigm for Similarly, last-born female patients were found to have identifying a genetic basis for some forms of schizo- lower social competence, more bizarre and self-destruc- phrenia. tive behavior, less education, and, if they worked, lower-status jobs and were less likely to marry than first-born female patients, despite the fact that social References class of origin did not differ between the birth rank groups (Schooler 1964). Adams, W.; Kendell, R.E.; Hare, E.H.; and Munk- Jorgensen, P. Epidemiological evidence that maternal Animal Models. Animal models can afford us a bridge influenza contributes to the aetiology of schizophrenia: to understand the complex genetic systems that are An analysis of Scottish, English, and Danish data. British involved in the regulation of behavior. It is thus of inter- Journal of Psychiatry, 163:522-534, 1993. est that paternal age is associated with learning capacity Asherson, P.; Walsh, C; Williams, J.; Sargeant, M.; in rodent models. The offspring of older rats are compar- Taylor, C; Clements, A.; Gill, M.; Owen, M.; and atively impaired in several tests of cognition and explo- McGuffin, P. Imprinting and anticipation: Are they rele- ration, despite having no noticeable physical anomalies vant to genetic studies of schizophrenia? British Journal (Auroux 1983). In mice, the offspring of either young of Psychiatry, 164:619-624, 1994.

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K24 and the G. Harold and Leila Y. Mathers Downloaded from https://academic.oup.com/schizophreniabulletin/article/27/3/379/1835092 by guest on 23 September 2021 receptor 3 in sporadic cases of achondroplasia occur Charitable Foundation. The author would like to thank exclusively on the paternally derived chromosome. J. Harkavy-Friedman, S. Yale, and C. Corcoran for American Journal of Human Genetics, 63:711-716,1998. their assistance with this manuscript and acknowledge Yu, K.; Herr, A.B.; Waksman, G.; and Ornitz, D.M. Loss her collaborators in the Jerusalem Perinatal Cohort of fibroblast growth factor receptor 2 ligand-binding Schizophrenia Study and the Schizophrenia Research specificity in apert syndrome. Proceedings of the National Unit Case Series Study: S. Harlap, E. Susser, S. Academy of Sciences of the United States of America, Fennig, M. Davidson, J. Rabinowitz, A. Brown, D. 97:14536-14541,2000. Goetz, A. Berman, C. Fahim, R. Goetz, X. Amador, Zenzes, M.T. Smoking and reproduction: Gene damage to and J. Gorman. human gametes and embryos. Human Reproduction. Update, 6:122-131,2000. Zhang, S.L. [A study on effects of parents' age, birth order The Author and mental retardation of unknown etiology.] Zhonghua Dolores Malaspina, M.D., M.S.P.H., is Associate Sheng Jing Jing Shen Ke Za Xhi, 25:303-318, 1992. Professor of Clinical Psychiatry at Columbia University Zhang, Y.; Kreger, B.E.; Dorgan, J.F.; Cupples, L.A.; Department of Psychiatry/New York State Psychiatric Myers, R.H.; Splansky, G.L.; Schatzkin, A.; and Ellison, Institute, New York, New York.

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