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]. 379 Schizophrenia Bulletin, Vol. 27, No. 3, 2001 D. Malaspina 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