No Evidence for a Parent-of-Origin Effect Detected in
the Pattern of Inheritance of Schizophrenia
Lynn E. DeLisi, Kamran Razi, John Stewart, Margaret Relja, Gail Shields,
Angela B. Smith, Nigel Wellman, Veronica W. Larach, Josephine Loftus,
Antonio Vita, Margherita Comazzi, and Timothy J. Crow
Background: Schizophrenia is a complex genetic
disor-der with no clear pattern of inheritance. Epigenetic modification of genes may thus play a role in its transmission.
Methods: In our study, 439 families with at least two ill
siblings with schizophrenia (208 with unilineal transmis-sion) were examined for evidence of a parent-of-origin effect (e.g., evidence of parental imprinting on the familial transmission of schizophrenia).
Results: No significant difference in the prevalence of
maternal compared with paternal transmission was found. In addition, affected male subjects did not differ from affected female subjects in the proportion of their off-spring diagnosed with schizophrenia.
Conclusions: Although the transmission of schizophrenia
may be influenced by epigenetic events, our study fails to find evidence that one epigenetic mechanism, a parent-of-origin imprinting effect, determines whether an individual
expresses the illness. Biol Psychiatry 2000;48:
706 –709 © 2000 Society of Biological Psychiatry
Key Words: Schizophrenia, genetic disorder, imprinting, epigenetics
Introduction
A
lthough a genetic predisposition for schizophrenia is evident, its pattern of inheritance is not simply Mendelian (reviewed by Kendler and Diehl 1993). Be-cause discordance for illness among monozygotic twins is relatively high (approximately 50%) and the risk to sec-ondary relatives is less than that which would be expected for a “genetic” disorder, it is generally thought that environmental or epigenetic mechanisms must contribute to the eventual expression (Gottesman and Shields 1982).Recently, epigenetic mechanisms, defined as nonenviron-mental modifications of gene expression, have gained some attention (Petronis et al 1999). One such mechanism, “anticipation,” an increase in severity from parental to offspring generation, has been observed in several neuro-degenerative disorders (reviewed in Petronis et al 1995; Wells and Warren 1998) and in some (Bassett and Honer 1994; Bassett and Husted 1997; Beckmann et al 1996; Chotai et al 1995; Gorwood et al 1996, 1997; Heiden et al 1999; Imamura et al 1998; Johnson et al 1997; McInnis et al 1999; Ohara et al 1997; Penrose 1991; Thibaut et al 1995; Valero et al 1998; Yaw et al 1996), but not all (Asherson et al 1994) studies of schizophrenia . Although it is difficult to separate true age-of-onset differences from family collection bias, anticipation is now known, at least in some diseases, to be due to expanding lengths of triplet repeats in coding regions of a gene (reviewed in Brannan and Bartolomei 1999; Ross et al 1993).
Another epigenetic mechanism, “imprinting,” has been less studied in psychiatric disorders but is known to be responsible for differential expression of some other ge-netic disorders. The classic example is Prader–Willi and Angelman syndromes (reviewed in Jablonka and Lamb 1995). Thus, a mutation in the same gene is expressed in different ways depending on whether the defect is trans-mitted maternally or paternally, and this in turn depends on whether there is differential parental methylation of the gene.
Imprinting as a determinant of schizophrenia has been examined in only a few studies, and all but one in relation to its effect on age of onset, rather than development of the disorder itself. No imprinting effect has generally been found (Asherson et al 1994; Gorwood et al 1996; Imamura et al 1998; Thibaut et al 1995; Valero et al 1998). Two studies (Husted et al 1998; Ohara et al 1997) found anticipation (as measured by younger age of onset in offspring of ill parents) to be greater from paternal than maternal inheritance, with a nonsignificant trend observed in a third study (Stober et al 1998). Yaw et al (1996), on the other hand, found the reverse and McInnis et al (1999) found anticipation in aunt:niece/nephew, but not in uncle:
From the Department of Psychiatry, SUNY Stony Brook, Stony Brook, New York (LED, KR, JS, MR, GS, ABS), the University Department of Psychiatry, The Warneford Hospital, Oxford, United Kingdom (NW, JL, TJC), University of Chile, Santiago, Chile (VWL), and University of Milan, Milan, Italy (AV, MC). Address reprint requests to Lynn E. DeLisi, M.D., State University of New York at Stony Brook, Department of Psychiatry, HSC T-10, Stony Brook NY 11794. Received January 26, 2000; revised March 20, 2000; accepted May 25, 2000.
niece/nephew pairs. In our study, we examined a large cohort of multiplex families, not for age of onset, but to test the hypothesis that a specific pattern of imprinting could be contributing to the pattern of inheritance of schizophrenia itself.
Methods and Materials
At the time of these analyses, data from 439 families with at least two affected siblings were available from an ongoing genetic study of schizophrenia. Families were ascertained from the United States, the United Kingdom, Italy, and Chile on the basis that they had two siblings available with schizophrenia or schizoaffective disorder (methods detailed in Garner et al 1996; Shaw et al 1998). Both ill siblings were considered the probands to which all information about pattern of inheritance relates. Written informed consent was obtained from all individuals who directly participated in this project, whether by donating a blood sample, submitting to a personal interview, or both. Family history was ascertained from multiple available members of each family to ascertain the pattern of inheritance of psychiatric disorders among family members in as accurate a manner as possible. Relatives were interviewed about other relatives who were not available using a structured questionnaire (Relative Psychiatric History Questionnaire: E.S. Gershon, revised, unpub-lished). These data were coded to maintain individual confiden-tiality. Structured diagnostic interviews were conducted with all available family members (including probands) using the Diag-nostic Interview for Genetic Studies (DIGS; Nurnberger et al 1994) and The Schedule for Affective Disorders and Schizophre-nia (Spitzer and Endicott 1978) for earlier ascertained individu-als. Medical records were also obtained for supplementing diagnostic information.
Diagnoses in this cohort were based on DSM-III-R criteria (American Psychiatric Association 1987) using all available information and determined by two independent diagnosticians who have established reliability first among themselves. In cases of disagreement, all diagnosers met to determine a final consen-sus diagnosis.
For each family, the pattern of inheritance was determined to be maternal, unilineal, bilineal, or unknown by noting first-, second-, and third-degree relatives (parents, offspring, grandpar-ents, aunts, uncles, and first cousins) with a history of schizo-phrenia, schizoaffective disorder, or psychosis, not otherwise specified. Affective and anxiety disorders were not included as “affected.” Offspring of the affected siblings were separately evaluated. Age of risk was not taken into account, however, because actual age at the time of intake was not available for many individuals.
Chi-square analyses were performed to determine whether significantly greater numbers of probands from unilineal families had maternal or paternal inheritance and whether significantly more offspring of male or female probands had schizophrenia.
Results
Of the 439 families, 122 (28% of the total) had unilineal maternal inheritance, 88 (20% of the total) of which had a
nonaffected mother; 86 (20% of the total) had unilineal paternal inheritance, 73 (17% of the total) of which had a nonaffected father. There were 34 mothers (8%) and 13 fathers (3%) with schizophrenia from the 439 families. Forty-four (10%) probands had bilineal inheritance, and 187 (43%) had no known psychosis in other relatives. There was no significant difference in frequency of uni-lineal maternal and paternal inheritance in the sample as a whole, although a trend for more maternal than paternal inheritance was present (x2 5 3.14, p , .08). When ill parents were excluded from the analysis, however, no difference remained (x25 0.86, p5 .35).
There were 156 offspring of probands with schizophre-nia; 22 (14%) of these had a diagnosis of schizophrenia, and 22 affected male subjects had a total of 31 offspring, five of whom had schizophrenia (16%). Of the affected female subjects, 61 had a total of 125 offspring, 17 of whom had schizophrenia (13.6%). Thus, whereas affected male subjects had fewer offspring than affected female subjects (x2 5 11.5, p 5 .0007), the percentage of schizophrenia among the offspring of men and women with schizophrenia was not significantly different (x25
0.10, p5.75). There was no difference in age at the time of evaluation between the offspring of male compared with female probands.
Discussion
Our investigation was an attempt to determine whether differential imprinting of a gene could account for the pattern of inheritance of schizophrenia within families. This hypothesis was based in part on previous literature, which has shown that risks of illness to first-, second-, and third-degree relatives of probands with schizophrenia are less than would be predicted by Mendelian inheritance. Some other genetic disorders depend on the parental origin of the defect—for example, the Prader–Willi defect on chromosome 15q (Hall 1990) and Turner’s (XO) syn-drome. For the latter, some behavioral and cognitive deficits are evident when the sole X in the affected individual is maternal, but not paternal (Skuse et al 1997). Imprinting is also of interest in neuropsychiatric disor-ders since normal development is largely dependent on the timing of imprinting of genes involved in migration and differentiation of neurons (Jablonka and Lamb 1995; Keverne et al 1996). It is conceivable that a deviation in this process could be responsible for the development of neuronal pathways that lead to psychosis susceptibility.
Focusing on the notion that imprinting of a gene depends on the parent of origin (Keverne et al 1996), we hypothesized that there would then be a significant mater-nal versus patermater-nal difference in inheritance of schizophre-nia. Age-of-onset and fertility effects introduce a potential
Parent-of-Origin Effect and Schizophrenia BIOL PSYCHIATRY 707
bias, however. Because women tend to have later onset of schizophrenia than men, they will be more likely to have offspring before becoming ill, leading to an apparently higher frequency of unilineal maternal than paternal fam-ilies. However, when we examined this relationship after restricting the analysis to those families in which there was unilineal transmission and the transmitting parent was well, no difference in risk was observed. We also focused on a later generation and examined only those probands with schizophrenia who had offspring. In this analysis, again, we found no difference in rates of schizophrenia in offspring of men with schizophrenia compared with off-spring of women with schizophrenia. These data are preliminary, given that this is the youngest generation and still within the age of risk for future development of schizophrenia. Because the number of offspring was small, we also did not examine whether a later age of onset in female compared with male offspring could have contributed to these negative results. Our previous find-ings in a subsample of this population (McInnis et al 1999) indicate that age of onset, as evidence of anticipation, interacts with gender, and thus this should be taken into account. Nonetheless, taken together, both sets of analyses in our present study show a lack of evidence for differen-tial parental imprinting to be operating on a gene that leads to schizophrenia.
Future studies might consider that a broader phenotype, such as that which includes affective and anxiety disor-ders, may contribute to the pattern of genetic transmission within families. These diagnoses are less reliably estab-lished and are less closely related to schizophrenia in family studies, however, and thus have not been included in the analyses presented here.
This study was partially supported by National Institute of Mental Health Grant No. R01-44245.
References
American Psychiatric Association (1987): The American
Psychi-atric Association diagnostic criteria from DSM-III-R.
Wash-ington, DC: APA Press.
Asherson P, Walsh C, Williams J, Sargeant M, Taylor C, Clements A, et al (1994): Imprinting and anticipation. Are they relevant to genetic studies of schizophrenia? Br J
Psychiatry 164:619 – 624.
Bassett AS, Honer WG (1994): Evidence for anticipation in schizophrenia. Am J Hum Genet 54:864 – 870.
Bassett AS, Husted J (1997): Anticipation or ascertainment bias in schizophrenia? Penrose’s familial mental illness sample.
Am J Hum Genet60:630 – 637.
Beckmann H, Franzek E, Stober G (1996): Genetic heterogeneity in catatonic schizophrenia: A family study. Am J Med Genet 67:289 –300.
Brannan CI, Bartolomei MS (1999): Mechanisms of genomic imprinting. Curr Opin Genet Dev 9:164 –170.
Chotai J, Engstrom C, Ekholm B, Berg ML, Adolfsson R, Nylander PO (1995): Anticipation in Swedish families with schizophrenia. Psychiatr Genet 5:181–186.
Garner C, Kelly M, Cardon L, Joslyn G, Carey A, LeDuc C, et al (1996) Linkage analyses of schizophrenia to chromosome 6p24 –p22: An attempt to replicate. Neuropsychiatr Genet 67:595– 610.
Gorwood P, Leboyer M, Falissard B, Jay M, Rouillon F, Feingold J (1996): Anticipation in schizophrenia: New light on a controversial problem. Am J Psychiatry 153:1173–1177. Gorwood P, Leboyer M, Falissard B, Rouillon F, Jay M, Feingold J (1997): Further epidemiological evidence for anticipation in schizophrenia. Biomed Pharmacother 51:376 – 380.
Gottesman II, Shields J (1982) Schizophrenia: The Epigenetic
Puzzle. Cambridge, UK: Cambridge University Press.
Hall JG (1990): Genomic imprinting: Review and relevance to human diseases. Am J Hum Genet 46:857– 873.
Heiden A, Willinger U, Scharfetter J, Meszaros K, Kasper S, Aschauer HN (1999): Anticipation in schizophrenia.
Schizo-phr Res 35:25–32.
Husted J, Scutt LE, Bassett AS (1998): Paternal transmission and anticipation in schizophrenia. Am J Med Genet 81:156 –162. Imamura A, Honda S, Nakane Y, Okazaki Y (1998): Anticipa-tion in Japanese families with schizophrenia. J Hum Genet 43:217–223.
Jablonka E, Lamb MJ (1995): Epigenetic Inheritance and
Evo-lution: The Lamarckian Dimension. Oxford, UK: Oxford
University Press.
Johnson JE, Cleary J, Ahsan H, Harkavy Friedman J, Malaspina D, Cloninger CR, et al (1997): Anticipation in schizophrenia: Biology or bias? Am J Med Genet 74:275–280.
Kendler KS, Diehl SR (1993): The genetics of schizophrenia: A current, genetic-epidemiologic perspective. Schizophr Bull 19:261–285.
Keverne EB, Fundele R, Narasimha M, Barton SC, Surani MA (1996): Genomic imprinting and the differential roles of parental genomes in brain development. Dev Brain Res 92:91–100.
McInnis MG, McMahon FJ, Crow TJ, Ross CA, DeLisi LE (1999): Anticipation in schizophrenia: A review and consid-eration. Am J Med Genet 88:686 – 693.
Nurnberger JI Jr, Blehar MC, Kaufmann CA, York-Cooler C, Simpson SG, Harkavy-Friedman J, et al (1994): Diagnostic interview for genetic studies: Rationale, unique features and training. Arch Gen Psychiatry 51:849 – 862.
Ohara K, Xu HD, Mori N, Suzuki Y, Xu DS, Ohara K, Wang ZC (1997): Anticipation and imprinting in schizophrenia. Biol
Psychiatry 42:760 –766.
Penrose LS (1991) Survey of cases of familial mental illness. Eur
Arch Psychiatry Neurol Sci 240:315–324.
Petronis A, Paterson AD, Kennedy JL (1999): Schizophrenia: An epigenetic puzzle? Schizophr Bull 25:639 – 655.
Petronis A, Sherrington RP, Paterson AD, Kennedy JL (1995): Genetic anticipation in schizophrenia: Pro and con. Clin
Neurosci 3:76 – 80.
708 BIOL PSYCHIATRY L.E. DeLisi et al
Ross CA, McInnis MG, Margolis RL, Li SH (1993): Genes with triplet repeats: Candidate mediators of neuropsychiatric dis-orders. Trends Neurosci 16:254 –260.
Shaw SH, Kelly M, Smith AB, Shields G, Hopkins PJ, Loftus J, et al (1998): A genome-wide screen for linkage to schizo-phrenia. Am J Med Genet 81:364 –376.
Skuse DH, James RS, Bishop DVM, Coppin B, Dalton P, Aamodt-Leeper G, et al (1997): Evidence from Turner’s syndrome of an imprinted X-linked locus affecting cognitive function. Nature 387:705–708.
Spitzer RL, Endicott J (1978): Schedule for Affective Disorders
and Schizophrenia (SADS). New York: New York State
Psychiatric Institute.
Stober G, Haubitz I, Franzek E, Beckmann H (1998): Parent-of-origin effect and evidence for differential transmission in periodic catatonia. Psychiatr Genet 8:213–219.
Thibaut F, Martinez M, Petit M, Jay M, Campion D (1995): Further evidence for anticipation in schizophrenia. Psychiatry
Res 59:25–33.
Valero J, Martorell L, Marine J, Vilella E, Labad A (1998): Anticipation and imprinting in Spanish families with schizo-phrenia. Acta Psychiatr Scand 97:343–350.
Parent-of-Origin Effect and Schizophrenia BIOL PSYCHIATRY 709
