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Pericentric region of chromosome 9 is a possible candidate region for linkage study of schizophrenia
BIOL PSYCHIATR~ 1993;33:655-658
655
Pericentric Region of Chromosome 9 is a Possible Candidate Region for Linkage Study of Schizophrenia Shinichiro Nanko, Hiroshi Kunugi, Tukasa Sasaki, Rimmei Fukuda, Tsuneta Kawate, and Hajime Kazamatsuri
We have undertaken a systematic G-banding survey to find structural chromosomal abnormalities among patients with schizophrenia. Of 120 patients with DSM-III-R schizophrenia, four (3.3%) had a pericentric inversion of chromosome 9 and three (2.5%) had a XIXX mosaicism. The frequency of pericentric inversion of chromosome 9 among Fatients with schizophrenia was statistically higher than those among newborns and Asian populations. Our results indicate that the pericentric region of chromosome 9 might be one of the potential regions of interest for linkage analysis of schizophrenia. Key Words: Schizophrenia, linkage study, chromoscome 9, pericentric inversion
Introduction Identifying a schizophrenia susceptibility locus by linkage studies has yielded conflicting results so far. Positive linkage results were reported on the short arm of chromosome 5 (Sherrington et al 1988), the long arm of chromosome 2 (Aschauer et al 1992), and the pseudoantosomal region (Collinge et al 1991). However, none has been replicated. In searching for schizophrenia susceptibility genes, there are three ways of proceeding to find a linkage, each of which has its pros and cons. The first is a random scan of the genome, which has been proved to be useful for Huntington's disease (GuseUa et al 1983). However, applying this approach is costly and time-consuming. The second is the candidate-gene approach. Genes encoding proteins
From the Department of Psychiatry, Teikyo University School of Medicine, gage, ltabashi, Tokyo, Japan. Address reprint re~m~t to Shinichim Nanko, MD, Depeltment of Psychialry, Teikyo University School of Medicine, 2-I I-I, Keg a, Itab~hi, Tokyo, 173 Japan. Received August 2, 1992', ~evised Februa~ 4, 1993 © 1993 Society of Biological Psychiatry
involved in neurotransmitter function are targeted in studies of schizophrenia, particularly dopaminergic or serotonergic systems. Many recent linkage studies have applied this approach (Moises et al 1991; Hallmayer et al 1992). Focusing on a candidate gene, however, requires a strong hypothesis to pinpoint the particular gene, because of the large number of genes expressed in the brain. The last ap~roach is to gain a clue from a schizophrenic patient with structural chromosome abnormalities, such as translocation, partial deletion, or partial trisomy. Those chromosomal abnormalities suggest regions on which to focus the initial search for responsible genes of schizophrenia by a genetic linkage strategy. For example, Duchenne muscular dystrophy and retinoblastoma are diseases in wlfich observation of cytogenetic abnormality has led to cloning of the implicated gene. Although a chromosome ~urv'ey among patients with schizophrenia has been conducted in a large sample size (Nanko 1985), the findings were limited to sex chromosome abnormalities, as they were assessed by examining 0006-3223/93/$06.00
656
BIOL PSYCHIATRY
S.
Nanko et al
1993;33:655-658
only X and/or Y chromatin. To detect structural chromosomal abnormalities, a G-banding technique is deftniieiy'~ccded. There are two possible ways of applying the G-banding survey approach One is to investigate a family with schizophrenia cosegregating with chromosomal abnormalities, which has been applied for studies of chromosome 5 (Bassett et al 1988). Systematic chromosome surveys among patients with a positive family history have also been conducted by Gorwood et al (1991). The other is to find some patients with schizophrenia who have structural chromosomal abnormalities. If some patients with schizophrenia have structural chromosomal abnormalities with the same breakpoint, then this point may suggest regions in which to focus a linkage study of schizophrenia. Following the last approach mentioned above, we have undertaken a systematic G-banding survey to find structural chromosomal abnormalities among patients with schizophrenia.
Norm9 Inv9 a) G-band
b) Cband c)
Material and Methods Subjects are the schizophrenic outpatients at the Psychiatric Clinic of Teikyo University Hospital from December 1991 to November 1992. A total of 120 outpatients (59 men and 61 women, aged 18-60 years) had blood samples taken for chromosomal examination after written informed consent was obtained. Diagnosis of schizophrenia was made according to DSM-III-R criteria (American Psychiatric Association 1987), which included schizophrenia (n = 116) and delusional disorder (n = 4). Peripheral lymphocyte culture and karyotyping of the subjects were performed. The G-banding by trypsin using Giemsa (GTG) was employed during this survey. At the initial phase, 20 metaphases were examined. When numerical abnormalities were suspected, an additional 80 metaphases were examined, for a total of 100 metaphase examinations. Mosaicism was determi~led if the proportion of minor cell population was more th~n 5%. On the other hand, when structural abnormalities were suspected, relevant banding techniques were applied to confirm the abnormality.
Results Of the 120 schizophrenic patients examined, three (2.5%) had a sex chromosome mosaicism and four (3.3%) had a pericentric inversion of chromosome 9. Those karyotypes were, three with 45, X/46,XX, three with 46,XX, inv(9)(pl Iql3): and one with 46,XY, inv(9)(pl lql3). In mosaic cases, the proportions of the cell populations with 45,X and 46,XX were 9:91, 15:85, and 15:85. Four cases with inversion of chromosome 9 were confirmed by Cbanding and high resolution banding techniques (Figure
Q
q13
Figure 1, The normal chromosome 9 (left) and its inverted homologue (right): a)G-banding, b)C-banding, c)schematic representation of normal and inverted chromosome9.
1). All were diagnosed as schizophrenic except a woman with 45,X/46,XX karyotype who was diagnosed as having a delusional disorder (Table 1).
Discussion Although the population examined was small, seven individuals with 45,X/46,XX mosaicisms or poricentric inversion of chromosome 9 were found among 120 schizophrenics. The 45,X/46,XX karyotype was a rare condition in the general population. Maeda et al (1991) found only one woman with 45,X/46,XX karyotype among 7,227 liveborn females (0.013%), whereas Nielsen and Wohlert (1991) found two women with this mosaic karyotype among 17,038 live-born females (0.012%). Our study's finding of an increased rate of chromosome mosaicism in schizophrenics, relat,ve to that of the general population, was compatible with the study of Kaplan (1970) who reported eight patients with 45,X/46,XX karyotype among 1,061 female schizophrenics (0.75%). This type of mosaicism was recently attracted by Crow (1988), with respect to the pseudoautosomal hypothesis of schizophrenia. We are interested in the pericentric inversion of chro-
Schizophrenia and Pericentric Inversion of Chromosome 9
Table I. Schizophrenic Patients with Chromosomal Abnormalities Case Age
1 2 3 4
57 5! 59 51
5
20
6
37
7
22
Karyotype
Diagnosis
45,X/46,XX 45,X/46,XX 45,X/46,XX 46,XX,Inv.(9)(pllql3)
Schizophrenia (residual type) Delusional disorder Schizophrenia (residual type) Schizophrenia (catatonic/residual type) 46,XY,Inv.(9)(pllq13) Schizophrenia(disorganized type) 46,XX,Inv.(9)(plIql3) Schizophrenia (paranoid/residual type) 46,XX,Inv.(9)(pllq13) Schizophrenia (undifferentiated type)
mosome 0 observed in three patients with schizophrenia. ' An inversion is a rotation of an intercalary segment between break points by 180° around a transverse axis and the reincorporation of the same site in the same chromosome. This may be regarded as a balanced rearrangement that contains the normal total amount of chromosomal material in a rearranged format (Figure It). Although the clinical relevance of this change has hitherto remained obscure, the rearrangement may interrupt the function of one or more genes close to the break points (Bassett 1992). Among pericentric inversions on human chromosomes, chromosome 9 is the most common. Serra et al (1990) estimated the prevalence of pericentric inversion of chromosome 9 as 0.85% (65/7,613) among 7,613 newborn infants based on cytogenetic surveys performed, whereas Nielsen and Wohlert (1991) failed to find anyone with an inversion of chromosome 9 among 35,000 newborn children. Maeda et al (1991) found only one with this chromosomal aberration among 14,835 Japanese liveborns. Hsu et al (1987) reported highly significant differences in the
BIOLPSYCHIATRY 1993;33:655-658
657
frequency of inversion of chromosome 9 for different ethnic groups, which was lowest in the Asian population (0.26% 1/384). The frequency of pericentric inversion of chromosome 9 in the present study was statistically higher than those reported by Serra et al and by Hsu et al (p < 0.05, x 2 = 5.64 (Yates' correction), df = l ; p = 0.013, Fisher's exact test, respectively). Although the exact frequency among the general population in Japan is not yet known, our observation of a high frequency of patients with this aberration indicates the association of schizophrenia with pericentric inversion of chromosome 9. Of reported pericentric inversions of chromosome 9, some cases had a psychiatric problem. Kumar et al (1989) reported a case of pericentric inversion with personality disorder, whereas Manolov et al (1985) reported an association of pericentric inversion of chromosome 9 in 15.8°~ (3/19) of male homosexuals. Most strikingly, a Swedish group showed an increased prevalence of patients ",~ith inversion of chromosome 9 among male patients with paranoid psychosis [9.7% (13/134)] (Axelsson and Wahlstr6m 1984). Although schizophrenia with pericentric inversion of chromosome 9 has not been reported in the literature to date, and although any candidate genes related to schizophrenia have not yet mapped to this region of chromosome 9, our results and the review of the literature indicate that the pericentric region of chromosome 9 might be one of the potential regions of interest for linkage analysis of schizophrenia. We agree with the recent report (Bassett 1992) that structural chromosomal abnormalities provide the clue to finding a candidate region for linkage studies of functional psychosis. Thus, in future research, the need to find chromosomal abnormalities associated with schizophrenia should be stressed.
References American Psychiatric Association (1987): Diagnostic and Statistical Manual of Mental Disorders, 3rd ed rev. Washington DC: American Psychiatric Association. Aschauer HN, Meszaros K, Asehauer-Triber G, et al (1992): RFLP linkage study i~l schizophrenia on chromosome 2. $chizophr Res 6:89. Axelsson R, Wahlstr6m M (1984): Chromosome aberrations in patients with paranoid psychosis. Hereditas 100:29-31. Bassett AS (1992): Chromosomal aberrations and schizophrenia. Br J Psychiatry 161:323-334. Bassett AS, McGillivray BC, Jones B, Pantzar JT, Langlois S (1988): Partial trisomy chromosome 5 co-segregating with schizophrenia. Lancet 1:799-801. Collinge J, DeLisi LE, Boccio A, et al (1991): Evidence for a pseudo-autosomal locus for schizophrenia using the method of affected sibling pairs. Br J Psychiatry 158:624-629.
Crow TJ (1988): Sex chromosomes and psychosis: The case for a pseudoautosomal locus. Br J Psychiatry 153:675-683. Gorwood P, Leboyer M, Hillaire D, et al (1991): Cytogenetic studies of familial schizophrenics. Biol Psychiatry 29:624625. Gusella JF, Wexler NS, Conneally PM, et al (1983): A polymorphic DNA marker genetically linked to Huntington's disease. Nature 306:234-238. Hallmayer J, Kennedy JL, Wettenberg L, Sj~gren B, Kidd KK, Cavalli-Sforza LL (1992): Exclusion of linkage between the serotonin 2 receptor and schizophrenia in a large Swedish kindred. Arch Gen Psychiatry 49:216--219. Hsu LYF, Benn PA, Tannenbaum HL, Perils TE, Carlson AD (1987): Chromosomal polymorphisms of I, 9, 16, and Y in 4 major ethnic groups, Am J Med Genet 26:95-101. Kaplan AR (1970): Chromosomal mosaicisms and occasional
658
BIOL PSYCHIATRY 1993;33:655-658
acentric chromosomal fragments in schizophrenic patients. Biol Psychiatry 2:89-94. Kumar HV, MeMahon KI, Allman KM, McCaffrey B, Rowan A (1989): Pericentric inversion chromosome 9 and personality disorder, Br J Psychiatry 155:408-410. Maeda T, Ohno M, Matsunobu A, Yoshihara K, Yabe N (1991): A cytogenetic survey of 14,835 consecutive liveboms. Jpn J Hum Genet 36:! 17-129. Manolov (3, Manolov Y, Sonnabend J, Lipscomb H, P~i|n T (1985): Chromosome aberrations in peripheral lymp~ocytes of male homosexuals. Cancer Genet Cytogenet 18:337-350. Moises HW, Gelernter J, Giuffra LA, et al (1991): No linkage' between D2-dopamine receptor gene region and schizophrenia. Arch 6en Psychiatry 48:643-647.
S. Nanko et al
Nanko S (1985): X and Y chromatin survey among 8000 inpatients in Japanese mental hospital. In Sakai T, Tsuboi T (eds), Genetic Aspects of Human Behavior. Tokyo: Igaku-Shoin, pp 209-214. Nielsen J, Wohlert M (1991): Chromosome abnormalities found among 34,910 newborn children: Results from a 13-year incidence study in Arhus, Denmark. Hum Genet 87:81-83. Serra A, Brahe C, Millington-Ward A, et al (1990): Pericentric inversion of chromosome 9: Prevalence in 300 Down syndrome families and molecular studies of nondisjunction. Am J Med Genet 7:162-168. Sherrington R, Brynjolfsson J, Petursson H, et al (1988): Localization of a susceptibility locus for schizophrenia on chromosome 5. Nature 336:164-167.
655
Pericentric Region of Chromosome 9 is a Possible Candidate Region for Linkage Study of Schizophrenia Shinichiro Nanko, Hiroshi Kunugi, Tukasa Sasaki, Rimmei Fukuda, Tsuneta Kawate, and Hajime Kazamatsuri
We have undertaken a systematic G-banding survey to find structural chromosomal abnormalities among patients with schizophrenia. Of 120 patients with DSM-III-R schizophrenia, four (3.3%) had a pericentric inversion of chromosome 9 and three (2.5%) had a XIXX mosaicism. The frequency of pericentric inversion of chromosome 9 among Fatients with schizophrenia was statistically higher than those among newborns and Asian populations. Our results indicate that the pericentric region of chromosome 9 might be one of the potential regions of interest for linkage analysis of schizophrenia. Key Words: Schizophrenia, linkage study, chromoscome 9, pericentric inversion
Introduction Identifying a schizophrenia susceptibility locus by linkage studies has yielded conflicting results so far. Positive linkage results were reported on the short arm of chromosome 5 (Sherrington et al 1988), the long arm of chromosome 2 (Aschauer et al 1992), and the pseudoantosomal region (Collinge et al 1991). However, none has been replicated. In searching for schizophrenia susceptibility genes, there are three ways of proceeding to find a linkage, each of which has its pros and cons. The first is a random scan of the genome, which has been proved to be useful for Huntington's disease (GuseUa et al 1983). However, applying this approach is costly and time-consuming. The second is the candidate-gene approach. Genes encoding proteins
From the Department of Psychiatry, Teikyo University School of Medicine, gage, ltabashi, Tokyo, Japan. Address reprint re~m~t to Shinichim Nanko, MD, Depeltment of Psychialry, Teikyo University School of Medicine, 2-I I-I, Keg a, Itab~hi, Tokyo, 173 Japan. Received August 2, 1992', ~evised Februa~ 4, 1993 © 1993 Society of Biological Psychiatry
involved in neurotransmitter function are targeted in studies of schizophrenia, particularly dopaminergic or serotonergic systems. Many recent linkage studies have applied this approach (Moises et al 1991; Hallmayer et al 1992). Focusing on a candidate gene, however, requires a strong hypothesis to pinpoint the particular gene, because of the large number of genes expressed in the brain. The last ap~roach is to gain a clue from a schizophrenic patient with structural chromosome abnormalities, such as translocation, partial deletion, or partial trisomy. Those chromosomal abnormalities suggest regions on which to focus the initial search for responsible genes of schizophrenia by a genetic linkage strategy. For example, Duchenne muscular dystrophy and retinoblastoma are diseases in wlfich observation of cytogenetic abnormality has led to cloning of the implicated gene. Although a chromosome ~urv'ey among patients with schizophrenia has been conducted in a large sample size (Nanko 1985), the findings were limited to sex chromosome abnormalities, as they were assessed by examining 0006-3223/93/$06.00
656
BIOL PSYCHIATRY
S.
Nanko et al
1993;33:655-658
only X and/or Y chromatin. To detect structural chromosomal abnormalities, a G-banding technique is deftniieiy'~ccded. There are two possible ways of applying the G-banding survey approach One is to investigate a family with schizophrenia cosegregating with chromosomal abnormalities, which has been applied for studies of chromosome 5 (Bassett et al 1988). Systematic chromosome surveys among patients with a positive family history have also been conducted by Gorwood et al (1991). The other is to find some patients with schizophrenia who have structural chromosomal abnormalities. If some patients with schizophrenia have structural chromosomal abnormalities with the same breakpoint, then this point may suggest regions in which to focus a linkage study of schizophrenia. Following the last approach mentioned above, we have undertaken a systematic G-banding survey to find structural chromosomal abnormalities among patients with schizophrenia.
Norm9 Inv9 a) G-band
b) Cband c)
Material and Methods Subjects are the schizophrenic outpatients at the Psychiatric Clinic of Teikyo University Hospital from December 1991 to November 1992. A total of 120 outpatients (59 men and 61 women, aged 18-60 years) had blood samples taken for chromosomal examination after written informed consent was obtained. Diagnosis of schizophrenia was made according to DSM-III-R criteria (American Psychiatric Association 1987), which included schizophrenia (n = 116) and delusional disorder (n = 4). Peripheral lymphocyte culture and karyotyping of the subjects were performed. The G-banding by trypsin using Giemsa (GTG) was employed during this survey. At the initial phase, 20 metaphases were examined. When numerical abnormalities were suspected, an additional 80 metaphases were examined, for a total of 100 metaphase examinations. Mosaicism was determi~led if the proportion of minor cell population was more th~n 5%. On the other hand, when structural abnormalities were suspected, relevant banding techniques were applied to confirm the abnormality.
Results Of the 120 schizophrenic patients examined, three (2.5%) had a sex chromosome mosaicism and four (3.3%) had a pericentric inversion of chromosome 9. Those karyotypes were, three with 45, X/46,XX, three with 46,XX, inv(9)(pl Iql3): and one with 46,XY, inv(9)(pl lql3). In mosaic cases, the proportions of the cell populations with 45,X and 46,XX were 9:91, 15:85, and 15:85. Four cases with inversion of chromosome 9 were confirmed by Cbanding and high resolution banding techniques (Figure
Q
q13
Figure 1, The normal chromosome 9 (left) and its inverted homologue (right): a)G-banding, b)C-banding, c)schematic representation of normal and inverted chromosome9.
1). All were diagnosed as schizophrenic except a woman with 45,X/46,XX karyotype who was diagnosed as having a delusional disorder (Table 1).
Discussion Although the population examined was small, seven individuals with 45,X/46,XX mosaicisms or poricentric inversion of chromosome 9 were found among 120 schizophrenics. The 45,X/46,XX karyotype was a rare condition in the general population. Maeda et al (1991) found only one woman with 45,X/46,XX karyotype among 7,227 liveborn females (0.013%), whereas Nielsen and Wohlert (1991) found two women with this mosaic karyotype among 17,038 live-born females (0.012%). Our study's finding of an increased rate of chromosome mosaicism in schizophrenics, relat,ve to that of the general population, was compatible with the study of Kaplan (1970) who reported eight patients with 45,X/46,XX karyotype among 1,061 female schizophrenics (0.75%). This type of mosaicism was recently attracted by Crow (1988), with respect to the pseudoautosomal hypothesis of schizophrenia. We are interested in the pericentric inversion of chro-
Schizophrenia and Pericentric Inversion of Chromosome 9
Table I. Schizophrenic Patients with Chromosomal Abnormalities Case Age
1 2 3 4
57 5! 59 51
5
20
6
37
7
22
Karyotype
Diagnosis
45,X/46,XX 45,X/46,XX 45,X/46,XX 46,XX,Inv.(9)(pllql3)
Schizophrenia (residual type) Delusional disorder Schizophrenia (residual type) Schizophrenia (catatonic/residual type) 46,XY,Inv.(9)(pllq13) Schizophrenia(disorganized type) 46,XX,Inv.(9)(plIql3) Schizophrenia (paranoid/residual type) 46,XX,Inv.(9)(pllq13) Schizophrenia (undifferentiated type)
mosome 0 observed in three patients with schizophrenia. ' An inversion is a rotation of an intercalary segment between break points by 180° around a transverse axis and the reincorporation of the same site in the same chromosome. This may be regarded as a balanced rearrangement that contains the normal total amount of chromosomal material in a rearranged format (Figure It). Although the clinical relevance of this change has hitherto remained obscure, the rearrangement may interrupt the function of one or more genes close to the break points (Bassett 1992). Among pericentric inversions on human chromosomes, chromosome 9 is the most common. Serra et al (1990) estimated the prevalence of pericentric inversion of chromosome 9 as 0.85% (65/7,613) among 7,613 newborn infants based on cytogenetic surveys performed, whereas Nielsen and Wohlert (1991) failed to find anyone with an inversion of chromosome 9 among 35,000 newborn children. Maeda et al (1991) found only one with this chromosomal aberration among 14,835 Japanese liveborns. Hsu et al (1987) reported highly significant differences in the
BIOLPSYCHIATRY 1993;33:655-658
657
frequency of inversion of chromosome 9 for different ethnic groups, which was lowest in the Asian population (0.26% 1/384). The frequency of pericentric inversion of chromosome 9 in the present study was statistically higher than those reported by Serra et al and by Hsu et al (p < 0.05, x 2 = 5.64 (Yates' correction), df = l ; p = 0.013, Fisher's exact test, respectively). Although the exact frequency among the general population in Japan is not yet known, our observation of a high frequency of patients with this aberration indicates the association of schizophrenia with pericentric inversion of chromosome 9. Of reported pericentric inversions of chromosome 9, some cases had a psychiatric problem. Kumar et al (1989) reported a case of pericentric inversion with personality disorder, whereas Manolov et al (1985) reported an association of pericentric inversion of chromosome 9 in 15.8°~ (3/19) of male homosexuals. Most strikingly, a Swedish group showed an increased prevalence of patients ",~ith inversion of chromosome 9 among male patients with paranoid psychosis [9.7% (13/134)] (Axelsson and Wahlstr6m 1984). Although schizophrenia with pericentric inversion of chromosome 9 has not been reported in the literature to date, and although any candidate genes related to schizophrenia have not yet mapped to this region of chromosome 9, our results and the review of the literature indicate that the pericentric region of chromosome 9 might be one of the potential regions of interest for linkage analysis of schizophrenia. We agree with the recent report (Bassett 1992) that structural chromosomal abnormalities provide the clue to finding a candidate region for linkage studies of functional psychosis. Thus, in future research, the need to find chromosomal abnormalities associated with schizophrenia should be stressed.
References American Psychiatric Association (1987): Diagnostic and Statistical Manual of Mental Disorders, 3rd ed rev. Washington DC: American Psychiatric Association. Aschauer HN, Meszaros K, Asehauer-Triber G, et al (1992): RFLP linkage study i~l schizophrenia on chromosome 2. $chizophr Res 6:89. Axelsson R, Wahlstr6m M (1984): Chromosome aberrations in patients with paranoid psychosis. Hereditas 100:29-31. Bassett AS (1992): Chromosomal aberrations and schizophrenia. Br J Psychiatry 161:323-334. Bassett AS, McGillivray BC, Jones B, Pantzar JT, Langlois S (1988): Partial trisomy chromosome 5 co-segregating with schizophrenia. Lancet 1:799-801. Collinge J, DeLisi LE, Boccio A, et al (1991): Evidence for a pseudo-autosomal locus for schizophrenia using the method of affected sibling pairs. Br J Psychiatry 158:624-629.
Crow TJ (1988): Sex chromosomes and psychosis: The case for a pseudoautosomal locus. Br J Psychiatry 153:675-683. Gorwood P, Leboyer M, Hillaire D, et al (1991): Cytogenetic studies of familial schizophrenics. Biol Psychiatry 29:624625. Gusella JF, Wexler NS, Conneally PM, et al (1983): A polymorphic DNA marker genetically linked to Huntington's disease. Nature 306:234-238. Hallmayer J, Kennedy JL, Wettenberg L, Sj~gren B, Kidd KK, Cavalli-Sforza LL (1992): Exclusion of linkage between the serotonin 2 receptor and schizophrenia in a large Swedish kindred. Arch Gen Psychiatry 49:216--219. Hsu LYF, Benn PA, Tannenbaum HL, Perils TE, Carlson AD (1987): Chromosomal polymorphisms of I, 9, 16, and Y in 4 major ethnic groups, Am J Med Genet 26:95-101. Kaplan AR (1970): Chromosomal mosaicisms and occasional
658
BIOL PSYCHIATRY 1993;33:655-658
acentric chromosomal fragments in schizophrenic patients. Biol Psychiatry 2:89-94. Kumar HV, MeMahon KI, Allman KM, McCaffrey B, Rowan A (1989): Pericentric inversion chromosome 9 and personality disorder, Br J Psychiatry 155:408-410. Maeda T, Ohno M, Matsunobu A, Yoshihara K, Yabe N (1991): A cytogenetic survey of 14,835 consecutive liveboms. Jpn J Hum Genet 36:! 17-129. Manolov (3, Manolov Y, Sonnabend J, Lipscomb H, P~i|n T (1985): Chromosome aberrations in peripheral lymp~ocytes of male homosexuals. Cancer Genet Cytogenet 18:337-350. Moises HW, Gelernter J, Giuffra LA, et al (1991): No linkage' between D2-dopamine receptor gene region and schizophrenia. Arch 6en Psychiatry 48:643-647.
S. Nanko et al
Nanko S (1985): X and Y chromatin survey among 8000 inpatients in Japanese mental hospital. In Sakai T, Tsuboi T (eds), Genetic Aspects of Human Behavior. Tokyo: Igaku-Shoin, pp 209-214. Nielsen J, Wohlert M (1991): Chromosome abnormalities found among 34,910 newborn children: Results from a 13-year incidence study in Arhus, Denmark. Hum Genet 87:81-83. Serra A, Brahe C, Millington-Ward A, et al (1990): Pericentric inversion of chromosome 9: Prevalence in 300 Down syndrome families and molecular studies of nondisjunction. Am J Med Genet 7:162-168. Sherrington R, Brynjolfsson J, Petursson H, et al (1988): Localization of a susceptibility locus for schizophrenia on chromosome 5. Nature 336:164-167.