Lack of association between the apolipoprotein E ε4 allele (APOE ε4) and chronic schizophrenia
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Letter to the Editor Lack of Association Between the Apolipoprotein E e4 Allele (APOE e4) and Chronic Schizophrenia To the Editor: In a previous study, Harrington et al. [1995] hypoth- esized a neurodegenerative role for apolipoprotein E (APOE) in schizophrenia, and reported an increased e4 allele frequency in patients with schizophrenia. In a later study, Joober et al. [1996] was unable to replicate this association, finding no significant difference in e4 carrier status between schizophrenic patients and con- trols. We investigated this association in 63 clinically diagnosed schizophrenics and in 301 controls. Our find- ings concur with those of Joober et al., in that the APOE e4 allele was equally represented in both the schizophrenic group (14.3%) and the control group (13.6%), indicating no association between schizophre- nia and the e4 allele. The APOE gene codes for a lipoprotein involved in cholesterol and phospholipid transport. A polymorphic site within the gene has three common forms (e2, e3, e4) which code for three common isoforms (E2, E3, E4). The APOE e4 allele has been consistently associated with increased risk for sporadic and familial Alzhei- mer’s disease (AD) and an earlier onset [Saunders et al., 1993; Strittmatter et al., 1993; Poirier et al., 1993]. This genetic association has led to many investigations into the role of APOE in AD pathogenesis and in other neurodegenerative disorders. One such hypothesis is that APOE may play a significant role in the central nervous system response to injury, in particular medi- ating growth in the telencephalic hippocampal region due to AD neurodegeneration [Poirier et al., 1994]. Evi- dence of cognitive dysfunction, associated with hippo- campal degeneration in chronic schizophrenics can be seen in the high incidence of cognitive intrusion errors on verbal learning tests, such as the California Verbal Learning Test [Heinrichs and Awad, 1993]. DNA was extracted from lymphocytes using 300 ml of *Correspondence to: Michael Mullan, M.D. Ph.D., Ros- kamp Professor in Biological Psychiatry, University of South Florida, 3515 Fletcher Ave., Tampa, FL 33613. E-mail: [email protected] Received 8 April 1997 TABLE I. APOE Allele and Genotype Frequencies in Schizophrenics and Controls APOE alleles Schizophrenia Controls e2 .095 .056 e3 .762 .807 e4 .143 .136 (n 4 126) (n 4 602) x 2 4 2.52, P 4 .284 Genotypes 2,3 .159 .093 3,3 .571 .648 2,4 .032 .020 3,4 .222 .226 4,4 .016 .013 (n 4 63) (n 4 301) x 2 4 2.74, P 4 .602 TABLE II. APOE e4 Carrier Frequencies and Powers for Each Study and Combined Data Harrington et al. Joober et al. Town et al. Combined SZ Controls SZ Controls SZ Controls SZ Controls e4 carriers .452 .267 .157 .200 .270 .259 .282 .257 non e4 carriers .548 .733 .843 .800 .730 .741 .718 .743 mean age 65.8 76.1 41.5 65.4 42.9 71.7 48.6 72.5 (SD) (17.3) (14.4) (9.1) (12.0) (8.67) (7.63) (11.7) (10.3) n 42 131 51 35 63 301 156 467 Power 63% 36% 60% 93% x 2 4 0.376, P 4 .54 American Journal of Medical Genetics (Neuropsychiatric Genetics) 74:451–452 (1997) © 1997 Wiley-Liss, Inc.
Transcript of Lack of association between the apolipoprotein E ε4 allele (APOE ε4) and chronic schizophrenia
Letter to the Editor
Lack of Association Between the Apolipoprotein Ee4 Allele (APOE e4) and Chronic Schizophrenia
To the Editor:
In a previous study, Harrington et al. [1995] hypoth-esized a neurodegenerative role for apolipoprotein E(APOE) in schizophrenia, and reported an increased e4allele frequency in patients with schizophrenia. In alater study, Joober et al. [1996] was unable to replicatethis association, finding no significant difference in e4carrier status between schizophrenic patients and con-trols. We investigated this association in 63 clinicallydiagnosed schizophrenics and in 301 controls. Our find-ings concur with those of Joober et al., in that theAPOE e4 allele was equally represented in both theschizophrenic group (14.3%) and the control group(13.6%), indicating no association between schizophre-nia and the e4 allele.
The APOE gene codes for a lipoprotein involved incholesterol and phospholipid transport. A polymorphicsite within the gene has three common forms (e2, e3,e4) which code for three common isoforms (E2, E3, E4).The APOE e4 allele has been consistently associatedwith increased risk for sporadic and familial Alzhei-mer’s disease (AD) and an earlier onset [Saunders etal., 1993; Strittmatter et al., 1993; Poirier et al., 1993].This genetic association has led to many investigationsinto the role of APOE in AD pathogenesis and in otherneurodegenerative disorders. One such hypothesis isthat APOE may play a significant role in the central
nervous system response to injury, in particular medi-ating growth in the telencephalic hippocampal regiondue to AD neurodegeneration [Poirier et al., 1994]. Evi-dence of cognitive dysfunction, associated with hippo-campal degeneration in chronic schizophrenics can beseen in the high incidence of cognitive intrusion errorson verbal learning tests, such as the California VerbalLearning Test [Heinrichs and Awad, 1993].
DNA was extracted from lymphocytes using 300 ml of
*Correspondence to: Michael Mullan, M.D. Ph.D., Ros-kamp Professor in Biological Psychiatry, University of SouthFlorida, 3515 Fletcher Ave., Tampa, FL 33613. E-mail:[email protected]
Received 8 April 1997
TABLE I. APOE Allele and Genotype Frequencies inSchizophrenics and Controls
APOE alleles Schizophrenia Controls
e2 .095 .056e3 .762 .807e4 .143 .136
(n 4 126) (n 4 602)
x2 4 2.52, P 4 .284
Genotypes
2,3 .159 .0933,3 .571 .6482,4 .032 .0203,4 .222 .2264,4 .016 .013
(n 4 63) (n 4 301)
x2 4 2.74, P 4 .602
TABLE II. APOE e4 Carrier Frequencies and Powers for Each Study and Combined Data
Harrington et al. Joober et al. Town et al. Combined
SZ Controls SZ Controls SZ Controls SZ Controls
e4 carriers .452 .267 .157 .200 .270 .259 .282 .257non e4 carriers .548 .733 .843 .800 .730 .741 .718 .743mean age 65.8 76.1 41.5 65.4 42.9 71.7 48.6 72.5(SD) (17.3) (14.4) (9.1) (12.0) (8.67) (7.63) (11.7) (10.3)n 42 131 51 35 63 301 156 467Power 63% 36% 60% 93%
x2 4 0.376, P 4 .54
American Journal of Medical Genetics (Neuropsychiatric Genetics) 74:451–452 (1997)
© 1997 Wiley-Liss, Inc.
whole blood drawn from 63 clinically diagnosed schizo-phrenics (based on the DSM-IIIR criteria, mean age42.9, SD 4 8.67) and 301 community-based controls(mean age 71.7, SD 4 7.63) with no previous report ofpsychiatric problems. APOE genotyping was performedaccording to the methods of Wenham et al. [1991].
As shown in Table I, the APOE e4 allele frequenciesin our sample were not significantly different betweenchronic schizophrenics and controls (x2 4 2.52,P 4 0.28), nor were any significant genotypic differ-ences seen between these two groups (x2 4 2.74,P 4 0.60). Our sample size provides greater power(60% versus 35.6%) than the previous study reporting anull association [Joober et al, 1996], thus reducing thelikelihood of a type II error. To further confirm ourresult, we combined the data of all three studies (in-creasing the power to 93%), and again found no asso-ciation between e4 carrier status and schizophrenia di-agnosis (x2 4 0.376, P 4 0.540; see Table II). All threestudies were conducted in Caucasian populations usingDSM-IIIR criteria for diagnosis. Although the meanages for the three schizophrenic groups are different(see Table II), Harrington et al. [1995] found no inter-action between age and the APOE-schizophrenia asso-ciation, indicating that the differences in age shouldnot affect the outcome of the overall group analysis.
These results taken together strongly suggest no as-sociation between APOE and schizophrenia.
REFERENCESHarrington C, Roth M, Xuereb J, McKenna P, Wischik C (1995): Apolipo-
protein E type E4 allele frequency is increased in patients with schizo-phrenia. Neurosc Letters 202:101–104.
Heinrichs R, Awad A (1993): Neurocognitive subtypes of chronic schizo-phrenia. Schizophr Res 9:49–58.
Joober R, Rouleau G, Fon E, Lal S, Palmour R, Bloom D, Labelle A, Ben-kelfat C (1996): Apolipoprotein E Genotype in Schizophrenia. Neuro-psyc Genet 67:235.
Poirier J, Davignon J, Bouthillier D, Kogan S, Bertrand P, Gauthier S(1993): Apolipoprotein E Polymorphism and Alzheimer’s Disease. Lan-cet, 342:697–699.
Poirier J (1994): Apolipoprotein E in animal models of CNS injury and inalzheimer’s disease. TINS 17:525–530.
Saunders A, Schmader K, Breitner J, Benson M, Brown W, Goldfarb L,Goldgaber D, Manwering M, Szymanski M, McCrown N, Dole K, Sch-mechel D, Strittmatter W, Pericak-Vance M, Roses A (1993): Apolipo-protein E E4 allele distributions in late-onset Alzheimer’s disease andin other amyloid-forming diseases. Lancet 342:710–711.
Strittmatter W, Saunders A, Schmechel D, Pericak-Vance M, Enghild J,Salvesen G, Roses A (1993): Apolipoprotein E: high avidity binding toB-amyloid and to increased frequency of type 4 allele in late-onsetfamilial Alzheimer’s disease. Proc Natl Acad Sci USA 90:1977–1981.
Wenham PR, Price WH, Blundell G (1991): Apolipoprotein E genotyping byone-stage PCR. Lancet 337:1158–1159.
T. TownD. FallinF. CrawfordRoskamp Laboratories, Department of Psychiatry,University of South Florida, Tampa, Florida
S. WalshR. SolomonG. Pierce Wood Memorial HospitalArcadia, Florida
M. Mullan*Roskamp Laboratories, Department of Psychiatry,University of South Florida, Tampa, Florida
452 Town et al.
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