- Email: [email protected]
No association between APOE and major depressive disorder in a community sample of 17,507 adults
Journal of Psychiatric Research 43 (2009) 843–847
Contents lists available at ScienceDirect
Journal of Psychiatric Research journal homepage: www.elsevier.com/locate/jpsychires
No association between APOE and major depressive disorder in a community sample of 17,507 adults Paul G. Surtees a,*, Nicholas W.J. Wainwright a, Richard Bowman b, Robert N. Luben a, Nicholas J. Wareham c, Kay-Tee Khaw d, Sheila A. Bingham b,e a
Strangeways Research Laboratory and University of Cambridge Department of Public Health and Primary Care, Worts Causeway, Cambridge CB1 8RN, UK Medical Research Council Dunn Human Nutrition Unit, Cambridge CB2 0XY, UK c MRC Epidemiology Unit, Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge CB2 0QQ, UK d Clinical Gerontology Unit, University of Cambridge School of Clinical Medicine, Addenbrooke’s Hospital, Cambridge CB2 2QQ, UK e Medical Research Council Centre for Nutritional Epidemiology in Cancer Prevention and Survival, Department of Public Health and Primary Care, Cambridge CB1 8RN, UK b
a r t i c l e
i n f o
Article history: Received 27 August 2008 Received in revised form 30 October 2008 Accepted 1 December 2008
Keywords: APOE Association study Depression Epidemiology Neuroticism Psychological distress
a b s t r a c t Mood-related phenotypes are commonly comorbid with, and have been implicated in the development of, neurological disorders. APOE is a major susceptibility gene for neurodegeneration. Recent evidence from case-control studies has suggested that the apoE 2 allele is associated with major depressive disorder (MDD). However, evidence from large-scale community-based studies is limited. APOE was genotyped for 17,507 men and women, aged 41–80 years, participating in the European Prospective Investigation into Cancer–Norfolk study, who had also completed a psychosocial assessment that included measures of emotional health status defined by MDD, psychological distress (as represented by the Mental Health Inventory, MHI-5), and by an assessment of neuroticism. No associations were found between APOE genotypes and measures either of past-year or lifetime MDD, or of emotional health defined according to the MHI-5 or by neuroticism. Data from this large-scale, community-based, study are not supportive of an association between either MDD or associated measures of emotional state and APOE genotype. These findings suggest that the association between APOE and MDD risk is more modest than has been previously reported. Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction APOE is regarded as a major susceptibility gene associated with cellular uptake of lipoproteins, neuronal maintenance and repair, sporadic and familial Alzheimer’s disease, coronary disease and possibly age-related macular degeneration, stroke and subarachnoid hemorrhage (including subsequent adverse outcome) (Strittmatter et al., 1993; Mahley and Rall, 2000; Song et al., 2004; Sudlow et al., 2006; Mahley et al., 2006; Thakkinstian et al., 2006; Coon et al., 2007; Bennet et al., 2007; Lanterna et al., 2007; Tzourio et al., 2008). Complementary evidence has shown mood-related phenotypes to be implicated in the onset of (and to be commonly comorbid with) many of these physical health outcomes, particularly neurological disorders (Devanand et al., 1996; Wulsin and Singal, 2003; Dal Forno et al., 2005; Kanner, 2005; Salaycik et al., 2007; Surtees et al.,2008a,b), leading to the suggestion that depression is likely to be a neurological disorder with psychiatric symptoms (Kanner, 2004). * Corresponding author. Tel.: +44 1223 740651; fax: +44 1223 740147. E-mail address: [email protected] (P.G. Surtees). 0022-3956/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.jpsychires.2008.12.001
APOE has three major isoforms (apoE2, apoE3, and apoE4) encoded by three alleles (2; 3, and 4) from two single nucleotide polymorphisms at residues 112 (rs429358) and 158 (rs7412) (Mahley and Rall, 2000). Evidence suggests that apoE2 may be the most beneficial APOE isoform, while apoE4 carries the most risk of neurodegeneration (Mahley et al., 2006). Evidence from a recent meta-analysis of case-control studies, considering a range of candidate major depressive disorder (MDD) susceptibility genes, suggested that the APOE 2 allele was associated with MDD (López-León et al., 2007). This analysis combined studies with patients of differing ethnic origin, and that varied in their application of age of depression onset criteria. The scarcity of studies, their limited power, and the need to evaluate broader depression-related phenotypes (Krishnan, 2005) collectively act to limit understanding of the relationship between APOE and depression, and potentially their joint role in neurodegeneration. Using data from 17,507 participants in the European Prospective Investigation into Cancer (EPIC)-Norfolk study, a communitybased cohort study, we now investigate the association between APOE polymorphisms and selected broad-based established measures of emotional health.
844
P.G. Surtees et al. / Journal of Psychiatric Research 43 (2009) 843–847
2. Materials and methods
4. Statistical analysis
Residents of Norfolk (UK) were recruited into the EPIC–Norfolk study during 1993–1997 using general practice age-sex registers (Day et al., 1999). The study was approved by the Norwich District Health Authority Ethics Committee, and all participants gave signed informed consent. The Health and Life Experiences Questionnaire (HLEQ), an assessment of social and psychological circumstances, was completed between 1996 and 2000 by a total of 20,921 (73.2 percent of eligible) EPIC–Norfolk participants. The HLEQ included a structured self-assessment approach to psychiatric symptoms that enabled application of restricted Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) (American Psychiatric Association, 1994) criteria for episodic MDD. The assessment, designed to identify those study participants thought likely to have met a putative diagnosis of MDD at any time in their lives, depends upon participants initially disclosing details of their most recently experienced episode of depression (if more than one) that has endured for two weeks or more and that fulfils the required concurrent DSM-IV MDD symptom criteria. Additionally, operational criteria for clinically significant impairment and helpseeking were included and participants were requested to estimate episode onset and (if appropriate) offset timings (see Surtees et al., 2000 for the HLEQ MDD assessment module). Past-year MDD was defined as any episode that was either current at the time of HLEQ completion or ended within the 12 months preceding assessment. In addition, the HLEQ included an assessment of neuroticism through completion of a short form of the Eysenck Personality Questionnaire (Eysenck et al., 1985), and scored within the range from 0 to 12 with higher scores indicating increased neuroticism. The HLEQ also included a five-item version of the Mental Health Inventory (MHI-5), with one or more items representing anxiety, depression, loss of behavioral/emotional control, and psychological well-being during the past 4-weeks, as part of a validated generic measure of subjective health status, the anglicised version of the Short Form 36 (SF-36) (Ware et al., 1993). The MHI-5 was scored on a scale from 0 to 100 where a lower score represents greater psychological distress.
Lifetime and past-year prevalence of MDD are presented according to APOE genotype, with odds ratios and 95% confidence intervals for comparisons against the 3=3 genotype as baseline. Mean and standard deviation neuroticism and MHI-5 scores are presented according to APOE genotype with b coefficients and 95% confidence intervals obtained from linear regression. Associations with APOE genotype were tested through 5 degree of freedom v2 -tests (for binary measures) and F-tests (for continuous measures). For increased power, a 1 degree of freedom test of linear association was also performed with genotypes ordered as 2=2; 2=3; 2=4; 3=3; 3=4, and 4=4, consistent with evidence reported in a recent meta-analysis of linear association with both LDL cholesterol and coronary disease risk (where LDL cholesterol and coronary disease risk were lowest in those with the 2=2 genotype and highest in those with the 4=4 genotype) (Bennet et al., 2007). In addition, and consistent with data presentation from previous studies (López-León et al., 2007), a 1 degree of freedom (per-allele) test of association was used to compare carriers of the 2 allele with those of the 3 allele (with the 2=4 genotype omitted from analysis, and where 3=3 was taken as baseline = 0 alleles, 2=3 ¼ 1, and 2=2 ¼ 2 alleles). Similarly a 1 degree of freedom (per-allele) test of association was used to compare carriers of the 4 allele with those of the 3 allele.
3. Genotyping DNA for genotyping was extracted from blood in EDTA and from remnant red blood cell samples (and buffy coats) at either of two health checks (see Wu et al. (2007) for further details). APOE polymorphisms were genotyped for 24,513 EPIC–Norfolk participants using Pyrosequencing. PCR was performed to obtain an amplicon of 185 bp covering the area of interest, amino acids 112 and 158, with primers 50 -GGG CGC GGA CAT GGA GG-30 and a 50 biotin labelled primer 50 -Biotin-CCC CGG CCT GGT ACA CTG-30 designed by Pyrosequencing Assay Design Software (Pyrosequencing AB, Sweden). A 50 lL PCR mixture was prepared with 1 PCR Buffer, 2 mM MgCl2 , 5% DMSO, 0.125 mM of each dNTP with 75% of dGTP replaced by dITP, 10 pmol of each primer, two units of Taq Gold and 12 ng of DNA. The annealing temperature was 62 °C and PCR was performed for 45 cycles in a DNA Thermal Cycler (PTC-225; MJ Research, Inc., Watertown, MA, USA). The amplicon was prepared as described elsewhere (Ronaghi et al., 1996) with the two sequencing primers: 50 -GAC ATG GAG GAC GTG-30 for site 112 and 50 -CCG ATG ACC TGC AGA-30 for site 158. The Pyrosequencing (Pyrosequencing, AB, Sweden) machine was prepared as recommended by the manufacturer and the samples were loaded into the machine and scored using the PSQ 96MA 2.1 operating system. An additional 135 samples were genotyped by RFLP (restriction fragment length polymorphism) with full concordance (Wu et al., 2007).
5. Results APOE genotype data were available for 17,623 participants who had completed the HLEQ assessment. After excluding 59 participants of unknown ethnicity and a further 57 from ethnic groups other than white, a sample of 17,507 participants, 7771 men and 9736 women, aged between 41 and 80 years (mean age = 60.9 years), was used for analysis. Genotype and allele frequencies were similar to those previously reported in Caucasian populations in the United Kingdom (Mahley and Rall, 2000; Wu et al., 2007). No differences in genotype frequencies were observed by sex (v2 ¼ 5:1 on 5 df, p = 0.41). Of this sample, 2694 (15.4%) participants reported a lifetime history of MDD and 894 (5.1%) reported an episode of MDD within 12 months of assessment. Table 1 shows lifetime and past-year prevalence rates of MDD according to APOE genotype. Compared to participants with the 3=3 genotype, those with the 2=2 genotype had lower rates of past-year and lifetime MDD, and those with the 4=4 genotype had higher rates of past-year and lifetime MDD. However, these associations were not significant either for a 5 degree of freedom test across APOE genotypes (Table 1), or according to a 1 degree of freedom test of linear association (p = 0.62 for lifetime MDD and p = 0.96 for past-year MDD). In addition, while observed differences in MDD prevalence were greatest for participants with the 2=2 genotype in comparison to those with the 4=4 genotype, these differences were not significant (odds ratio for 2=2 versus 4=4 0.60 (95% confidence interval 0.32–1.13), p = 0.11 for lifetime MDD, and 0.49 (0.17–1.43), p = 0.19 for past-year MDD). In these data, odds ratios per 2 allele were 1.05 (95% confidence interval 0.94–1.18) for lifetime and 1.01 (0.84–1.22) for past-year MDD; and per 4 allele were 1.03 (0.95–1.12) for lifetime and 1.03 (0.90–1.18) for past-year MDD. No associations were observed between APOE genotype and either past-year or lifetime MDD, for men or for women, or for subgroups of participants defined according to whether they were aged less than 65, or 65 years and older, at the time of psychosocial assessment. Table 2 shows mean neuroticism and MHI-5 scores, according to APOE genotype. While participants with the 2=2 genotype (compared with those who had the 3=3 genotype) had lower
845
P.G. Surtees et al. / Journal of Psychiatric Research 43 (2009) 843–847 Table 1 Number (%) of participants with lifetime and past-year major depressive disorder (MDD) and odds ratios (95% confidence intervals) according to APOE genotype. Lifetime MDD
Genotype 2=2 2=3 2=4 3=3 3=4 4=4 *
n 107 2,177 434 10,242 4,151 396
(%) (0.6) (12.4) (2.5) (58.5) (23.7) (2.3)
Past-year MDD
Yes n (%)
No n (%)
OR
(95% CI)
13 357 65 1,560 626 73
94 1,769 362 8,474 3,447 316
0.75 1.10 0.98 1 0.99 1.25
(0.42–1.34) (0.97–1.24) (0.74–1.28)
*
P
Yes n (%)
No n (%)
4 116 20 525 200 29
100 1,986 402 9,398 3,827 358
OR
(95% CI)
0.72 1.05 0.89 1 0.94 1.45
(0.26–1.95) (0.85–1.29) (0.56–1.41)
0.29 (12.1) (16.8) (15.2) (15.5) (15.4) (18.8)
(87.9) (83.2) (84.8) (84.5) (84.6) (81.2)
(0.89–1.09) (0.97–1.63)
P* 0.40
(3.8) (5.5) (4.7) (5.3) (5.0) (7.5)
(96.2) (94.5) (95.3) (94.7) (95.0) (92.5)
(0.79–1.11) (0.98–2.14)
5 degree of freedom test across all genotypes.
Table 2 Mean (SD) neuroticism and 5-item Mental Health Inventory (MHI-5) scale scores and b coefficients (95% confidence intervals) according to APOE genotype. Neuroticism
Genotype 2=2 2=3 2=4 3=3 3=4 4=4 *
n 107 2,190 436 10,312 4,179 399
(%) (0.6) (12.4) (2.5) (58.5) (23.7) (2.3)
MHI-5 P*
Mean
(SD)
b
(95% CI)
4.23 4.30 4.48 4.37 4.37 4.37
(3.05) (3.22) (3.20) (3.28) (3.24) (3.20)
0.13 0.06 0.12 0 0.00 0.00
(0.75–0.49) (0.21–0.09) (0.20–0.43)
Mean
(SD)
b
(95% CI)
79.4 77.4 77.0 77.4 76.8 77.2
(14.3) (16.2) (15.6) (16.1) (16.2) (16.8)
2.01 0.06 0.34 0 0.58 0.17
(1.07–5.10) (0.69–0.81) (1.90–1.22)
0.92
(0.12–0.12) (0.33–0.33)
P* 0.29
(1.17–0.00) (1.81–1.46)
5 degree of freedom test across all genotypes.
neuroticism scores (representing reduced neuroticism) and higher MHI-5 scores (representing increased psychological well-being), these associations were not significant, either for a 5 degree of freedom test of association across APOE genotypes (Table 2) or according to a 1 degree of freedom test of linear association (p = 0.50 for neuroticism and p = 0.10 for MHI-5 scores). 6. Discussion We found no evidence of association between APOE genotype and MDD based on data from 17,507 participants in the EPIC–Norfolk study. A recent meta-analysis (López-León et al., 2007) that included younger (Fan et al., 2006), and older (Butters et al., 2003; Forsell et al., 1997) participants than those in the present study, concluded that the APOE 2 allele was associated with a reduced risk of depression (odds ratio per allele 0.51 (95% confidence interval 0.27–0.97)). This association was based on a combined total of 827 MDD cases and 1616 controls, that persisted following restriction only to Caucasian study population groups (odds ratio per allele 0.72 (95% confidence interval 0.51–1.00)), though was not significant once data from the first published study of only 45 elderly inpatients (Zubenko et al., 1996) was excluded from analysis. Overall support for this association is therefore weakened by our findings of no association (odds ratio per allele 1.05 (95% confidence interval 0.94–1.18) for lifetime MDD and 1.01 (0.84–1.22) for past-year MDD)), based on 2694 lifetime and 894 past-year MDD cases. While the meta-analysis included data from 7 casecontrol studies (López-León et al., 2007), evidence from large-scale community-based studies is rare. Our findings are consistent, however, with a report of no overall association between APOE and depression, based on data from a community study of 3492 men and women aged 65 and older (Steffens et al., 2003). In this study, all four measures of emotional status considered (lifetime and past-year MDD, neuroticism and psychological distress) indicated lower depression risk for participants with the 2=2 genotype. These data are perhaps suggestive that an association with depression is restricted to carriers of two copies of the 2 allele. In addition, prevalence of both lifetime and past-year
MDD were increased in participants with the 4=4 genotype, perhaps suggestive of accentuated differences between participants with the 2=2 compared to the 4=4 genotype. However, these comparisons were not significant in these data, and given the small proportion of participants in the population with these genotypes, such associations would be of more modest clinical importance. The major strength of this study is the very large sample size, with 90% power to detect odds ratios of 0.82 for a test of association between the 2 allele and lifetime MDD, and 0.71 for past-year MDD; effect sizes of more modest magnitude than previously reported (López-León et al., 2007). The main limitation of this study is through the self-report assessment of lifetime history of MDD. The structured HLEQ self-assessment approach represents a pragmatic solution to enabling a measure of emotional state, representative of core DSM-IV diagnostic criteria, to be included in a largescale chronic disease epidemiology setting. Prevalence estimates together with demographic and chronic disease risk profiles associated with the MDD measure used in this study have been shown to be broadly similar to those derived from dedicated large-scale psychiatric epidemiology research studies (Surtees et al., 2000, 2003; Wainwright and Surtees, 2002; Surtees et al., 2008a,b). However, errors of measurement can result in attenuation in the magnitude of observed associations and may therefore provide an alternative explanation for our findings of no association. A further strength of this study is the availability of a more general measure of psychological distress, defined by the MHI-5, a measure of depression severity (Berwick et al., 1991; Rumpf et al., 2001; Rogers et al., 2005), and of neuroticism, a marker of liability to major depression (Kendler et al., 1993), alongside the HLEQ measure of MDD defined according to diagnostic criteria. We might have expected, but did not find, evidence of association between APOE genotype and these measures of psychological distress and of neuroticism. Data from this large-scale, community-based study are not supportive of an association between either MDD or associated measures of psychological state and APOE genotype. Our results therefore increase the likelihood either that APOE does not contribute to MDD risk, or that the association, perhaps restricted to
846
P.G. Surtees et al. / Journal of Psychiatric Research 43 (2009) 843–847
individuals with two copies of the 2 allele, is more modest than previous evidence has suggested. The ‘vascular depression hypothesis’ (Alexopoulos et al., 1997) states that cerebrovascular disease ‘can predispose, precipitate, or perpetuate a depressive syndrome in older adults’ (Alexopoulos, 2006), and proposes subcortical ischemic vascular depression as a distinct and valid disease entity (Taylor et al., 2006; Sneed et al., 2008). Recent evidence, based upon a longitudinal study of participants aged 70–79 years, has reported that both symptomatic (e.g. angina) and asymptomatic/covert conditions (e.g. low HDL, high fasting glucose) were associated with increased risk of depression, providing support for the hypothesis (Mast et al., 2008). The possibility remains therefore that APOE is a susceptibility gene for depression phenotypes defined by more focused hypotheses. Conflict of interest statement There are no conflicts of interest. Contributors PGS conceived the study and with NWJW wrote the first draft of the paper. NWJW is responsible for data analysis. RB is responsible for genotyping. RNL is responsible for EPIC–Norfolk research programme data management. All authors contributed to, and have approved, the final manuscript. Role of the funding source Funding for this study was provided by programme grants from the Medical Research Council UK (G9502233, G0300128) and Cancer Research UK (C865/A2883) with additional support from the European Union, Stroke Association, British Heart Foundation, Department of Health and the Wellcome Trust. These funding agencies had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication. Acknowledgements We thank the participants and general practitioners who took part in this study and the staff associated with the EPIC–Norfolk research programme. References Alexopoulos GS. The vascular depression hypothesis: 10 years later. Biological Psychiatry 2006;60:1304–5. Alexopoulos GS, Meyers BS, Young RC, Campbell S, Silbersweig D, Charlson M. ‘Vascular depression’ hypothesis. Archives of General Psychiatry 1997;54: 915–22. American Psychiatric Association, Diagnostic and statistical manual of mental disorders. 4th ed. Washington, DC: American Psychiatric Association (APA); 1994. Bennet AM, Di Angelantonio E, Ye Z, Wensley F, Dahlin A, Ahlbom A, et al. Association of apolipoprotein E genotypes with lipid levels and coronary risk. Journal of the American Medical Association 2007;298:1300–11. Berwick DM, Murphy JM, Goldman PA, Ware JE, Barsky AJ, Weinstein MC. Performance of a five-item mental health screening test. Medical Care 1991;29:169–76. Butters MA, Sweet RA, Mulsant BH, Kamboh MI, Pollock BG, Begley AE, et al. APOE is associated with age-of-onset, but not cognitive functioning, in late-life depression. International Journal of Geriatric Psychiatry 2003;18:1075–81. Coon KD, Myers AJ, Craig DW, Webster JA, Pearson JV, Lince DH, et al. A high-density whole-genome association study reveals that APOE is the major susceptibility gene for sporadic late-onset Alzheimer’s disease. Journal of Clinical Psychiatry 2007;68:613–8. Dal Forno G, Palermo MT, Donohue JE, Karagiozis H, Zonderman AB, Kawas CH. Depressive symptoms, sex, and risk for Alzheimer’s disease. Annals of Neurology 2005;57:381–7.
Day N, Oakes S, Luben R, Khaw KT, Bingham S, Welch A, et al. EPIC–Norfolk: study design and characteristics of the cohort. British Journal of Cancer 1999;80;(Suppl. 1):95–103. Devanand DP, Sano M, Tang MX, Taylor S, Gurland BJ, Wilder D, et al. Depressed mood and the incidence of Alzheimer’s disease in the elderly living in the community. Archives of General Psychiatry 1996;53:175–82. Eysenck SBG, Eysenck HJ, Barrett P. A revised version of the Psychoticism scale. Personality and Individual Differences 1985;6:21–9. Fan PL, Chen CD, Kao WT, Shu BC, Lung FW. Protective effect of the apo epsilon 2 allele in major depressive disorder in Taiwanese. Acta Psychiatrica Scandinavica 2006;113:48–53. Forsell Y, Corder EH, Basun H, Lannfelt L, Viitanen M, Winblad B. Depression and dementia in relation to apolipoprotein E polymorphism in a population sample age 75+. Biological Psychiatry 1997;42:898–903. Kanner AM. Is major depression a neurologic disorder with psychiatric symptoms? Epilepsy and Behavior 2004;5:636–44. Kanner AM. Depression and the risk of neurological disorders. Lancet 2005;366:1147–8. Kendler KS, Neale MC, Kessler RC, Heath AC, Eaves LJ. A longitudinal twin study of personality and major depression in women. Archives of General Psychiatry 1993;50:853–62. Krishnan KR. Psychiatric disease in the genomic era: rational approach. Molecular Psychiatry 2005;10:978–84. Lanterna LA, Ruigrok Y, Alexander S, Tang J, Biroli F, Dunn LT, et al. Meta-analysis of APOE genotype and subarachnoid hemorrhage - clinical outcome and delayed ischemia. Neurology 2007;69:766–75. López-León A, Janssens ACJW, González-Zuloeta Ladd AM, Del-Favero J, Claes SJ, Oostra BA, et al. Meta-analyses of genetic studies on major depressive disorder. Molecular Psychiatry 2007;13:772–85. Mahley RW, Rall SC. Apolipoprotein E: far more than a lipid transport protein. Annual Review Of Genomics And Human Genetics 2000;1:507–37. Mahley RW, Weisgraber KH, Huang YD. Apolipoprotein E4: a causative factor and therapeutic target in neuropathology including Alzheimer’s disease. Proceedings of the National Academy of Sciences 2006;103:5644–51. Mast BT, Miles T, Penninx BW, Yaffe K, Rosano C, Satterfield S, et al. Vascular disease and future risk of depressive symptomatology in older adults: findings from the HEALTH, aging, and body composition study. Biological Psychiatry 2008;64: 320–6. Rogers WH, Adler DA, Bungay KM, Wilson IB. Depression screening instruments made good severity measures in a cross-sectional analysis. Journal of Clinical Epidemiology 2005;58:370–7. Ronaghi M, Karamohamed S, Pettersson B, Uhlen M, Nyren P. Real-time DNA sequencing using detection of pyrophosphate release. Analytical Biochemistry 1996;242:84–9. Rumpf HM, Meyer C, Hapke U, John U. Screening for mental health: validity of the MHI-5 using DSM-IV Axis I psychiatric disorders as gold standard. Psychiatry Research 2001;105:243–53. Salaycik KJ, Kelly-Hayes M, Beiser A, Nguyen AH, Brady SM, Kase CS, et al. Depressive symptoms and risk of stroke: the Framingham study. Stroke 2007;38:16–21. Sneed JR, Rindskopf D, Steffens DC, Krishnan KRR, Roose SP. The vascular depression subtype: evidence of internal validity. Biological Psychiatry 2008;64:491–7. Song YQ, Stampfer MJ, Liu SM. Meta-analysis: apolipoprotein E genotypes and risk for coronary heart disease. Annals of Internal Medicine 2004;141: 137–47. Steffens DC, Norton MC, Hart AD, Skoog I, Corcoran C, Breitner JCS. Apolipoprotein E genotype and major depression in a community of older adults. The cache county study. Psychological Medicine 2003;33:541–7. Strittmatter WJ, Saunders AM, Schmechel D, Pericakvance M, Enghild J, Salvesen GS, et al. Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type-4 allele in late-onset familial Alzheimer disease. Proceedings of the National Academy of Sciences 1993;90:1977–81. Sudlow C, Gonzalez NAM, Kim J, Clark C. Does apolipoprotein E genotype influence the risk of ischemic stroke, intracerebral hemorrhage, or subarachnoid hemorrhage? systematic review and meta-analyses of 31 studies among 5961 cases and 17,965 controls. Stroke 2006;37:364–70. Surtees PG, Wainwright NWJ, Brayne C. Psychosocial aetiology of chronic disease: a pragmatic approach to the assessment of lifetime affective morbidity in an EPIC component study. Journal of Epidemiology and Community Health 2000;54: 114–22. Surtees PG, Wainwright NWJ, Khaw KT, Day NE. Functional health status, chronic medical conditions and disorders of mood. British Journal of Psychiatry 2003;183:299–303. Surtees PG, Wainwright NWJ, Luben RN, Wareham NJ, Bingham SA, Khaw KT. Depression and ischemic heart disease mortality: evidence from the EPIC– Norfolk United Kingdom prospective cohort study. American Journal of Psychiatry 2008a;165:515–23. Surtees PG, Wainwright NWJ, Luben RN, Wareham NJ, Bingham SA, Khaw KT. Psychological distress, major depressive disorder and risk of stroke. Neurology 2008b;70:788–94. Taylor WD, Steffens DC, Krishnan KR. Psychiatric disease in the twenty-first century: the case for subcortical ischemic depression. Biological Psychiatry 2006;60:1299–303. Thakkinstian A, Bowe S, McEvoy M, Smith W, Attia J. Association between apolipoprotein E polymorphisms and age-related macular degeneration: a
P.G. Surtees et al. / Journal of Psychiatric Research 43 (2009) 843–847 HuGE review and meta-analysis. American Journal of Epidemiology 2006;164:813–22. Tzourio C, Arima H, Harrap S, Anderson C, Godin O, Woodward M, et al. APOE genotype, ethnicity, and the risk of cerebral hemorrhage. Neurology 2008;70:1322–8. Wainwright NWJ, Surtees PG. Childhood adversity, gender and depression over the life-course. Journal of Affective Disorders 2002;72:33–44. Ware JE, Snow KK, Kosinski M, Gandek B. SF-36 health survey: manual and interpretation guide. Boston: Nimrod Press; 1993.
847
Wu K, Bowman R, Welch AA, Luben RN, Wareham N, Khaw KT, et al. Apolipoprotein E polymorphisms, dietary fat and fibre, and serum lipids: the EPIC Norfolk study. European Heart Journal 2007;28:2930–6. Wulsin LR, Singal BM. Do depressive symptoms increase the risk for the onset of coronary disease? a systematic quantitative review. Psychosomatic Medicine 2003;65:201–10. Zubenko GS, Henderson R, Stiffler JS, Stabler S, Rosen J, Kaplan BB. Association of the APOE epsilon 4 allele with clinical subtypes of late life depression. Biological Psychiatry 1996;40:1008–16.
Contents lists available at ScienceDirect
Journal of Psychiatric Research journal homepage: www.elsevier.com/locate/jpsychires
No association between APOE and major depressive disorder in a community sample of 17,507 adults Paul G. Surtees a,*, Nicholas W.J. Wainwright a, Richard Bowman b, Robert N. Luben a, Nicholas J. Wareham c, Kay-Tee Khaw d, Sheila A. Bingham b,e a
Strangeways Research Laboratory and University of Cambridge Department of Public Health and Primary Care, Worts Causeway, Cambridge CB1 8RN, UK Medical Research Council Dunn Human Nutrition Unit, Cambridge CB2 0XY, UK c MRC Epidemiology Unit, Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge CB2 0QQ, UK d Clinical Gerontology Unit, University of Cambridge School of Clinical Medicine, Addenbrooke’s Hospital, Cambridge CB2 2QQ, UK e Medical Research Council Centre for Nutritional Epidemiology in Cancer Prevention and Survival, Department of Public Health and Primary Care, Cambridge CB1 8RN, UK b
a r t i c l e
i n f o
Article history: Received 27 August 2008 Received in revised form 30 October 2008 Accepted 1 December 2008
Keywords: APOE Association study Depression Epidemiology Neuroticism Psychological distress
a b s t r a c t Mood-related phenotypes are commonly comorbid with, and have been implicated in the development of, neurological disorders. APOE is a major susceptibility gene for neurodegeneration. Recent evidence from case-control studies has suggested that the apoE 2 allele is associated with major depressive disorder (MDD). However, evidence from large-scale community-based studies is limited. APOE was genotyped for 17,507 men and women, aged 41–80 years, participating in the European Prospective Investigation into Cancer–Norfolk study, who had also completed a psychosocial assessment that included measures of emotional health status defined by MDD, psychological distress (as represented by the Mental Health Inventory, MHI-5), and by an assessment of neuroticism. No associations were found between APOE genotypes and measures either of past-year or lifetime MDD, or of emotional health defined according to the MHI-5 or by neuroticism. Data from this large-scale, community-based, study are not supportive of an association between either MDD or associated measures of emotional state and APOE genotype. These findings suggest that the association between APOE and MDD risk is more modest than has been previously reported. Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction APOE is regarded as a major susceptibility gene associated with cellular uptake of lipoproteins, neuronal maintenance and repair, sporadic and familial Alzheimer’s disease, coronary disease and possibly age-related macular degeneration, stroke and subarachnoid hemorrhage (including subsequent adverse outcome) (Strittmatter et al., 1993; Mahley and Rall, 2000; Song et al., 2004; Sudlow et al., 2006; Mahley et al., 2006; Thakkinstian et al., 2006; Coon et al., 2007; Bennet et al., 2007; Lanterna et al., 2007; Tzourio et al., 2008). Complementary evidence has shown mood-related phenotypes to be implicated in the onset of (and to be commonly comorbid with) many of these physical health outcomes, particularly neurological disorders (Devanand et al., 1996; Wulsin and Singal, 2003; Dal Forno et al., 2005; Kanner, 2005; Salaycik et al., 2007; Surtees et al.,2008a,b), leading to the suggestion that depression is likely to be a neurological disorder with psychiatric symptoms (Kanner, 2004). * Corresponding author. Tel.: +44 1223 740651; fax: +44 1223 740147. E-mail address: [email protected] (P.G. Surtees). 0022-3956/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.jpsychires.2008.12.001
APOE has three major isoforms (apoE2, apoE3, and apoE4) encoded by three alleles (2; 3, and 4) from two single nucleotide polymorphisms at residues 112 (rs429358) and 158 (rs7412) (Mahley and Rall, 2000). Evidence suggests that apoE2 may be the most beneficial APOE isoform, while apoE4 carries the most risk of neurodegeneration (Mahley et al., 2006). Evidence from a recent meta-analysis of case-control studies, considering a range of candidate major depressive disorder (MDD) susceptibility genes, suggested that the APOE 2 allele was associated with MDD (López-León et al., 2007). This analysis combined studies with patients of differing ethnic origin, and that varied in their application of age of depression onset criteria. The scarcity of studies, their limited power, and the need to evaluate broader depression-related phenotypes (Krishnan, 2005) collectively act to limit understanding of the relationship between APOE and depression, and potentially their joint role in neurodegeneration. Using data from 17,507 participants in the European Prospective Investigation into Cancer (EPIC)-Norfolk study, a communitybased cohort study, we now investigate the association between APOE polymorphisms and selected broad-based established measures of emotional health.
844
P.G. Surtees et al. / Journal of Psychiatric Research 43 (2009) 843–847
2. Materials and methods
4. Statistical analysis
Residents of Norfolk (UK) were recruited into the EPIC–Norfolk study during 1993–1997 using general practice age-sex registers (Day et al., 1999). The study was approved by the Norwich District Health Authority Ethics Committee, and all participants gave signed informed consent. The Health and Life Experiences Questionnaire (HLEQ), an assessment of social and psychological circumstances, was completed between 1996 and 2000 by a total of 20,921 (73.2 percent of eligible) EPIC–Norfolk participants. The HLEQ included a structured self-assessment approach to psychiatric symptoms that enabled application of restricted Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) (American Psychiatric Association, 1994) criteria for episodic MDD. The assessment, designed to identify those study participants thought likely to have met a putative diagnosis of MDD at any time in their lives, depends upon participants initially disclosing details of their most recently experienced episode of depression (if more than one) that has endured for two weeks or more and that fulfils the required concurrent DSM-IV MDD symptom criteria. Additionally, operational criteria for clinically significant impairment and helpseeking were included and participants were requested to estimate episode onset and (if appropriate) offset timings (see Surtees et al., 2000 for the HLEQ MDD assessment module). Past-year MDD was defined as any episode that was either current at the time of HLEQ completion or ended within the 12 months preceding assessment. In addition, the HLEQ included an assessment of neuroticism through completion of a short form of the Eysenck Personality Questionnaire (Eysenck et al., 1985), and scored within the range from 0 to 12 with higher scores indicating increased neuroticism. The HLEQ also included a five-item version of the Mental Health Inventory (MHI-5), with one or more items representing anxiety, depression, loss of behavioral/emotional control, and psychological well-being during the past 4-weeks, as part of a validated generic measure of subjective health status, the anglicised version of the Short Form 36 (SF-36) (Ware et al., 1993). The MHI-5 was scored on a scale from 0 to 100 where a lower score represents greater psychological distress.
Lifetime and past-year prevalence of MDD are presented according to APOE genotype, with odds ratios and 95% confidence intervals for comparisons against the 3=3 genotype as baseline. Mean and standard deviation neuroticism and MHI-5 scores are presented according to APOE genotype with b coefficients and 95% confidence intervals obtained from linear regression. Associations with APOE genotype were tested through 5 degree of freedom v2 -tests (for binary measures) and F-tests (for continuous measures). For increased power, a 1 degree of freedom test of linear association was also performed with genotypes ordered as 2=2; 2=3; 2=4; 3=3; 3=4, and 4=4, consistent with evidence reported in a recent meta-analysis of linear association with both LDL cholesterol and coronary disease risk (where LDL cholesterol and coronary disease risk were lowest in those with the 2=2 genotype and highest in those with the 4=4 genotype) (Bennet et al., 2007). In addition, and consistent with data presentation from previous studies (López-León et al., 2007), a 1 degree of freedom (per-allele) test of association was used to compare carriers of the 2 allele with those of the 3 allele (with the 2=4 genotype omitted from analysis, and where 3=3 was taken as baseline = 0 alleles, 2=3 ¼ 1, and 2=2 ¼ 2 alleles). Similarly a 1 degree of freedom (per-allele) test of association was used to compare carriers of the 4 allele with those of the 3 allele.
3. Genotyping DNA for genotyping was extracted from blood in EDTA and from remnant red blood cell samples (and buffy coats) at either of two health checks (see Wu et al. (2007) for further details). APOE polymorphisms were genotyped for 24,513 EPIC–Norfolk participants using Pyrosequencing. PCR was performed to obtain an amplicon of 185 bp covering the area of interest, amino acids 112 and 158, with primers 50 -GGG CGC GGA CAT GGA GG-30 and a 50 biotin labelled primer 50 -Biotin-CCC CGG CCT GGT ACA CTG-30 designed by Pyrosequencing Assay Design Software (Pyrosequencing AB, Sweden). A 50 lL PCR mixture was prepared with 1 PCR Buffer, 2 mM MgCl2 , 5% DMSO, 0.125 mM of each dNTP with 75% of dGTP replaced by dITP, 10 pmol of each primer, two units of Taq Gold and 12 ng of DNA. The annealing temperature was 62 °C and PCR was performed for 45 cycles in a DNA Thermal Cycler (PTC-225; MJ Research, Inc., Watertown, MA, USA). The amplicon was prepared as described elsewhere (Ronaghi et al., 1996) with the two sequencing primers: 50 -GAC ATG GAG GAC GTG-30 for site 112 and 50 -CCG ATG ACC TGC AGA-30 for site 158. The Pyrosequencing (Pyrosequencing, AB, Sweden) machine was prepared as recommended by the manufacturer and the samples were loaded into the machine and scored using the PSQ 96MA 2.1 operating system. An additional 135 samples were genotyped by RFLP (restriction fragment length polymorphism) with full concordance (Wu et al., 2007).
5. Results APOE genotype data were available for 17,623 participants who had completed the HLEQ assessment. After excluding 59 participants of unknown ethnicity and a further 57 from ethnic groups other than white, a sample of 17,507 participants, 7771 men and 9736 women, aged between 41 and 80 years (mean age = 60.9 years), was used for analysis. Genotype and allele frequencies were similar to those previously reported in Caucasian populations in the United Kingdom (Mahley and Rall, 2000; Wu et al., 2007). No differences in genotype frequencies were observed by sex (v2 ¼ 5:1 on 5 df, p = 0.41). Of this sample, 2694 (15.4%) participants reported a lifetime history of MDD and 894 (5.1%) reported an episode of MDD within 12 months of assessment. Table 1 shows lifetime and past-year prevalence rates of MDD according to APOE genotype. Compared to participants with the 3=3 genotype, those with the 2=2 genotype had lower rates of past-year and lifetime MDD, and those with the 4=4 genotype had higher rates of past-year and lifetime MDD. However, these associations were not significant either for a 5 degree of freedom test across APOE genotypes (Table 1), or according to a 1 degree of freedom test of linear association (p = 0.62 for lifetime MDD and p = 0.96 for past-year MDD). In addition, while observed differences in MDD prevalence were greatest for participants with the 2=2 genotype in comparison to those with the 4=4 genotype, these differences were not significant (odds ratio for 2=2 versus 4=4 0.60 (95% confidence interval 0.32–1.13), p = 0.11 for lifetime MDD, and 0.49 (0.17–1.43), p = 0.19 for past-year MDD). In these data, odds ratios per 2 allele were 1.05 (95% confidence interval 0.94–1.18) for lifetime and 1.01 (0.84–1.22) for past-year MDD; and per 4 allele were 1.03 (0.95–1.12) for lifetime and 1.03 (0.90–1.18) for past-year MDD. No associations were observed between APOE genotype and either past-year or lifetime MDD, for men or for women, or for subgroups of participants defined according to whether they were aged less than 65, or 65 years and older, at the time of psychosocial assessment. Table 2 shows mean neuroticism and MHI-5 scores, according to APOE genotype. While participants with the 2=2 genotype (compared with those who had the 3=3 genotype) had lower
845
P.G. Surtees et al. / Journal of Psychiatric Research 43 (2009) 843–847 Table 1 Number (%) of participants with lifetime and past-year major depressive disorder (MDD) and odds ratios (95% confidence intervals) according to APOE genotype. Lifetime MDD
Genotype 2=2 2=3 2=4 3=3 3=4 4=4 *
n 107 2,177 434 10,242 4,151 396
(%) (0.6) (12.4) (2.5) (58.5) (23.7) (2.3)
Past-year MDD
Yes n (%)
No n (%)
OR
(95% CI)
13 357 65 1,560 626 73
94 1,769 362 8,474 3,447 316
0.75 1.10 0.98 1 0.99 1.25
(0.42–1.34) (0.97–1.24) (0.74–1.28)
*
P
Yes n (%)
No n (%)
4 116 20 525 200 29
100 1,986 402 9,398 3,827 358
OR
(95% CI)
0.72 1.05 0.89 1 0.94 1.45
(0.26–1.95) (0.85–1.29) (0.56–1.41)
0.29 (12.1) (16.8) (15.2) (15.5) (15.4) (18.8)
(87.9) (83.2) (84.8) (84.5) (84.6) (81.2)
(0.89–1.09) (0.97–1.63)
P* 0.40
(3.8) (5.5) (4.7) (5.3) (5.0) (7.5)
(96.2) (94.5) (95.3) (94.7) (95.0) (92.5)
(0.79–1.11) (0.98–2.14)
5 degree of freedom test across all genotypes.
Table 2 Mean (SD) neuroticism and 5-item Mental Health Inventory (MHI-5) scale scores and b coefficients (95% confidence intervals) according to APOE genotype. Neuroticism
Genotype 2=2 2=3 2=4 3=3 3=4 4=4 *
n 107 2,190 436 10,312 4,179 399
(%) (0.6) (12.4) (2.5) (58.5) (23.7) (2.3)
MHI-5 P*
Mean
(SD)
b
(95% CI)
4.23 4.30 4.48 4.37 4.37 4.37
(3.05) (3.22) (3.20) (3.28) (3.24) (3.20)
0.13 0.06 0.12 0 0.00 0.00
(0.75–0.49) (0.21–0.09) (0.20–0.43)
Mean
(SD)
b
(95% CI)
79.4 77.4 77.0 77.4 76.8 77.2
(14.3) (16.2) (15.6) (16.1) (16.2) (16.8)
2.01 0.06 0.34 0 0.58 0.17
(1.07–5.10) (0.69–0.81) (1.90–1.22)
0.92
(0.12–0.12) (0.33–0.33)
P* 0.29
(1.17–0.00) (1.81–1.46)
5 degree of freedom test across all genotypes.
neuroticism scores (representing reduced neuroticism) and higher MHI-5 scores (representing increased psychological well-being), these associations were not significant, either for a 5 degree of freedom test of association across APOE genotypes (Table 2) or according to a 1 degree of freedom test of linear association (p = 0.50 for neuroticism and p = 0.10 for MHI-5 scores). 6. Discussion We found no evidence of association between APOE genotype and MDD based on data from 17,507 participants in the EPIC–Norfolk study. A recent meta-analysis (López-León et al., 2007) that included younger (Fan et al., 2006), and older (Butters et al., 2003; Forsell et al., 1997) participants than those in the present study, concluded that the APOE 2 allele was associated with a reduced risk of depression (odds ratio per allele 0.51 (95% confidence interval 0.27–0.97)). This association was based on a combined total of 827 MDD cases and 1616 controls, that persisted following restriction only to Caucasian study population groups (odds ratio per allele 0.72 (95% confidence interval 0.51–1.00)), though was not significant once data from the first published study of only 45 elderly inpatients (Zubenko et al., 1996) was excluded from analysis. Overall support for this association is therefore weakened by our findings of no association (odds ratio per allele 1.05 (95% confidence interval 0.94–1.18) for lifetime MDD and 1.01 (0.84–1.22) for past-year MDD)), based on 2694 lifetime and 894 past-year MDD cases. While the meta-analysis included data from 7 casecontrol studies (López-León et al., 2007), evidence from large-scale community-based studies is rare. Our findings are consistent, however, with a report of no overall association between APOE and depression, based on data from a community study of 3492 men and women aged 65 and older (Steffens et al., 2003). In this study, all four measures of emotional status considered (lifetime and past-year MDD, neuroticism and psychological distress) indicated lower depression risk for participants with the 2=2 genotype. These data are perhaps suggestive that an association with depression is restricted to carriers of two copies of the 2 allele. In addition, prevalence of both lifetime and past-year
MDD were increased in participants with the 4=4 genotype, perhaps suggestive of accentuated differences between participants with the 2=2 compared to the 4=4 genotype. However, these comparisons were not significant in these data, and given the small proportion of participants in the population with these genotypes, such associations would be of more modest clinical importance. The major strength of this study is the very large sample size, with 90% power to detect odds ratios of 0.82 for a test of association between the 2 allele and lifetime MDD, and 0.71 for past-year MDD; effect sizes of more modest magnitude than previously reported (López-León et al., 2007). The main limitation of this study is through the self-report assessment of lifetime history of MDD. The structured HLEQ self-assessment approach represents a pragmatic solution to enabling a measure of emotional state, representative of core DSM-IV diagnostic criteria, to be included in a largescale chronic disease epidemiology setting. Prevalence estimates together with demographic and chronic disease risk profiles associated with the MDD measure used in this study have been shown to be broadly similar to those derived from dedicated large-scale psychiatric epidemiology research studies (Surtees et al., 2000, 2003; Wainwright and Surtees, 2002; Surtees et al., 2008a,b). However, errors of measurement can result in attenuation in the magnitude of observed associations and may therefore provide an alternative explanation for our findings of no association. A further strength of this study is the availability of a more general measure of psychological distress, defined by the MHI-5, a measure of depression severity (Berwick et al., 1991; Rumpf et al., 2001; Rogers et al., 2005), and of neuroticism, a marker of liability to major depression (Kendler et al., 1993), alongside the HLEQ measure of MDD defined according to diagnostic criteria. We might have expected, but did not find, evidence of association between APOE genotype and these measures of psychological distress and of neuroticism. Data from this large-scale, community-based study are not supportive of an association between either MDD or associated measures of psychological state and APOE genotype. Our results therefore increase the likelihood either that APOE does not contribute to MDD risk, or that the association, perhaps restricted to
846
P.G. Surtees et al. / Journal of Psychiatric Research 43 (2009) 843–847
individuals with two copies of the 2 allele, is more modest than previous evidence has suggested. The ‘vascular depression hypothesis’ (Alexopoulos et al., 1997) states that cerebrovascular disease ‘can predispose, precipitate, or perpetuate a depressive syndrome in older adults’ (Alexopoulos, 2006), and proposes subcortical ischemic vascular depression as a distinct and valid disease entity (Taylor et al., 2006; Sneed et al., 2008). Recent evidence, based upon a longitudinal study of participants aged 70–79 years, has reported that both symptomatic (e.g. angina) and asymptomatic/covert conditions (e.g. low HDL, high fasting glucose) were associated with increased risk of depression, providing support for the hypothesis (Mast et al., 2008). The possibility remains therefore that APOE is a susceptibility gene for depression phenotypes defined by more focused hypotheses. Conflict of interest statement There are no conflicts of interest. Contributors PGS conceived the study and with NWJW wrote the first draft of the paper. NWJW is responsible for data analysis. RB is responsible for genotyping. RNL is responsible for EPIC–Norfolk research programme data management. All authors contributed to, and have approved, the final manuscript. Role of the funding source Funding for this study was provided by programme grants from the Medical Research Council UK (G9502233, G0300128) and Cancer Research UK (C865/A2883) with additional support from the European Union, Stroke Association, British Heart Foundation, Department of Health and the Wellcome Trust. These funding agencies had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication. Acknowledgements We thank the participants and general practitioners who took part in this study and the staff associated with the EPIC–Norfolk research programme. References Alexopoulos GS. The vascular depression hypothesis: 10 years later. Biological Psychiatry 2006;60:1304–5. Alexopoulos GS, Meyers BS, Young RC, Campbell S, Silbersweig D, Charlson M. ‘Vascular depression’ hypothesis. Archives of General Psychiatry 1997;54: 915–22. American Psychiatric Association, Diagnostic and statistical manual of mental disorders. 4th ed. Washington, DC: American Psychiatric Association (APA); 1994. Bennet AM, Di Angelantonio E, Ye Z, Wensley F, Dahlin A, Ahlbom A, et al. Association of apolipoprotein E genotypes with lipid levels and coronary risk. Journal of the American Medical Association 2007;298:1300–11. Berwick DM, Murphy JM, Goldman PA, Ware JE, Barsky AJ, Weinstein MC. Performance of a five-item mental health screening test. Medical Care 1991;29:169–76. Butters MA, Sweet RA, Mulsant BH, Kamboh MI, Pollock BG, Begley AE, et al. APOE is associated with age-of-onset, but not cognitive functioning, in late-life depression. International Journal of Geriatric Psychiatry 2003;18:1075–81. Coon KD, Myers AJ, Craig DW, Webster JA, Pearson JV, Lince DH, et al. A high-density whole-genome association study reveals that APOE is the major susceptibility gene for sporadic late-onset Alzheimer’s disease. Journal of Clinical Psychiatry 2007;68:613–8. Dal Forno G, Palermo MT, Donohue JE, Karagiozis H, Zonderman AB, Kawas CH. Depressive symptoms, sex, and risk for Alzheimer’s disease. Annals of Neurology 2005;57:381–7.
Day N, Oakes S, Luben R, Khaw KT, Bingham S, Welch A, et al. EPIC–Norfolk: study design and characteristics of the cohort. British Journal of Cancer 1999;80;(Suppl. 1):95–103. Devanand DP, Sano M, Tang MX, Taylor S, Gurland BJ, Wilder D, et al. Depressed mood and the incidence of Alzheimer’s disease in the elderly living in the community. Archives of General Psychiatry 1996;53:175–82. Eysenck SBG, Eysenck HJ, Barrett P. A revised version of the Psychoticism scale. Personality and Individual Differences 1985;6:21–9. Fan PL, Chen CD, Kao WT, Shu BC, Lung FW. Protective effect of the apo epsilon 2 allele in major depressive disorder in Taiwanese. Acta Psychiatrica Scandinavica 2006;113:48–53. Forsell Y, Corder EH, Basun H, Lannfelt L, Viitanen M, Winblad B. Depression and dementia in relation to apolipoprotein E polymorphism in a population sample age 75+. Biological Psychiatry 1997;42:898–903. Kanner AM. Is major depression a neurologic disorder with psychiatric symptoms? Epilepsy and Behavior 2004;5:636–44. Kanner AM. Depression and the risk of neurological disorders. Lancet 2005;366:1147–8. Kendler KS, Neale MC, Kessler RC, Heath AC, Eaves LJ. A longitudinal twin study of personality and major depression in women. Archives of General Psychiatry 1993;50:853–62. Krishnan KR. Psychiatric disease in the genomic era: rational approach. Molecular Psychiatry 2005;10:978–84. Lanterna LA, Ruigrok Y, Alexander S, Tang J, Biroli F, Dunn LT, et al. Meta-analysis of APOE genotype and subarachnoid hemorrhage - clinical outcome and delayed ischemia. Neurology 2007;69:766–75. López-León A, Janssens ACJW, González-Zuloeta Ladd AM, Del-Favero J, Claes SJ, Oostra BA, et al. Meta-analyses of genetic studies on major depressive disorder. Molecular Psychiatry 2007;13:772–85. Mahley RW, Rall SC. Apolipoprotein E: far more than a lipid transport protein. Annual Review Of Genomics And Human Genetics 2000;1:507–37. Mahley RW, Weisgraber KH, Huang YD. Apolipoprotein E4: a causative factor and therapeutic target in neuropathology including Alzheimer’s disease. Proceedings of the National Academy of Sciences 2006;103:5644–51. Mast BT, Miles T, Penninx BW, Yaffe K, Rosano C, Satterfield S, et al. Vascular disease and future risk of depressive symptomatology in older adults: findings from the HEALTH, aging, and body composition study. Biological Psychiatry 2008;64: 320–6. Rogers WH, Adler DA, Bungay KM, Wilson IB. Depression screening instruments made good severity measures in a cross-sectional analysis. Journal of Clinical Epidemiology 2005;58:370–7. Ronaghi M, Karamohamed S, Pettersson B, Uhlen M, Nyren P. Real-time DNA sequencing using detection of pyrophosphate release. Analytical Biochemistry 1996;242:84–9. Rumpf HM, Meyer C, Hapke U, John U. Screening for mental health: validity of the MHI-5 using DSM-IV Axis I psychiatric disorders as gold standard. Psychiatry Research 2001;105:243–53. Salaycik KJ, Kelly-Hayes M, Beiser A, Nguyen AH, Brady SM, Kase CS, et al. Depressive symptoms and risk of stroke: the Framingham study. Stroke 2007;38:16–21. Sneed JR, Rindskopf D, Steffens DC, Krishnan KRR, Roose SP. The vascular depression subtype: evidence of internal validity. Biological Psychiatry 2008;64:491–7. Song YQ, Stampfer MJ, Liu SM. Meta-analysis: apolipoprotein E genotypes and risk for coronary heart disease. Annals of Internal Medicine 2004;141: 137–47. Steffens DC, Norton MC, Hart AD, Skoog I, Corcoran C, Breitner JCS. Apolipoprotein E genotype and major depression in a community of older adults. The cache county study. Psychological Medicine 2003;33:541–7. Strittmatter WJ, Saunders AM, Schmechel D, Pericakvance M, Enghild J, Salvesen GS, et al. Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type-4 allele in late-onset familial Alzheimer disease. Proceedings of the National Academy of Sciences 1993;90:1977–81. Sudlow C, Gonzalez NAM, Kim J, Clark C. Does apolipoprotein E genotype influence the risk of ischemic stroke, intracerebral hemorrhage, or subarachnoid hemorrhage? systematic review and meta-analyses of 31 studies among 5961 cases and 17,965 controls. Stroke 2006;37:364–70. Surtees PG, Wainwright NWJ, Brayne C. Psychosocial aetiology of chronic disease: a pragmatic approach to the assessment of lifetime affective morbidity in an EPIC component study. Journal of Epidemiology and Community Health 2000;54: 114–22. Surtees PG, Wainwright NWJ, Khaw KT, Day NE. Functional health status, chronic medical conditions and disorders of mood. British Journal of Psychiatry 2003;183:299–303. Surtees PG, Wainwright NWJ, Luben RN, Wareham NJ, Bingham SA, Khaw KT. Depression and ischemic heart disease mortality: evidence from the EPIC– Norfolk United Kingdom prospective cohort study. American Journal of Psychiatry 2008a;165:515–23. Surtees PG, Wainwright NWJ, Luben RN, Wareham NJ, Bingham SA, Khaw KT. Psychological distress, major depressive disorder and risk of stroke. Neurology 2008b;70:788–94. Taylor WD, Steffens DC, Krishnan KR. Psychiatric disease in the twenty-first century: the case for subcortical ischemic depression. Biological Psychiatry 2006;60:1299–303. Thakkinstian A, Bowe S, McEvoy M, Smith W, Attia J. Association between apolipoprotein E polymorphisms and age-related macular degeneration: a
P.G. Surtees et al. / Journal of Psychiatric Research 43 (2009) 843–847 HuGE review and meta-analysis. American Journal of Epidemiology 2006;164:813–22. Tzourio C, Arima H, Harrap S, Anderson C, Godin O, Woodward M, et al. APOE genotype, ethnicity, and the risk of cerebral hemorrhage. Neurology 2008;70:1322–8. Wainwright NWJ, Surtees PG. Childhood adversity, gender and depression over the life-course. Journal of Affective Disorders 2002;72:33–44. Ware JE, Snow KK, Kosinski M, Gandek B. SF-36 health survey: manual and interpretation guide. Boston: Nimrod Press; 1993.
847
Wu K, Bowman R, Welch AA, Luben RN, Wareham N, Khaw KT, et al. Apolipoprotein E polymorphisms, dietary fat and fibre, and serum lipids: the EPIC Norfolk study. European Heart Journal 2007;28:2930–6. Wulsin LR, Singal BM. Do depressive symptoms increase the risk for the onset of coronary disease? a systematic quantitative review. Psychosomatic Medicine 2003;65:201–10. Zubenko GS, Henderson R, Stiffler JS, Stabler S, Rosen J, Kaplan BB. Association of the APOE epsilon 4 allele with clinical subtypes of late life depression. Biological Psychiatry 1996;40:1008–16.