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Longer telomere length in patients with schizophrenia
Schizophrenia Research 149 (2013) 116–120
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Longer telomere length in patients with schizophrenia Vanessa Nieratschker a,b,⁎, Jenni Lahtinen c, Sandra Meier a, Jana Strohmaier a, Josef Frank a, Angela Heinrich a, René Breuer a, Stephanie H. Witt a, Markus M. Nöthen d,e,f,1, Marcella Rietschel a,⁎⁎,1, Iiris Hovatta c,g,1 a
Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, J 5, 68159 Mannheim, Germany Department of Psychiatry and Psychotherapy, University of Tuebingen, Calwerstrasse 14, 72076 Tuebingen, Germany Department of Biosciences, Viikki Biocenter, University of Helsinki, Finland d Department of Genomics, Life & Brain Center, University of Bonn, Sigmund-Freud-Straße 25, 53127 Bonn, Germany e Institute of Human Genetics, University of Bonn, Sigmund-Freud-Straße 25, 53127 Bonn, Germany f German Center for Neurodegenerative Disorders (DZNE), Ludwig-Erhard-Allee 2, 53175 Bonn, Germany g Mental Health and Substance Abuse Services, National Institute for Health and Welfare, Helsinki, Finland b c
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Article history: Received 29 January 2013 Received in revised form 2 June 2013 Accepted 29 June 2013 Available online 17 July 2013 Keywords: Telomere length Schizophrenia Severity Subphenotype DNA extraction method Case–control design
a b s t r a c t Previous studies have reported an association between shorter leukocyte telomere length and schizophrenia (SCZ). The aim of the present study was to replicate this finding in a large sample of SCZ patients (n = 539) and population-based controls (n = 519). In addition, the possible influence of SCZ severity on telomere length – as measured by age of onset, mode of onset, and course of the disorder – was investigated. Telomere length was negatively associated with age in both patients and controls. This is a consistently reported phenomenon, related to the problem of DNA end-replication. However, in contrast to previous findings, SCZ patients displayed longer telomeres compared to controls (p = 0.015). No association was found with any SCZ-severity subphenotype. Interestingly, recent studies have reported associations between longer leukocyte telomere length and both smaller hippocampal volume, and poorer episodic memory performance. Both phenotypes are common in patients with SCZ. Further studies are warranted to investigate whether the present association between SCZ and increased telomere length was driven by such associations, or rather by association with the clinical disease per se or other associated phenotypes, endophenotypes or lifestyle factors. © 2013 Elsevier B.V. All rights reserved.
1. Introduction Telomeres form the ends of linear chromosomes, consist of nucleotide repeats and associated proteins (de Lange, 2002), and protect chromosomal termini from the loss of genetic material and from Abbreviations: SCZ, schizophrenia; NGFN, National Genome Research Network; DSM-IV, Diagnostic and Statistical Manual of Mental Disorders Fourth Edition; SCID, Structured Clinical Interview for DSM-IV axis I disorders; OPCRIT, Operational Criteria Checklist for Psychotic Illness; FNTD, Fagerstrom Test of Nicotine Dependence; DNA, deoxyribonucleic acid; EDTA, ethylenediaminetetraacetic; dsDNA, double strand; qPCR, quantitative Polymerase chain reaction; Hgb, β-hemoglobin; ng, nanograms; μl, microliter; nM, nanomolar; CV, inter-assay coefficient of variation. ⁎ Correspondence to: V. Nieratschker, Department of Psychiatry and Psychotherapy, University of Tuebingen, Calwerstrasse 14, 72076 Tuebingen, Germany. Tel.: +49 7071 2985523; fax: +49 7071 29 8 5903. ⁎⁎ Corresponding author. Tel.: +49 621 17036051; fax: +49 621 17036055. E-mail addresses: [email protected] (V. Nieratschker), jenni.j.lahtinen@helsinki.fi (J. Lahtinen), [email protected] (S. Meier), [email protected] (J. Strohmaier), [email protected] (J. Frank), [email protected] (A. Heinrich), [email protected] (R. Breuer), [email protected] (S.H. Witt), [email protected] (M.M. Nöthen), [email protected] (M. Rietschel), iiris.hovatta@helsinki.fi (I. Hovatta). 1 Contributed equally. 0920-9964/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.schres.2013.06.043
end-to-end recombination. Telomeres are therefore crucial for the maintenance of chromosomal integrity. However, the average telomere length of most proliferating cells (including blood leukocytes) declines substantially with age (Iwama et al., 1998; Blackburn, 2001). Whether short telomeres actually contribute to the aging process, or are merely a sign of aging, remains unknown. Telomere length and attrition are also influenced by genetic (Slagboom et al., 1994; Nordfjall et al., 2010; Codd et al., 2013), and environmental factors. The latter include smoking (Saliques et al., 2010; Babizhayev and Yegorov, 2011) and psychological stress, both of which lead to a decrease in telomere length. Implicated psychological stress factors include childhood adversity, care-giving, work-related stress, ambivalent social relationships, experience of major negative life events, and chronic pain (von Zglinicki, 2002; Epel et al., 2004; Simon et al., 2006; Damjanovic et al., 2007; Houben et al., 2008; Kananen et al., 2010; Tyrka et al., 2010; Drury et al., 2011; Entringer et al., 2011; Kiecolt-Glaser et al., 2011; Malan et al., 2011; Ahola et al., 2012; Humphreys et al., 2012; Shalev et al., 2012; Sibille et al., 2012; Uchino et al., 2012). In the case of psychiatric disorders, associations have been reported between decreased telomere length and anxiety disorders (Kananen et al., 2010; Hoen et al., 2012), posttraumatic stress disorder (Malan et al.,
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2011; O'Donovan et al., 2011), mood disorders (Simon et al., 2006), and major depression (Simon et al., 2006; Lung et al., 2007; Hartmann et al., 2010; Hoen et al., 2011; Wolkowitz et al., 2011). An association with decreased telomere length has also been reported for schizophrenia (SCZ), although each individual study investigated relatively small samples (Kao et al., 2008; Yu et al., 2008; Fernandez-Egea et al., 2009; Mansour et al., 2011). Kao et al., investigated telomere length in a sample of 51 SCZ patients, 24 unaffected family members, and 53 controls (Kao et al., 2008). The authors found significantly shorter telomeres in the SCZ patients compared to family members and controls. In a study of 68 SCZ patients and 76 controls, Yu et al., found an association between telomere length and disease severity, with more severely affected patients displaying shorter telomere length compared to both controls and less severely affected patients (Yu et al., 2008). Fernandez-Egea et al., measured telomere DNA content, which is highly correlated with telomere length, in 41 individuals with nonaffective psychosis (including n = 27 with SCZ and 9 with schizophreniform disorder), and 41 controls (Fernandez-Egea et al., 2009). The authors found significantly decreased telomere DNA content in individuals with nonaffective psychosis compared to controls. In contrast, Mansour et al. (2011) compared 60 SCZ cases with 60 controls and found no association between SCZ and telomere length. The aim of the present study was to replicate previous findings of shorter telomere length in SCZ in a large sample of SCZ patients and population-based control individuals.
2. Materials and methods 2.1. Study participants 722 SCZ patients and 722 population-based control individuals of German descent were included. All patients and the majority of the controls (n = 491) were recruited between 1988 and 2005 within the German National Genome Research Network (NGFN) (Hoefgen et al., 2005). Additional control individuals (n = 231) were recruited with the cooperation of the residents' registration office in Mannheim and the Red Cross administration of Baden-Württemberg, as well as via newspaper and internet advertisements. Lifetime best estimate diagnoses were assigned according to DSM-IV criteria by two experienced psychiatrists or psychologists on the basis of multiple sources of information, including interviews with the German version of the Structured Clinical Interview for DSM-IV axis I disorders (SCID) (First et al., 1998), the Operational Criteria Checklist for Psychotic Illness (OPCRIT) (McGuffin et al., 1991), medical records, and family history. Age of onset, mode of onset, course of disorder, and lifetime smoking were also assessed. Age at onset was defined as the age at which a patient showed the first symptoms of SCZ. Mode of the disorder and course of the disorder were assessed by the raters involved in performing best estimate diagnoses using OPCRIT (item numbers 5 and 90, OPCRIT version v3.32) as quantitative categories containing 5 levels each. In controls lifetime psychiatric symptoms were assessed using a structured self-report questionnaire (adapted from the German version of the International Diagnostic Interview (IDD); Zimmerman et al., 1986; Kühner, 1997). Life-time smoking behavior was assessed using the Fagerstrom Test of Nicotine Dependence (FNTD) (Fagerstrom et al., 1990). Quality control criteria for telomere length measurement data as described in Section 2.2 were fulfilled in 584 of the 722 SCZ patients (326 male and 258 female) aged between 17 and 80 years (mean age 37.00 ± SD 11.65), and in 644 of the 722 control individuals (368 male and 276 female) aged between 18 and 80 years (mean age 37.07 ± SD 11.52). No significant difference in mean telomere length was observed between samples omitted from further analyses and samples that passed the quality control filters. In total, 77.7% of
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the patients and 44.3% of the control individuals had a lifetime history of smoking. The study protocol was approved by the Ethics Committees of the Medical Faculties of the Universities of Bonn and Heidelberg, and the study was conducted in accordance with the Declaration of Helsinki. All participants provided written informed consent prior to participation.
2.2. Telomere length assessment For telomere measurement, a qPCR-based method was used (Cawthon, 2002), as described elsewhere (Kao et al., 2008; Eerola et al., 2010; Kananen et al., 2010) (for details see Supplementary material). Leukocyte telomere length was measured using DNA extracted from peripheral blood samples. Extraction of genomic DNA was either performed manually (Miller et al., 1988), or using an automated system (PerkinElmer Chemagen Technologie GmbH; Rodgau; Germany). DNA concentration and integrity were assessed using fluorescent measurement of dsDNA (Quant-iT™ PicoGreen®; Invitrogen; life technologies GmbH; Darmstadt, Germany).
2.3. Statistical analyses Sex and age of the participants, as well as the batch used for telomere length measurement, were included as covariates in all models in order to rule out confounding effects. Monotonic relationships between clinical status, age, lifetime smoking, severity of SCZ measures (age of onset, mode of onset, and course of the disorder) and telomere length were assessed by linear regression. All statistical analyses were performed with IBM SPSS 20.0 (Chicago, Illinois, USA).
3. Results 3.1. DNA extraction method affects telomere length The DNA extraction method had a significant influence on telomere length measurement, with longer telomeres being observed in DNA samples extracted automatically (p b 0.00001, data not shown) compared to manually extracted DNA samples. This finding is in accordance with our earlier observation in the Finrisk cohort (n = 4300), in which DNA was extracted using five different methods. In a linear regression analysis of the Finrisk sample, the effect of DNA extraction method on telomere length was highly significant (p = 3.1E-81; adjusted for age and sex), with the automated extraction method producing the longest measurement values (J.L. and I.H., unpublished). For the majority of patients and controls, DNA was extracted manually (Miller et al., 1988). Therefore, the analyses were restricted to manually extracted DNA samples (n = 562 patients and n = 523 controls). To exclude potential bias secondary to outliers, individuals with relative telomere length more than 3 standard deviations different from the mean (n = 23 patients and n = 4 controls) were excluded from further analysis (for sample characteristics see Supplemental Table in Appendix A).
3.2. Longer telomeres in SCZ patients compared to controls Telomere length was significantly longer in patients with SCZ (n = 539) compared to controls (n = 519) (B = 0.073, p = 0.015; adjusted for age, batch, and sex) (Fig. 1). Smoking rates were significantly higher in SCZ patients than in controls (SCZ: 79.5%; controls: 44.4%; x2 = 92.12, p b 0.001). However, the finding of longer telomere length in SCZ patients remained significant after adjustment for smoking (B = 0.073, p = 0.034).
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Fig. 1. Scattergram of telomere length: Telomere length is significantly longer in schizophrenia patients than in control individuals (B = 0.073, p = 0.015). Mean values and 95% confidence intervals are indicated in blue.
4. Discussion The present study failed to confirm the hypothesis that leukocyte telomere length is reduced in SCZ patients. In contrast, SCZ patients in the present sample displayed longer telomere length than populationbased controls. However, the robust negative association between age and telomere length (e.g. Rampazzo et al., 2010) was replicated in both the overall sample and in separate analyses of patients and controls (see Supplementary material and Fig. S1 in Appendix A), thus suggesting that telomere measurement in the present study was reliable. The effects sizes of the age effect observed in our analysis are comparable to those described in previous reports (Eerola et al., 2010; Kananen et al., 2010), thus providing further confidence that the present findings are valid. Our observation that telomere length was longer in SCZ patients than in controls was an unexpected finding, since most previous studies have reported shorter telomere length in SCZ compared to controls (Kao et al., 2008; Yu et al., 2008; Fernandez-Egea et al., 2009). Assuming that reduced leukocyte telomere length is a biomarker for exposure to stress, short telomeres would be expected in patients with SCZ, since these individuals experience high levels of stress as a result of their symptoms. Interestingly, however, the present finding is consistent with a recent study by Savolainen et al., which investigated associations between telomere length and a history of psychiatric illness and prescription of psychotropic medication. The study included n = 1956 individuals, 116 of whom had a history of a psychiatric diagnosis. The authors found that hospitalized psychiatric patients receiving psychotropic medication, displayed longer telomere length compared to healthy individuals (Savolainen et al., 2012). The present study investigated the largest SCZ sample to date in the field of telomere length research, and can therefore be regarded as the most powerful study in terms of demonstrating an effect. However, various alternative explanations for our finding must be considered. Longer telomere length in SCZ patients compared to control individuals may reflect an association at the endophenotype level. Wikgren et al. (2012a) for example found an association between increased leukocyte telomere length and reduced hippocampal volume in healthy APOE ε3/ε3 individuals (Wikgren et al., 2012a). However, this study must be interpreted with caution, as the sample size was very small (29 ε3/ε3 individuals, 28 ε4 carriers) and included only nonpsychotic individuals. In a second study, Wikgren et al. reported that APOE ε4 carriers with longer telomeres showed poorer performance during episodic memory tasks than those with shorter telomeres (Wikgren et al., 2012b). Poor episodic memory as well as reduced hippocampal volume are features
of SCZ (e.g. Aleman et al., 1999; Adriano et al., 2012), and episodic memory is dependent on an intact hippocampal function. However, the relationship between neuropsychological function and abnormal hippocampal volume remains a subject of debate as episodic memory does not only depend on hippocampal function, but also on prefrontal structures (Ragland et al., 2009). Nevertheless, a possible explanation for the present unexpected finding of longer telomeres in SCZ could be an underlying association between longer telomeres and reduced hippocampal volume and/or impaired episodic memory. However, caution must be exercised in relating the finding of Wikgren et al., to the present result, since Wikgren et al., investigated nonpsychotic individuals. We were unable to replicate a link between telomere length and either episodic memory or hippocampal volume as no such data were available for our sample. An alternative explanation – as was suggested by Savolainen et al. (2012) when interpreting their data – is that psychotropic medications may have antioxidative effects and thus prevent telomere attrition. Since all our hospitalized patients received psychotropic medication, this could have contributed to our finding. Unfortunately, however, our sample included no untreated SCZ patients and no information concerning lifetime amount of psychotropic medication was available and we are therefore unable to clarify whether the association with longer telomeres was due to psychotropic medication or with SCZ per se. One interesting finding, which has been reported consistently across large longitudinal cohorts such as the Framingham study, the Cebu Longitudinal Health and Nutrition survey, the NHLBI-Heart study, the Longitudinal Study of Aging Danish Twins, and the Amish Family Osteoporosis Study, is that advanced paternal age is associated with increased telomere length in the offspring, and that the correlation between paternal age and telomere length persists in the offspring over their entire life-span (Unryn et al., 2005; Njajou et al., 2007; Kimura et al., 2008; Nordfjall et al., 2010; Eisenberg et al., 2012; Broer et al., 2013). Higher paternal age has also been identified as a consistent risk factor for SCZ (for review see Perrin et al., 2007). The hypothesized underlying mechanism for this phenomenon is that the number of new rare mutations increases with paternal age, which in turn increases the risk for SCZ. Telomere length may thus be a marker of the age of the father at the time of conception, rather than a causal factor for the disease. However, we were unable to substantiate this hypothesis in the present sample as no data concerning paternal age were available. Finally, we cannot fully exclude the possibility that our finding might be biased by an underlying association with increased mortality observed among SCZ patients. For some of the disorders that contribute to increased mortality in SCZ patients, such as cancer and cardiovascular disease (Saha et al., 2007; Laursen et al., 2009; Bushe et al., 2010; Heald, 2010), associations with reduced telomere length have been reported (Brouilette et al., 2003; Sampson and Hughes, 2006; Fitzpatrick et al., 2007; Artandi and DePinho, 2010; Butt et al., 2010). We addressed this potential bias by performing separate analyses in the younger and older halves of our SCZ and control samples. The association between increased telomere length and SCZ was stronger in the younger cohort compared to the older cohort, suggesting that our finding in the entire sample was not based on a mortality bias. To fully exclude this potential bias, a large longitudinal follow up study of first-episode SCZ patients would be necessary. However, sample sizes for this type of study design are typically small and thus prone to statistical bias. The extent to which altered telomere length is a cause, or a consequence, of disease associations observed remains a matter of debate (De Meyer et al., 2008). The finding of longer telomere length in patients in the present sample could thus represent either a consequence of or a prerequisite for SCZ development. The first longitudinal studies of telomere length have indicated that besides age, the most powerful predictor of shorter telomere length is baseline telomere length, with
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an exaggerated attrition being observed in individuals with longer telomeres compared to individuals with shorter telomeres. The present study was cross-sectional and involved measurement of telomere length at only one time point, and thus no data on telomere attrition rate are available. In conclusion, increased telomere length was observed in SCZ patients in the present sample, which represents the largest case–control study reported to date. However, a range of possible explanations for this finding exists, and further studies are therefore warranted. An interesting possible explanation is that an underlying association with endophenotypes exists, which acts beyond the currently available diagnostic boundaries for SCZ. Role of funding source This work was supported by grants 01GS08144 (MMN) and 01GS08147 (MR) from the National Genome Research Network (NGFN-plus) of the German Federal Ministry of Education and Research (BMBF). MR was also supported by the 7th Framework Programme of the European Union (ADAMS project, HEALTH-F4-2009-242257). VN received support from the Olympia-Morata-Programme of the University of Heidelberg. IH received support from the Academy of Finland. Contributors VN, MR, IH were responsible for the study concept and design. SM, JS, RB, MR, and MMN contributed to the acquisition of material and data. VN, JL, and IH were responsible for the laboratory analysis, JL, SM, JF, and IH analyzed the data, VN drafted the manuscript, JL, SM, JF, SHW, JS, AH, RB, MMN, and MR provided critical revision of the manuscript. All authors critically reviewed the content of the final version of the manuscript, and approved its submission for publication. Conflict of interest The authors have no conflicts of interest to declare. Acknowledgments We thank C. Hohmeyer for her excellent technical assistance and C. Schmähl for language editing.
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Schizophrenia Research journal homepage: www.elsevier.com/locate/schres
Longer telomere length in patients with schizophrenia Vanessa Nieratschker a,b,⁎, Jenni Lahtinen c, Sandra Meier a, Jana Strohmaier a, Josef Frank a, Angela Heinrich a, René Breuer a, Stephanie H. Witt a, Markus M. Nöthen d,e,f,1, Marcella Rietschel a,⁎⁎,1, Iiris Hovatta c,g,1 a
Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, J 5, 68159 Mannheim, Germany Department of Psychiatry and Psychotherapy, University of Tuebingen, Calwerstrasse 14, 72076 Tuebingen, Germany Department of Biosciences, Viikki Biocenter, University of Helsinki, Finland d Department of Genomics, Life & Brain Center, University of Bonn, Sigmund-Freud-Straße 25, 53127 Bonn, Germany e Institute of Human Genetics, University of Bonn, Sigmund-Freud-Straße 25, 53127 Bonn, Germany f German Center for Neurodegenerative Disorders (DZNE), Ludwig-Erhard-Allee 2, 53175 Bonn, Germany g Mental Health and Substance Abuse Services, National Institute for Health and Welfare, Helsinki, Finland b c
a r t i c l e
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Article history: Received 29 January 2013 Received in revised form 2 June 2013 Accepted 29 June 2013 Available online 17 July 2013 Keywords: Telomere length Schizophrenia Severity Subphenotype DNA extraction method Case–control design
a b s t r a c t Previous studies have reported an association between shorter leukocyte telomere length and schizophrenia (SCZ). The aim of the present study was to replicate this finding in a large sample of SCZ patients (n = 539) and population-based controls (n = 519). In addition, the possible influence of SCZ severity on telomere length – as measured by age of onset, mode of onset, and course of the disorder – was investigated. Telomere length was negatively associated with age in both patients and controls. This is a consistently reported phenomenon, related to the problem of DNA end-replication. However, in contrast to previous findings, SCZ patients displayed longer telomeres compared to controls (p = 0.015). No association was found with any SCZ-severity subphenotype. Interestingly, recent studies have reported associations between longer leukocyte telomere length and both smaller hippocampal volume, and poorer episodic memory performance. Both phenotypes are common in patients with SCZ. Further studies are warranted to investigate whether the present association between SCZ and increased telomere length was driven by such associations, or rather by association with the clinical disease per se or other associated phenotypes, endophenotypes or lifestyle factors. © 2013 Elsevier B.V. All rights reserved.
1. Introduction Telomeres form the ends of linear chromosomes, consist of nucleotide repeats and associated proteins (de Lange, 2002), and protect chromosomal termini from the loss of genetic material and from Abbreviations: SCZ, schizophrenia; NGFN, National Genome Research Network; DSM-IV, Diagnostic and Statistical Manual of Mental Disorders Fourth Edition; SCID, Structured Clinical Interview for DSM-IV axis I disorders; OPCRIT, Operational Criteria Checklist for Psychotic Illness; FNTD, Fagerstrom Test of Nicotine Dependence; DNA, deoxyribonucleic acid; EDTA, ethylenediaminetetraacetic; dsDNA, double strand; qPCR, quantitative Polymerase chain reaction; Hgb, β-hemoglobin; ng, nanograms; μl, microliter; nM, nanomolar; CV, inter-assay coefficient of variation. ⁎ Correspondence to: V. Nieratschker, Department of Psychiatry and Psychotherapy, University of Tuebingen, Calwerstrasse 14, 72076 Tuebingen, Germany. Tel.: +49 7071 2985523; fax: +49 7071 29 8 5903. ⁎⁎ Corresponding author. Tel.: +49 621 17036051; fax: +49 621 17036055. E-mail addresses: [email protected] (V. Nieratschker), jenni.j.lahtinen@helsinki.fi (J. Lahtinen), [email protected] (S. Meier), [email protected] (J. Strohmaier), [email protected] (J. Frank), [email protected] (A. Heinrich), [email protected] (R. Breuer), [email protected] (S.H. Witt), [email protected] (M.M. Nöthen), [email protected] (M. Rietschel), iiris.hovatta@helsinki.fi (I. Hovatta). 1 Contributed equally. 0920-9964/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.schres.2013.06.043
end-to-end recombination. Telomeres are therefore crucial for the maintenance of chromosomal integrity. However, the average telomere length of most proliferating cells (including blood leukocytes) declines substantially with age (Iwama et al., 1998; Blackburn, 2001). Whether short telomeres actually contribute to the aging process, or are merely a sign of aging, remains unknown. Telomere length and attrition are also influenced by genetic (Slagboom et al., 1994; Nordfjall et al., 2010; Codd et al., 2013), and environmental factors. The latter include smoking (Saliques et al., 2010; Babizhayev and Yegorov, 2011) and psychological stress, both of which lead to a decrease in telomere length. Implicated psychological stress factors include childhood adversity, care-giving, work-related stress, ambivalent social relationships, experience of major negative life events, and chronic pain (von Zglinicki, 2002; Epel et al., 2004; Simon et al., 2006; Damjanovic et al., 2007; Houben et al., 2008; Kananen et al., 2010; Tyrka et al., 2010; Drury et al., 2011; Entringer et al., 2011; Kiecolt-Glaser et al., 2011; Malan et al., 2011; Ahola et al., 2012; Humphreys et al., 2012; Shalev et al., 2012; Sibille et al., 2012; Uchino et al., 2012). In the case of psychiatric disorders, associations have been reported between decreased telomere length and anxiety disorders (Kananen et al., 2010; Hoen et al., 2012), posttraumatic stress disorder (Malan et al.,
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2011; O'Donovan et al., 2011), mood disorders (Simon et al., 2006), and major depression (Simon et al., 2006; Lung et al., 2007; Hartmann et al., 2010; Hoen et al., 2011; Wolkowitz et al., 2011). An association with decreased telomere length has also been reported for schizophrenia (SCZ), although each individual study investigated relatively small samples (Kao et al., 2008; Yu et al., 2008; Fernandez-Egea et al., 2009; Mansour et al., 2011). Kao et al., investigated telomere length in a sample of 51 SCZ patients, 24 unaffected family members, and 53 controls (Kao et al., 2008). The authors found significantly shorter telomeres in the SCZ patients compared to family members and controls. In a study of 68 SCZ patients and 76 controls, Yu et al., found an association between telomere length and disease severity, with more severely affected patients displaying shorter telomere length compared to both controls and less severely affected patients (Yu et al., 2008). Fernandez-Egea et al., measured telomere DNA content, which is highly correlated with telomere length, in 41 individuals with nonaffective psychosis (including n = 27 with SCZ and 9 with schizophreniform disorder), and 41 controls (Fernandez-Egea et al., 2009). The authors found significantly decreased telomere DNA content in individuals with nonaffective psychosis compared to controls. In contrast, Mansour et al. (2011) compared 60 SCZ cases with 60 controls and found no association between SCZ and telomere length. The aim of the present study was to replicate previous findings of shorter telomere length in SCZ in a large sample of SCZ patients and population-based control individuals.
2. Materials and methods 2.1. Study participants 722 SCZ patients and 722 population-based control individuals of German descent were included. All patients and the majority of the controls (n = 491) were recruited between 1988 and 2005 within the German National Genome Research Network (NGFN) (Hoefgen et al., 2005). Additional control individuals (n = 231) were recruited with the cooperation of the residents' registration office in Mannheim and the Red Cross administration of Baden-Württemberg, as well as via newspaper and internet advertisements. Lifetime best estimate diagnoses were assigned according to DSM-IV criteria by two experienced psychiatrists or psychologists on the basis of multiple sources of information, including interviews with the German version of the Structured Clinical Interview for DSM-IV axis I disorders (SCID) (First et al., 1998), the Operational Criteria Checklist for Psychotic Illness (OPCRIT) (McGuffin et al., 1991), medical records, and family history. Age of onset, mode of onset, course of disorder, and lifetime smoking were also assessed. Age at onset was defined as the age at which a patient showed the first symptoms of SCZ. Mode of the disorder and course of the disorder were assessed by the raters involved in performing best estimate diagnoses using OPCRIT (item numbers 5 and 90, OPCRIT version v3.32) as quantitative categories containing 5 levels each. In controls lifetime psychiatric symptoms were assessed using a structured self-report questionnaire (adapted from the German version of the International Diagnostic Interview (IDD); Zimmerman et al., 1986; Kühner, 1997). Life-time smoking behavior was assessed using the Fagerstrom Test of Nicotine Dependence (FNTD) (Fagerstrom et al., 1990). Quality control criteria for telomere length measurement data as described in Section 2.2 were fulfilled in 584 of the 722 SCZ patients (326 male and 258 female) aged between 17 and 80 years (mean age 37.00 ± SD 11.65), and in 644 of the 722 control individuals (368 male and 276 female) aged between 18 and 80 years (mean age 37.07 ± SD 11.52). No significant difference in mean telomere length was observed between samples omitted from further analyses and samples that passed the quality control filters. In total, 77.7% of
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the patients and 44.3% of the control individuals had a lifetime history of smoking. The study protocol was approved by the Ethics Committees of the Medical Faculties of the Universities of Bonn and Heidelberg, and the study was conducted in accordance with the Declaration of Helsinki. All participants provided written informed consent prior to participation.
2.2. Telomere length assessment For telomere measurement, a qPCR-based method was used (Cawthon, 2002), as described elsewhere (Kao et al., 2008; Eerola et al., 2010; Kananen et al., 2010) (for details see Supplementary material). Leukocyte telomere length was measured using DNA extracted from peripheral blood samples. Extraction of genomic DNA was either performed manually (Miller et al., 1988), or using an automated system (PerkinElmer Chemagen Technologie GmbH; Rodgau; Germany). DNA concentration and integrity were assessed using fluorescent measurement of dsDNA (Quant-iT™ PicoGreen®; Invitrogen; life technologies GmbH; Darmstadt, Germany).
2.3. Statistical analyses Sex and age of the participants, as well as the batch used for telomere length measurement, were included as covariates in all models in order to rule out confounding effects. Monotonic relationships between clinical status, age, lifetime smoking, severity of SCZ measures (age of onset, mode of onset, and course of the disorder) and telomere length were assessed by linear regression. All statistical analyses were performed with IBM SPSS 20.0 (Chicago, Illinois, USA).
3. Results 3.1. DNA extraction method affects telomere length The DNA extraction method had a significant influence on telomere length measurement, with longer telomeres being observed in DNA samples extracted automatically (p b 0.00001, data not shown) compared to manually extracted DNA samples. This finding is in accordance with our earlier observation in the Finrisk cohort (n = 4300), in which DNA was extracted using five different methods. In a linear regression analysis of the Finrisk sample, the effect of DNA extraction method on telomere length was highly significant (p = 3.1E-81; adjusted for age and sex), with the automated extraction method producing the longest measurement values (J.L. and I.H., unpublished). For the majority of patients and controls, DNA was extracted manually (Miller et al., 1988). Therefore, the analyses were restricted to manually extracted DNA samples (n = 562 patients and n = 523 controls). To exclude potential bias secondary to outliers, individuals with relative telomere length more than 3 standard deviations different from the mean (n = 23 patients and n = 4 controls) were excluded from further analysis (for sample characteristics see Supplemental Table in Appendix A).
3.2. Longer telomeres in SCZ patients compared to controls Telomere length was significantly longer in patients with SCZ (n = 539) compared to controls (n = 519) (B = 0.073, p = 0.015; adjusted for age, batch, and sex) (Fig. 1). Smoking rates were significantly higher in SCZ patients than in controls (SCZ: 79.5%; controls: 44.4%; x2 = 92.12, p b 0.001). However, the finding of longer telomere length in SCZ patients remained significant after adjustment for smoking (B = 0.073, p = 0.034).
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Fig. 1. Scattergram of telomere length: Telomere length is significantly longer in schizophrenia patients than in control individuals (B = 0.073, p = 0.015). Mean values and 95% confidence intervals are indicated in blue.
4. Discussion The present study failed to confirm the hypothesis that leukocyte telomere length is reduced in SCZ patients. In contrast, SCZ patients in the present sample displayed longer telomere length than populationbased controls. However, the robust negative association between age and telomere length (e.g. Rampazzo et al., 2010) was replicated in both the overall sample and in separate analyses of patients and controls (see Supplementary material and Fig. S1 in Appendix A), thus suggesting that telomere measurement in the present study was reliable. The effects sizes of the age effect observed in our analysis are comparable to those described in previous reports (Eerola et al., 2010; Kananen et al., 2010), thus providing further confidence that the present findings are valid. Our observation that telomere length was longer in SCZ patients than in controls was an unexpected finding, since most previous studies have reported shorter telomere length in SCZ compared to controls (Kao et al., 2008; Yu et al., 2008; Fernandez-Egea et al., 2009). Assuming that reduced leukocyte telomere length is a biomarker for exposure to stress, short telomeres would be expected in patients with SCZ, since these individuals experience high levels of stress as a result of their symptoms. Interestingly, however, the present finding is consistent with a recent study by Savolainen et al., which investigated associations between telomere length and a history of psychiatric illness and prescription of psychotropic medication. The study included n = 1956 individuals, 116 of whom had a history of a psychiatric diagnosis. The authors found that hospitalized psychiatric patients receiving psychotropic medication, displayed longer telomere length compared to healthy individuals (Savolainen et al., 2012). The present study investigated the largest SCZ sample to date in the field of telomere length research, and can therefore be regarded as the most powerful study in terms of demonstrating an effect. However, various alternative explanations for our finding must be considered. Longer telomere length in SCZ patients compared to control individuals may reflect an association at the endophenotype level. Wikgren et al. (2012a) for example found an association between increased leukocyte telomere length and reduced hippocampal volume in healthy APOE ε3/ε3 individuals (Wikgren et al., 2012a). However, this study must be interpreted with caution, as the sample size was very small (29 ε3/ε3 individuals, 28 ε4 carriers) and included only nonpsychotic individuals. In a second study, Wikgren et al. reported that APOE ε4 carriers with longer telomeres showed poorer performance during episodic memory tasks than those with shorter telomeres (Wikgren et al., 2012b). Poor episodic memory as well as reduced hippocampal volume are features
of SCZ (e.g. Aleman et al., 1999; Adriano et al., 2012), and episodic memory is dependent on an intact hippocampal function. However, the relationship between neuropsychological function and abnormal hippocampal volume remains a subject of debate as episodic memory does not only depend on hippocampal function, but also on prefrontal structures (Ragland et al., 2009). Nevertheless, a possible explanation for the present unexpected finding of longer telomeres in SCZ could be an underlying association between longer telomeres and reduced hippocampal volume and/or impaired episodic memory. However, caution must be exercised in relating the finding of Wikgren et al., to the present result, since Wikgren et al., investigated nonpsychotic individuals. We were unable to replicate a link between telomere length and either episodic memory or hippocampal volume as no such data were available for our sample. An alternative explanation – as was suggested by Savolainen et al. (2012) when interpreting their data – is that psychotropic medications may have antioxidative effects and thus prevent telomere attrition. Since all our hospitalized patients received psychotropic medication, this could have contributed to our finding. Unfortunately, however, our sample included no untreated SCZ patients and no information concerning lifetime amount of psychotropic medication was available and we are therefore unable to clarify whether the association with longer telomeres was due to psychotropic medication or with SCZ per se. One interesting finding, which has been reported consistently across large longitudinal cohorts such as the Framingham study, the Cebu Longitudinal Health and Nutrition survey, the NHLBI-Heart study, the Longitudinal Study of Aging Danish Twins, and the Amish Family Osteoporosis Study, is that advanced paternal age is associated with increased telomere length in the offspring, and that the correlation between paternal age and telomere length persists in the offspring over their entire life-span (Unryn et al., 2005; Njajou et al., 2007; Kimura et al., 2008; Nordfjall et al., 2010; Eisenberg et al., 2012; Broer et al., 2013). Higher paternal age has also been identified as a consistent risk factor for SCZ (for review see Perrin et al., 2007). The hypothesized underlying mechanism for this phenomenon is that the number of new rare mutations increases with paternal age, which in turn increases the risk for SCZ. Telomere length may thus be a marker of the age of the father at the time of conception, rather than a causal factor for the disease. However, we were unable to substantiate this hypothesis in the present sample as no data concerning paternal age were available. Finally, we cannot fully exclude the possibility that our finding might be biased by an underlying association with increased mortality observed among SCZ patients. For some of the disorders that contribute to increased mortality in SCZ patients, such as cancer and cardiovascular disease (Saha et al., 2007; Laursen et al., 2009; Bushe et al., 2010; Heald, 2010), associations with reduced telomere length have been reported (Brouilette et al., 2003; Sampson and Hughes, 2006; Fitzpatrick et al., 2007; Artandi and DePinho, 2010; Butt et al., 2010). We addressed this potential bias by performing separate analyses in the younger and older halves of our SCZ and control samples. The association between increased telomere length and SCZ was stronger in the younger cohort compared to the older cohort, suggesting that our finding in the entire sample was not based on a mortality bias. To fully exclude this potential bias, a large longitudinal follow up study of first-episode SCZ patients would be necessary. However, sample sizes for this type of study design are typically small and thus prone to statistical bias. The extent to which altered telomere length is a cause, or a consequence, of disease associations observed remains a matter of debate (De Meyer et al., 2008). The finding of longer telomere length in patients in the present sample could thus represent either a consequence of or a prerequisite for SCZ development. The first longitudinal studies of telomere length have indicated that besides age, the most powerful predictor of shorter telomere length is baseline telomere length, with
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an exaggerated attrition being observed in individuals with longer telomeres compared to individuals with shorter telomeres. The present study was cross-sectional and involved measurement of telomere length at only one time point, and thus no data on telomere attrition rate are available. In conclusion, increased telomere length was observed in SCZ patients in the present sample, which represents the largest case–control study reported to date. However, a range of possible explanations for this finding exists, and further studies are therefore warranted. An interesting possible explanation is that an underlying association with endophenotypes exists, which acts beyond the currently available diagnostic boundaries for SCZ. Role of funding source This work was supported by grants 01GS08144 (MMN) and 01GS08147 (MR) from the National Genome Research Network (NGFN-plus) of the German Federal Ministry of Education and Research (BMBF). MR was also supported by the 7th Framework Programme of the European Union (ADAMS project, HEALTH-F4-2009-242257). VN received support from the Olympia-Morata-Programme of the University of Heidelberg. IH received support from the Academy of Finland. Contributors VN, MR, IH were responsible for the study concept and design. SM, JS, RB, MR, and MMN contributed to the acquisition of material and data. VN, JL, and IH were responsible for the laboratory analysis, JL, SM, JF, and IH analyzed the data, VN drafted the manuscript, JL, SM, JF, SHW, JS, AH, RB, MMN, and MR provided critical revision of the manuscript. All authors critically reviewed the content of the final version of the manuscript, and approved its submission for publication. Conflict of interest The authors have no conflicts of interest to declare. Acknowledgments We thank C. Hohmeyer for her excellent technical assistance and C. Schmähl for language editing.
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