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. Author manuscript; available in PMC: 2022 Jan 25.
Published in final edited form as: Schizophr Res. 2018 Apr 2;199:426–430. doi: 10.1016/j.schres.2018.02.059

Telomere length and early trauma in schizophrenia

Gabriella Riley a, Mary Perrin a,1, Leila M Vaez-Azizi a, Eugene Ruby b, Raymond R Goetz c,1, Roberta Dracxler a,d, Julie Walsh-Messinger e,i, David L Keefe d, Peter F Buckley f, Philip R Szeszko g,h, Dolores Malaspina h,*
PMCID: PMC8787687  NIHMSID: NIHMS1772685  PMID: 29618413

Abstract

Background:

Childhood trauma is emerging as a risk factor for schizophrenia, but its mechanism with respect to etiology is unknown. One possible pathway is through leucocyte telomere length (LTL) shortening, a measure of cellular aging associated with trauma. This study examined early trauma and LTL shortening in schizophrenia and considered sex effects.

Methods:

The early trauma inventory (ETI) was administered to 48 adults with DSM-5 schizophrenia and 18 comparison participants. LTL was measured using qPCR.

Outcomes:

Cases had significantly more global trauma (F = 4.10, p < 0.01) and traumatic events (F = 11.23, p < 0.001), but case and control groups had similar LTL (1.91 ± 0.74 and 1.83 ± 0.62: p = 0.68). The association of early trauma and LTL differed by sex in cases and controls (Fisher’s R: Z < 0.05). Significant negative associations were shown in male cases and, conversely, in female controls. For example, physical punishment was associated LTL shortening in males’ cases (r = −0.429, p < 01). Only female controls showed significant telomere shortening in association with early trauma.

Interpretation:

This data confirms the substantial excess of early trauma among schizophrenia cases. There were significant sex-differences in the relationship of the trauma to LTL, with only male cases showing the expected shortening. There were converse sex effects in the control group. Mean LTL was notably similar in cases and controls, despite the trauma-related shortening in male cases, cigarette smoking, older age and chronic illness of the cases. Factors may lengthen LTL in some schizophrenia cases. The converse sex differences in the cases are consistent with findings defective sexual differentiation in schizophrenia, consistent with other findings in the field.

Keywords: Early trauma, Schizophrenia, Childhood trauma, Leukocytes, Telomeres, Stress

1. Introduction

Early trauma exposure is a major risk factor for schizophrenia (Heins et al., 2011; Ruby et al., 2014; Varese et al., 2012), which is furthermore associated with clinical features in the disease, particularly with treatment refractory psychotic symptoms, including auditory hallucinations and command hallucinations (Carr et al., 2013; Heins et al., 2011; Rajkumar, 2015; Read et al., 2005; Ruby et al., 2017; Van Os et al., 2008; Varese et al., 2012). There are a number of possible pathways that could explain the relationship of early trauma to the development of schizophrenia (Read et al., 2001; Ruby et al., 2014; Veras et al., 2018) but none are yet shown to explain the association. One possible mechanism is the shortening telomere lengths by trauma. Shorter telomeres are a biological marker of cellular aging that has been linked to early trauma exposure in population studies (Epel et al., 2004; Kananen et al., 2010; Price et al., 2013; Shalev, 2012; Shalev et al., 2013).

Briefly, telomeres are tandem repeats of TTAGGG at both ends of mammalian chromosomes that form a protective cap to buffer genes against damage during replication. Telomere lengths decrease with each cell replication in somatic cells. Shorter telomeres predict fewer future cell divisions and more rapid cell senescence, ultimately triggering programmed cell death (apoptosis). Telomere length, usually measured as leukocyte telomere length (LTL) predicts lifespan as well as cellular aging (Armanios, 2013). Cortisol and dysregulated Hypothalamic Pituitary Axis (HPA) activity can reduce LTL, with shorter telomeres demonstrated in stressed women caring for partners with dementia and in numerous other comparable circumstances (Damjanovic et al., 2007; Oliveira et al., 2016). The enzyme telomerase, which normally lengthens telomeres in stem cells but is silenced in somatic cells, undergoes reduced activity from cortisol exposure in cultured T lymphocyte (Choi et al., 2008). Stress and elevated cortisol levels are furthermore linked to inflammation and oxidative stress, which also produce telomere erosion (Shalev, 2012). Glucocorticoids augment the oxidative stress that can produce double-stranded telomeric breaks leading to LTL shortening (Epel et al., 2004).Together these findings support a role for the HPA stress axis in telomere length maintenance.

Demonstrating that early trauma contributes to telomere shortening in schizophrenia may shed light on the contradictory findings concerning LTL in schizophrenia. An initial study reported shortened LTL in schizophrenia cases compared to controls, which was in keeping with the earlier mortality, cigarette smoking, cardiovascular diseases and chronic poor health of most persons with schizophrenia (Kao et al., 2008). For example, cigarette smoking is associated with shortened LTL in large population studies and the vast majority of cases, upwards of 80%, smoke cigarettes (McGrath et al., 2007). Moreover, shortened telomeres were observed in several other psychiatric disorders (Darrow et al., 2016). However subsequent studies found no mean difference in LTL between cases and controls and yet other reports described longer LTL in groups of schizophrenia cases (Nieratschker et al., 2013; Rao et al., 2016).

This study tested the hypothesis that childhood trauma is related to shorter LTL in schizophrenia. If so, then childhood adversity may contribute to the disease through cellular aging. We used a reliable and valid structured interview to assess trauma exposure in a sample of exceptionally well-characterized schizophrenia cases and healthy controls.

2. Materials and method

The study was conducted at a large urban public hospital and was approved by the Institutional Review Boards of NYU Medical Center and Bellevue Hospital Center. All participants provided written informed consent. Cases with schizophrenia or schizoaffective disorder on stable medication doses were recruited from inpatient and outpatient treatment settings and healthy controls were recruited from local postings and internet- recruitment sites. Healthy control participants were excluded if they met criteria for an Axis I diagnosis in the last two years, had ever taken psychiatric medications, or had any personal or family history of psychosis in first-degree relatives on structured interviews.

To determine DSM diagnosis, Master’s level clinicians conducted assessments with the Diagnostic Interview for Genetic Studies (DIGS) and utilized hospital records (Nurnberger et al., 1994). Childhood trauma exposure was assessed with the early trauma inventory (ETI) (Bremner et al., 2000), which includes measures of general traumatic events, physical abuse, emotional abuse, and sexual abuse before age 18, as well as general trauma after the age of 18. Analyses of inter-rater reliability, test-retest reliability, internal consistency, and convergent validity all indicate that the ETI is a reliable and valid assessment for the measurement of reported childhood trauma (Bremner et al., 2000). For all participants, cigarette smoking history was categorized as never, past, or current. Lifetime cumulative antipsychotic equivalents were not assessed, but cases were categorized based on their current psychiatric medications: those taking any Lithium, clozapine, Risperdal, aripiprazole, haloperidol injection, other atypical agents, none and unknown.

For LTL, DNA was extracted from lymphocytes (EAG Laboratories; Hercules, CA, USA) by quantitative polymerase chain reaction (qPCR) with iCycler real-time PCR system and several modifications, as we have previously detailed (Cawthon, 2002; Malaspina et al., 2014). Each sample was assayed in triplicate with the Rotor-Gene SYBR Green PCR Master Mix from Qiagen. LTL was determined by calculating the telomere to single copy gene ratio (T/S ratio) using ΔCt. The T/S ratio of each sample (x) was normalized relative to the mean T/S ratio of the reference sample [2 − (Δctx − ΔCtr) = 2 − ΔΔCt], which was used to construct standard curves for a reference and a validation sample.

3. Data analysis

Data was entered and verified using the SIR Database Management Software (SIR 2002, SIR Pty Ltd) and IBM/SPSS Statistics 23 was used for the analyses. Descriptive statistics and distributions of all measures were examined, whether continuous or categorical, to identify key features (e.g. non-normal distribution, outliers, skewness) that impacted inferential methods. Age, education, and LTL were compared across diagnosis and sex using ANOVA. Age of illness onset was compared across the male and female cases using the t-test statistic. The ETI Domains were analyzed using MANCOVA with age as a covariate. Smoking status was analyzed using the Chi-squared statistic. Due to the small sample size, spearman correlations were performed between LTL and the ETI Domains and scatterplots were run to assess for outliers. Male and female cases with outlier (elongated) LTL were determined statistically using the SPSS “Examine procedure,” which identifies values that are not within the interquartile range of values; i.e. within 1.5 standard deviations from the median. Post-hoc analysis investigated paternal age of male outliers.

4. Results

Schizophrenia cases were older and less educated than controls, and only two controls were current or past smokers compared to 32 of 48 cases, demonstrating a substantial group effect for smoking status among the schizophrenia cases (p < 0.001). Schizophrenia cases had significantly greater exposure to trauma than controls, particularly for general trauma and emotional abuse, with no significant sex differences in their trauma exposures or LTL measurements. However, the mean LTL measurements were similar for the groups of cases and controls, respectively 1.91 (0.74) and 1.83 (0.62). There was no significant group level association between LTL and subjects age (Spearman’s non-parametric statistics) in either the cases (rho = −0.009) or controls (rho = −0.203). In cases, LTL was also not significantly related to current medication groups, with sample sizes and mean LTL as follows: Lithium (n = 4), mean 1.57 (SD 0.12); clozapine (n = 6), 2.14 (0.67); Risperdal (n = 12), 1.95 (0.55); aripiprazole (n = 5), 2.32 (0.99); haloperidol injection (n = 1), 2.15; other atypical agents (n = 10), 1.74 (0.16); none (4), 1.92 (0.56) and unknown medications (6), 2.05 (0.53).

There were no significant associations between LTL and trauma indices for general events, physical punishment, emotional abuse, sexual events and the grand total of events (r’s = −0.20 to +0.22) for cases or controls. Sex-specific analyses showed significant sex differences in the correlations of LTL with early trauma exposure. LTL was shorter in association with trauma severity in male cases, but not in female cases (−0.320 vs. 0.447: Fisher’s R to Z Transformation < 0.05). The effect of trauma to shorten LTL with particularly strong for male cases exposed to early physical punishment and LTL (r = −0.429, p < 01). Conversely, female controls showed greater correlations between LTL reductions and trauma severity than male controls (−0.275 vs. 0.688: Fisher’s R to Z Transformation < 0.05).

5. Discussion

This study demonstrated significantly greater exposure to early trauma for schizophrenia cases than healthy control subjects, supporting a large prior literature. While the trauma severity was not significantly associated with the mean group-level LTL in cases or controls, there were significant sex differences regarding these associations in both groups. Only male schizophrenia cases demonstrated the hypothesized significant LTL shortening from early trauma. Conversely, only female controls showed this same effect.

The identification of sex specific findings in LTL shortening with respect to trauma in schizophrenia males is also novel. However, the female sex specific finding in control subjects matches a recent report of sex differences in depressed subjects in the associations between LTL shortening and stress exposures (Liu et al., 2017). Any protective mechanism against trauma-related LTL shortening in males with depression is absent in the schizophrenia cases. While longer LTL for our female schizophrenia cases and for our male controls in relationship with trauma severity could certainly be a spurious finding, the results highlight the importance of sex stratification in studies of LTL. If validated in larger studies, the sex differences may explain some of the inconsistency in the literature concerning measures of stress exposure and LTL.

Although this is the first study examining the relationship of LTL and childhood adversity in schizophrenia, a recent meta-analysis showed a small but significant association (−0.08) could be measured at a mean age of 42 years (Hanssen et al., 2017), similar to the age of our samples. LTL is reported from other samples with respect to stress measures, but the results remain convoluted (Mathur et al., 2016), perhaps because of sex and illness effects. Shorter LTL in healthy adults was associated with stress-related reductions in heart rate variability, a measure of vagal activity, and greater cortisol output, but these relationships did not withstand corrections for covariates (Woody et al., 2017). Similar LTL in un-medicated depressed patients and healthy controls is reported in another study, but stress activation only predicted shorter LTLs in the healthy group (Fair et al., 2017). Longitudinal perspectives of life course exposures are likewise conflicting. Recent stressors, but not childhood adversities, predicted shorter LTL in one study (Verhoeven et al., 2015). Psychosocial stress has also been reported to be unrelated to LTL in older adults, but LTL still demonstrated weak negative associations with early life adversity (Schaakxs et al., 2015).

Antipsychotic medication was not a predictor of LTL in this study, although we did not have the data to calculate cumulative life course exposures to medications, did not have longitudinal data, and the samples were relatively small. It is notable that our cases on lithium actually had the shortest LTL. Among bipolar cases, long-term lithium was reported to predict longer LTL (Martinsson et al., 2013), although this study did not account for psychosis and was cross-sectional, so it is difficult to interpret with respect to the current findings (Table 1).

Table 1.

Demographics, leukocyte telomere length and early trauma in controls and cases, data presented by sex. Includes ANOVA for age, education and LTL; t-test for onset age; Chi-square for smoking; MANCOVA with age as covariate for early trauma domains.

Healthy controls Schizophrenia cases Statistics
Males (N = 11) Females (N = 7) Males (N = 28) Females (N = 20) Diag. Sex Diag./sex
Mean (SD) Mean (SD) Mean (SD) Mean (SD) F F F
Age 36.5 (8.5) 37.3 (9.4) 41.9 (10.2) 43.3 (10.0) 4.21* 0.16 0.01
Onset age – – 20.1 (6.8) 21.3 (7.1) – t = 0.54 –
Education 15.2 (1.9) 13.9 (2.5) 12.1 (2.6) 13.9 (2.5) 4.57* 0.09 4.80*
LTL 1.92 (0.76) 1.58 (0.54) 2.04 (0.84) 1.82 (0.68) 0.72 1.68 0.08
Healthy controls Schizophrenia cases Statistics
Males (N = 11) Females (N = 6) Males (N = 23) Females (N = 18) Diag. Sex Diag./sex
F F F
Smokers: N (%) 1 (9%) 1 (17%) 19 (83%) 13 (72%) Chi2 = 21.77*** Chi2 = 0.00
Early trauma inventory
Healthy controls Schizophrenia cases Statistics
Males (N = 11) Females (N = 7) Males (N = 28) Females (N = 20) Diag. Sex Diag./sex
F F F
Multivariate Wilks’ Lambda statistics→ 4.10** 1.88 0.51
General events 5.9 (5.4) 8.7 (6.2) 19.7 (14.3) 15.9 (10.0) 6.76* 0.10 1.27
Punishment 4.1 (2.3) 3.0 (2.5) 6.5 (6.6) 5.5 (3.7) 2.08 0.68 0.00
Emotional 1.6 (2.3) 4.9 (9.6) 8.9 (7.9) 14.7 (10.8) 9.84** 3.25 t 0.26
Sexual 0.55 (1.3) 1.0 (1.9) 6.7 (13.0) 6.0 (8.6) 3.29 t 0.01 0.05
ETI overall total 12.2 (9.0) 17.6 (13.3) 41.8 (30.0) 42.0 (24.1) 11.23*** 0.09 0.18
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t = trend.

*

p < 0.050.

**

p < 0.010.

***

p = 0.001.

In light of their early trauma, cigarette smoking, medications, chronic illness and older ages, our cases did not have shorter LTL than the controls, consistent with a telomere lengthening mechanism, in at least some cases. The conflicting LTL findings in schizophrenia are consistent with etiological heterogeneity and different environmental exposures. While shorter or similar LTL in schizophrenia cases and controls have been reported (Czepielewski et al., 2016; Fernandez-Egea et al., 2009; Galletly et al., 2017; Kao et al., 2008; Mansour et al., 2011; Maurya et al., 2017; Polho et al., 2015; Rao et al., 2016; Wolkowitz et al., 2017), significantly longer LTL were demonstrated in a sample of over 500 schizophrenia cases (Nieratschker et al., 2013). One large meta-analytic study of subjects with diverse psychiatric disorders found LTL was not reduced in psychotic cases, whereas significant reductions were demonstrated for depressive and anxiety conditions (Darrow et al., 2016). Another study of elderly hospitalized schizophrenia cases in the Helsinki Birth Cohort Study likewise demonstrated longer LTL (Savolainen et al., 2012). These authors could not exclude a selection bias related to the late life survival of these elderly cases, particularly given the shorter lifespan of persons with mentally illness, but the finding still supports the heterogeneity of LTL in the disorder that may be useful. Both a family history of psychosis and with older paternal age are predictors of longer LTL in schizophrenia and both of these relationships suggest genetic effects (Aviv and Susser, 2013; Malaspina et al., 2001). If so, genes involved in telomere homeostasis are reasonable candidates (Rivera et al., 2017). Polymorphisms in the XRCC3 gene, which trims telomeres, are associated with schizophrenia (Odemis et al., 2016). Future studies could examine polymorphisms in XRCC3 with respect to person-specific LTL and clinical features. Schizophrenia cases with longer LTL in our previous study attained a higher education than other cases and demonstrated a preserved verbal intelligence with a lower performance IQ (Vaez-Azizi et al., 2015). As a family history of psychosis might also be related to greater adversity (Malaspina et al., 2014) it is clear that larger studies are needed to account for the impact of different etiological factors on LTL.

Strengths of the current study include the use of the early trauma inventory, which accounts for a much wider range of occurrences than other instruments that assess early trauma and is reliable (Bremner et al., 2007; Bremner et al., 2000). Furthermore, we used a clinician-administered version of the inventory that allows clinicians to determine the patient’s understanding of the questions being asked. Weaknesses included the small sample size, especially for the control group. As this was a cross-sectional study, another limitation is its reliance on recall and retrospective accounts of childhood trauma, which may be impaired by poor memory or biased in the cases. However, the reliability of psychotic patients’ abuse reports is well been established (Lataster et al., 2006). While qPCR has been proven to be an effective method for estimating TL, our study included leukocytes and not neurons with the understanding that LTL is strongly correlated with telomere length in other tissues. Studying medication free patients may be optimal, but is often impractical. Our few subjects taking no medications actually showed the same LTL as the group mean value. Ideally, longitudinal designs, such as epidemiological cohort studies with recordings of actual trauma, could be employed with actual trauma data.

While it remains to be determined how stress influences LTL, it is clear that stress exposure is a risk factor for psychosis, altering hypothalamic-pituitary-adrenal axis function, which may produce altered cognition and behaviors (Ruby et al., 2017). Further Illuminating the relationship between stress and telomere lengths is of great interest for psychiatric research and for understanding stress effects in the population.

This work highlights a novel male sex-specific association between severe early trauma exposure and LTL reduction. Furthermore, this association is converse of that in controls, wherein females showed the relationship between trauma and stress exposure. This converse sex-association in schizophrenia compared to the healthy controls is yet another measure suggesting that the pathobiology of schizophrenia may lie, in part, in the mechanisms related to sexual differentiation.

Acknowledgements

Supported by NIMH Challenge Grant RC1MH088843. Published posthumously by coauthor Mary Perrin, whose intellect and wit and resilience is dearly missed.

Funding sources

Study was funded by NIMH RC1MH088843 for assistance with costs related to LTL measurements.

Study was funded by NIMH Challenge Grant RC1MH088843.

Footnotes

Conflicts of interests

None exist.

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