Epigenetic age is accelerated in schizophrenia with age- and sex-specific effects and associated with polygenic disease risk

Abstract

Schizophrenia (SCZ) is a severe mental illness that is associated with an increased prevalence of age-related disability and morbidity compared to the general population. An accelerated aging process has therefore been hypothesized as a component of the SCZ disease trajectory. Here, we investigated differential aging using three DNA methylation (DNAm) clocks (i.e. Hannum, Horvath, Levine) in a multi-cohort SCZ whole blood sample consisting of 1,100 SCZ cases and 1,200 controls. It is known that all three DNAm clocks are highly predictive of chronological age and capture different features of biological aging.We found that blood-based DNAm aging is significantly altered in SCZ with age-and sexspecific effects that differ between clocks and map to distinct chronological age windows.Most notably, the predicted phenotypic age (Levine clock) in female cases, starting at age 36 and beyond, is 3.21 years older compared to matching control subjects (95% CI: 1.92-4.50, P=1.3e-06) explaining 7.7% of the variance in disease status. Female cases with high SCZ polygenic risk scores present the highest age acceleration in this age group with +7.03 years (95% CI: 3.87-10.18, P=1.7E-05). Since increased phenotypic age is associated with increased risk of all-cause mortality, our findings suggests that specific and identifiable patient groups are at increased mortality risk as measured by the Levine clock. These results provide new biological insights into the aging landscape of SCZ with age-and sexspecific effects and warrant further investigations into the potential of DNAm clocks as clinical biomarkers that may help with disease management in schizophrenia.

Accelerated aging in the brain, epigenetic aging in blood, and polygenic risk for schizophrenia

“…We found that epigenetic age was significantly accelerated by +2.3 year in schizophrenia patients as compared to healthy controls for the PhenoAge clock, but not for the DNAmAge clock. Previous reports suggest no accelerated epigenetic aging or association with premature mortality for schizophrenia in blood or post-mortem brain samples (McKinney et al, 2017; Voisey et al, 2017; McKinney et al, 2018; Kowalec et al, 2019), with some exceptions (Okazaki et al, 2019; Ori et al, 2019; Higgins-Chen, 2020).…”

“…Subjects included in this study were part of two longitudinal schizophrenia cohorts (van Haren et al, 2007; Boos et al, 2012). Brain age in these cohorts has been described before (Schnack et al, 2016) and these cohorts were part of a study on epigenetic aging in schizophrenia (Ori et al, 2019). Here we included unrelated subjects that had imaging data and either epigenetic or genetic data available, resulting in a dataset of 411 unrelated subjects (193 cases, 218 controls, 36% female) of European descent spanning a wide range of the adult lifespan (mean = 32.7 years, range = [16.7 - 67.5] at baseline).…”

“…The age of a tissue donor can be reliably estimated based on epigenetic methylation of DNA (Horvath et al, 2012; Horvath, 2013; Hannum et al, 2013; Levine et al, 2018). While no significant accelerated epigenetic aging has previously been observed schizophrenia, neither in post-mortem brain nor blood tissue (Viana et al, 2017; Voisey et al, 2017; McKinney et al, 2017; McKinney et al, 2018), a recent large-scale DNA methylation study now robustly demonstrated that epigenetic age is accelerated in whole blood samples and is strongly correlated with mortality risk (Ori et al, 2019; Higgins-Chen et al, 2020). The study furthermore reports that a subset of cases who carry high schizophrenia polygenic risk present the fastest age acceleration.…”

“…This shortened lifespan may be explained in terms of accelerated aging of the body (Kirkpatrick et al, 2008). In two separate studies we have previously reported on accelerated aging of the brain (Schnack et al, 2016) and epigenetic aging in blood (Ori et al, 2019) for schizophrenia patients. However, whether or not these different biomarkers of aging act in concert has noy yet been investigated.…”

DNA methylation signatures of aggression and closely related constructs: A meta-analysis of epigenome-wide studies across the lifespan

“…Therefore, we performed separate meta-analyses of peripheral blood collected after birth (N=14,434) and cord blood (N=2,425), followed by a combined meta-analysis (N=15,324) including an examination of heterogeneity of effects. Next, we tested the relationship between aggressive behavior and epigenetic clocks, as associations of lifetime stress , exposure to violence 25 , and psychiatric disorders 26,27 with accelerated epigenetic ageing have been reported. We performed extensive functional follow-up by integrating our findings with data on gene expression, mQTLs and DNA methylation in brain samples.…”