Abstract
Schizophrenia (SCZ) is associated with high mortality. DNA methylation levels vary over the life course, and pre-selected combinations of methylation array probes can be used to estimate “methylation age” (mAge). mAge correlates highly with chronological age but when it differs, termed mAge acceleration, it has been previously associated with all-cause mortality. We tested the association between mAge acceleration and mortality in SCZ and controls. We selected 190 SCZ cases and 190 controls from the Sweden Schizophrenia Study. Cases were identified from the Swedish Hospital Discharge Register with ≥5 specialist treatment contacts and ≥5 antipsychotic prescriptions. Controls had no psychotic disorder or antipsychotics. Subjects were selected if they had died or survived during follow-up (2:1 oversampling). Extracted DNA was assayed on the Illumina MethylationEPIC array. mAge was regressed on age at sampling to obtain mAge acceleration. Using Cox proportional hazards regression, the association between mAge acceleration and mortality was tested. After quality control, the following were available: n = 126 SCZ died, 63 SCZ alive, 127 controls died, 62 controls alive. In the primary analyses, we did not find a significant association between mAge acceleration and SCZ mortality (adjusted p > 0.005). Sensitivity analyses excluding SCZ cases with pre-existing cancer demonstrated a significant association between the Hannum mAge acceleration and mortality (hazard ratio = 1.13, 95% confidence interval = 1.04–1.22, p = 0.005). Per our pre-specified criteria, we did not confirm our primary hypothesis that mAge acceleration would predict subsequent mortality in people with SCZ, but we cannot rule out smaller effects or effects in patient subsets.
Highlights
Schizophrenia (SCZ) is associated with significantly higher mortality and 12–15 years decreased life expectancy compared to healthy individuals[1]
We conducted a well-powered case-control study within a Swedish study of SCZ and controls[17], finding the evidence was too weak to support our pre-specified primary hypothesis that methylation age” (mAge) acceleration is associated with mortality in SCZ. mAge acceleration has been previously associated with all-cause mortality, including in a large meta-analysis of 13,089 individuals (2734 deaths; p ≤ 8.2 × 10−9)[10], with similar findings in smaller cohorts[5,7,35]
These previous studies used population-based cohorts of individuals with no specific disease and it is possible that the underlying mechanism of mAge acceleration as a predictor of mortality differs in SCZ
Summary
Schizophrenia (SCZ) is associated with significantly higher mortality and 12–15 years decreased life expectancy compared to healthy individuals[1]. The causes of increased mortality in SCZ may include internal (i.e., genetic risk) and external factors, such as adverse health behaviors (i.e., smoking) or the under-diagnosis and under-treatment of common causes of mortality, including cancer and ischemic heart disease[1]. Another possibility for increased mortality relates to the hypothesis of accelerated aging, that is, factors associated with the disorder accelerates changes in biological status. The deviation between mAge and chronological age (i.e., accelerated mAge) has been identified as a potential risk factor for age-related diseases and all-cause mortality in nonpsychiatric studies[6,7,8,9,10]
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