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Epigenetic analysis suggests aberrant cerebellum brain aging in old-aged adults with autism spectrum disorder and schizophrenia


The aberrant aging hypothesis of schizophrenia (SCZ) and autism spectrum disorder (ASD) has been proposed, and the DNA methylation (DNAm) clock, which is a cumulative evaluation of DNAm levels at age-related CpGs, could serve as a biological aging indicator. This study evaluated epigenetic brain aging of ASD and SCZ using Horvath’s epigenetic clock, based on two public genome-wide DNA methylation datasets of post-mortem brain samples (NASD = 222; NSCZ = 142). Total subjects were further divided into subgroups by gender and age. The epigenetic age acceleration (AgeAccel) for each sample was calculated as the residual value resulting from the regression model and compared between groups. Results showed DNAm age has a strong correlation with chronological age in both datasets across multiple brain regions (P < 0.05). When divided into equally sized age groups, the AgeAccel of the cerebellum (CB) region from people over 45 years of age was greater compared to the control sample (AgeAccel of ASD vs control: 5.069 vs −6.249; P < 0.001). And a decelerated epigenetic aging process was observed in the CB region of individuals with SCZ aged 50–70 years (AgeAccel of SCZ vs control: −3.171 vs 2.418; P < 0.05). However, our results showed no significant difference in AgeAccel between ASD and control groups, and between SCZ and control groups in the total and gender-specific groups (P > 0.05). This study’s results revealed some evidence for aberrant epigenetic CB brain aging in old-aged patients with ASD and SCZ, indicating a different pattern of CB aging in older adults with these two diseases. However, further studies of larger ASD and SCZ cohorts are necessary to make definitive conclusions on this observation.

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Fig. 1: Assessment of epigenetic age in ASD patients and non-psychiatry controls.
Fig. 2: Assessment of epigenetic age in SCZ patients and non-psychiatry controls.
Fig. 3: Assessment of epigenetic age acceleration in ASD patients and non-psychiatry controls.
Fig. 4: Assessment of epigenetic age acceleration in SCZ patients and non-psychiatry controls.

Data availability

Brain sample metadata are provided in Table S1S7. Raw DNA methylation data for ASD and controls can be found in the PsychENCODE Knowledge Portal (!Synapse:syn8263588). Raw DNA methylation data for SCZ and controls are available in the Gene Expression Omnibus (GEO) datasets database (


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We thank Shanghai NewCore Biotechnology Co., Ltd. (, last accessed on 10 July 2023) for providing visualization support.


This work was supported by the Natural Science Basic Research Plan in Shaanxi Province of China [2021JCW-08], the Fundamental-clinical Research Program of the First Affiliated Hospital of Xi’an Jiaotong University [YXJLRH2022027]. This work was supported by US National Institutes of Health grant R01MH094714 to D.H.G. and is part of the PsychEncode Consortium. Data were generated as part of the PsychENCODE Consortium, supported by: U01DA048279, U01MH103339, U01MH103340, U01MH103346, U01MH103365, U01MH103392, U01MH116438, U01MH116441, U01MH116442, U01MH116488, U01MH116489, U01MH116492, U01MH122590, U01MH122591, U01MH122592, U01MH122849, U01MH122678, U01MH122681, U01MH116487, U01MH122509, R01MH094714, R01MH105472, R01MH105898, R01MH109677, R01MH109715, R01MH110905, R01MH110920, R01MH110921, R01MH110926, R01MH110927, R01MH110928, R01MH111721, R01MH117291, R01MH117292, R01MH117293, R21MH102791, R21MH103877, R21MH105853, R21MH105881, R21MH109956, R56MH114899, R56MH114901, R56MH114911, R01MH125516, and P50MH106934 awarded to: Alexej Abyzov, Nadav Ahituv, Schahram Akbarian, Alexander Arguello, Lora Bingaman, Kristin Brennand, Andrew Chess, Gregory Cooper, Gregory Crawford, Stella Dracheva, Peggy Farnham, Mark Gerstein, Daniel Geschwind, Fernando Goes, Vahram Haroutunian, Thomas M. Hyde, Andrew Jaffe, Peng Jin, Manolis Kellis, Joel Kleinman, James A. Knowles, Arnold Kriegstein, Chunyu Liu, Keri Martinowich, Eran Mukamel, Richard Myers, Charles Nemeroff, Mette Peters, Dalila Pinto, Katherine Pollard, Kerry Ressler, Panos Roussos, Stephan Sanders, Nenad Sestan, Pamela Sklar, Nick Sokol, Matthew State, Jason Stein, Patrick Sullivan, Flora Vaccarino, Stephen Warren, Daniel Weinberger, Sherman Weissman, Zhiping Weng, Kevin White, A. Jeremy Willsey, Hyejung Won, and Peter Zandi.

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LL and XQ drafted the manuscript. FZ, YJ, and YW designed the study. FZ provided the key datasets regarding our manuscript. SC, BC, and HL performed the statistical analyses. NZ, PM, XY, CP, YC, HZ, ZZ, JZ, and CL provided feasible advice on data analysis and drafting the manuscript. All authors read and approved the final manuscript. All authors discussed the results and commented on the manuscript.

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Correspondence to Feng Zhang.

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Liu, L., Qi, X., Cheng, S. et al. Epigenetic analysis suggests aberrant cerebellum brain aging in old-aged adults with autism spectrum disorder and schizophrenia. Mol Psychiatry (2023).

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