Additive effects of stress and alcohol exposure on accelerated epigenetic aging in alcohol use disorder

Jeesun Jung; Daniel L McCartney; Josephin Wagner; Joyce Yoo; Andrew S Bell; Lucas A Mavromatis; Daniel B Rosoff; Colin A Hodgkinson; Hui Sun; Melanie Schwandt; Nancy Diazgranados; Alicia K Smith; Vasiliki Michopoulos; Abigail Powers; Jennifer Stevens; Bekh Bradley; Negar Fani; Rosie M Walker; Archie Campbell; David J Porteous; Andrew M McIntosh; Steve Horvath; Riccardo E Marioni; Kathryn L Evans; David Goldman; Falk W Lohoff

doi:10.1016/j.biopsych.2022.06.036

Additive effects of stress and alcohol exposure on accelerated epigenetic aging in alcohol use disorder

Jeesun Jung, Daniel L McCartney, Josephin Wagner, Joyce Yoo, Andrew S Bell, Lucas A Mavromatis, Daniel B Rosoff, Colin A Hodgkinson, Hui Sun, Melanie Schwandt, Nancy Diazgranados, Alicia K Smith, Vasiliki Michopoulos, Abigail Powers, Jennifer Stevens, Bekh Bradley, Negar Fani, Rosie M Walker, Archie Campbell, David J PorteousAndrew M McIntosh, Steve Horvath, Riccardo E Marioni, Kathryn L Evans, David Goldman, Falk W Lohoff^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

Abstract / Description of output

BACKGROUND: Stress contributes to premature aging and susceptibility to alcohol use disorder (AUD), and AUD itself is a factor in premature aging; however, the interrelationships of stress, AUD, and premature aging are poorly understood.

METHODS: We constructed a composite score of stress from 13 stress-related outcomes in a discovery cohort of 317 individuals with AUD and control subjects. We then developed a novel methylation score of stress (MS stress) as a proxy of composite score of stress comprising 211 CpGs selected using a penalized regression model. The effects of MS stress on health outcomes and epigenetic aging were assessed in a sample of 615 patients with AUD and control subjects using epigenetic clocks and DNA methylation-based telomere length. Statistical analysis with an additive model using MS stress and a MS for alcohol consumption (MS alcohol) was conducted. Results were replicated in 2 independent cohorts (Generation Scotland, N = 7028 and the Grady Trauma Project, N = 795).

RESULTS: Composite score of stress and MS stress were strongly associated with heavy alcohol consumption, trauma experience, epigenetic age acceleration (EAA), and shortened DNA methylation-based telomere length in AUD. Together, MS stress and MS alcohol additively showed strong stepwise increases in EAA. Replication analyses showed robust association between MS stress and EAA in the Generation Scotland and Grady Trauma Project cohorts.

CONCLUSIONS: A methylation-derived score tracking stress exposure is associated with various stress-related phenotypes and EAA. Stress and alcohol have additive effects on aging, offering new insights into the pathophysiology of premature aging in AUD and, potentially, other aspects of gene dysregulation in this disorder.

Original language	English
Journal	Biological Psychiatry
Early online date	16 Jul 2022
DOIs	https://doi.org/10.1016/j.biopsych.2022.06.036
Publication status	E-pub ahead of print - 16 Jul 2022

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10.1016/j.biopsych.2022.06.036Licence: Creative Commons: Attribution-NonCommercial-NoDerivatives (CC BY-NC-ND)

PIIS0006322322014305Final published version, 1.74 MBLicence: CC BY-NC-ND

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Jung, J., McCartney, D. L., Wagner, J., Yoo, J., Bell, A. S., Mavromatis, L. A., Rosoff, D. B., Hodgkinson, C. A., Sun, H., Schwandt, M., Diazgranados, N., Smith, A. K., Michopoulos, V., Powers, A., Stevens, J., Bradley, B., Fani, N., Walker, R. M., Campbell, A., ... Lohoff, F. W. (2022). Additive effects of stress and alcohol exposure on accelerated epigenetic aging in alcohol use disorder. Biological Psychiatry. https://doi.org/10.1016/j.biopsych.2022.06.036

@article{3d3e5299fa604c32af898c753b4d6739,

title = "Additive effects of stress and alcohol exposure on accelerated epigenetic aging in alcohol use disorder",

abstract = "BACKGROUND: Stress contributes to premature aging and susceptibility to alcohol use disorder (AUD), and AUD itself is a factor in premature aging; however, the interrelationships of stress, AUD, and premature aging are poorly understood.METHODS: We constructed a composite score of stress from 13 stress-related outcomes in a discovery cohort of 317 individuals with AUD and control subjects. We then developed a novel methylation score of stress (MS stress) as a proxy of composite score of stress comprising 211 CpGs selected using a penalized regression model. The effects of MS stress on health outcomes and epigenetic aging were assessed in a sample of 615 patients with AUD and control subjects using epigenetic clocks and DNA methylation-based telomere length. Statistical analysis with an additive model using MS stress and a MS for alcohol consumption (MS alcohol) was conducted. Results were replicated in 2 independent cohorts (Generation Scotland, N = 7028 and the Grady Trauma Project, N = 795).RESULTS: Composite score of stress and MS stress were strongly associated with heavy alcohol consumption, trauma experience, epigenetic age acceleration (EAA), and shortened DNA methylation-based telomere length in AUD. Together, MS stress and MS alcohol additively showed strong stepwise increases in EAA. Replication analyses showed robust association between MS stress and EAA in the Generation Scotland and Grady Trauma Project cohorts.CONCLUSIONS: A methylation-derived score tracking stress exposure is associated with various stress-related phenotypes and EAA. Stress and alcohol have additive effects on aging, offering new insights into the pathophysiology of premature aging in AUD and, potentially, other aspects of gene dysregulation in this disorder.",

author = "Jeesun Jung and McCartney, {Daniel L} and Josephin Wagner and Joyce Yoo and Bell, {Andrew S} and Mavromatis, {Lucas A} and Rosoff, {Daniel B} and Hodgkinson, {Colin A} and Hui Sun and Melanie Schwandt and Nancy Diazgranados and Smith, {Alicia K} and Vasiliki Michopoulos and Abigail Powers and Jennifer Stevens and Bekh Bradley and Negar Fani and Walker, {Rosie M} and Archie Campbell and Porteous, {David J} and McIntosh, {Andrew M} and Steve Horvath and Marioni, {Riccardo E} and Evans, {Kathryn L} and David Goldman and Lohoff, {Falk W}",

note = "Published by Elsevier Inc.",

year = "2022",

month = jul,

day = "16",

doi = "10.1016/j.biopsych.2022.06.036",

language = "English",

journal = "Biological Psychiatry",

issn = "0006-3223",

publisher = "Elsevier",

}

Jung, J, McCartney, DL, Wagner, J, Yoo, J, Bell, AS, Mavromatis, LA, Rosoff, DB, Hodgkinson, CA, Sun, H, Schwandt, M, Diazgranados, N, Smith, AK, Michopoulos, V, Powers, A, Stevens, J, Bradley, B, Fani, N, Walker, RM , Campbell, A, Porteous, DJ, McIntosh, AM, Horvath, S, Marioni, RE , Evans, KL, Goldman, D & Lohoff, FW 2022, 'Additive effects of stress and alcohol exposure on accelerated epigenetic aging in alcohol use disorder', Biological Psychiatry. https://doi.org/10.1016/j.biopsych.2022.06.036

TY - JOUR

T1 - Additive effects of stress and alcohol exposure on accelerated epigenetic aging in alcohol use disorder

AU - Jung, Jeesun

AU - McCartney, Daniel L

AU - Wagner, Josephin

AU - Yoo, Joyce

AU - Bell, Andrew S

AU - Mavromatis, Lucas A

AU - Rosoff, Daniel B

AU - Hodgkinson, Colin A

AU - Sun, Hui

AU - Schwandt, Melanie

AU - Diazgranados, Nancy

AU - Smith, Alicia K

AU - Michopoulos, Vasiliki

AU - Powers, Abigail

AU - Stevens, Jennifer

AU - Bradley, Bekh

AU - Fani, Negar

AU - Walker, Rosie M

AU - Campbell, Archie

AU - Porteous, David J

AU - McIntosh, Andrew M

AU - Horvath, Steve

AU - Marioni, Riccardo E

AU - Evans, Kathryn L

AU - Goldman, David

AU - Lohoff, Falk W

N1 - Published by Elsevier Inc.

PY - 2022/7/16

Y1 - 2022/7/16

N2 - BACKGROUND: Stress contributes to premature aging and susceptibility to alcohol use disorder (AUD), and AUD itself is a factor in premature aging; however, the interrelationships of stress, AUD, and premature aging are poorly understood.METHODS: We constructed a composite score of stress from 13 stress-related outcomes in a discovery cohort of 317 individuals with AUD and control subjects. We then developed a novel methylation score of stress (MS stress) as a proxy of composite score of stress comprising 211 CpGs selected using a penalized regression model. The effects of MS stress on health outcomes and epigenetic aging were assessed in a sample of 615 patients with AUD and control subjects using epigenetic clocks and DNA methylation-based telomere length. Statistical analysis with an additive model using MS stress and a MS for alcohol consumption (MS alcohol) was conducted. Results were replicated in 2 independent cohorts (Generation Scotland, N = 7028 and the Grady Trauma Project, N = 795).RESULTS: Composite score of stress and MS stress were strongly associated with heavy alcohol consumption, trauma experience, epigenetic age acceleration (EAA), and shortened DNA methylation-based telomere length in AUD. Together, MS stress and MS alcohol additively showed strong stepwise increases in EAA. Replication analyses showed robust association between MS stress and EAA in the Generation Scotland and Grady Trauma Project cohorts.CONCLUSIONS: A methylation-derived score tracking stress exposure is associated with various stress-related phenotypes and EAA. Stress and alcohol have additive effects on aging, offering new insights into the pathophysiology of premature aging in AUD and, potentially, other aspects of gene dysregulation in this disorder.

AB - BACKGROUND: Stress contributes to premature aging and susceptibility to alcohol use disorder (AUD), and AUD itself is a factor in premature aging; however, the interrelationships of stress, AUD, and premature aging are poorly understood.METHODS: We constructed a composite score of stress from 13 stress-related outcomes in a discovery cohort of 317 individuals with AUD and control subjects. We then developed a novel methylation score of stress (MS stress) as a proxy of composite score of stress comprising 211 CpGs selected using a penalized regression model. The effects of MS stress on health outcomes and epigenetic aging were assessed in a sample of 615 patients with AUD and control subjects using epigenetic clocks and DNA methylation-based telomere length. Statistical analysis with an additive model using MS stress and a MS for alcohol consumption (MS alcohol) was conducted. Results were replicated in 2 independent cohorts (Generation Scotland, N = 7028 and the Grady Trauma Project, N = 795).RESULTS: Composite score of stress and MS stress were strongly associated with heavy alcohol consumption, trauma experience, epigenetic age acceleration (EAA), and shortened DNA methylation-based telomere length in AUD. Together, MS stress and MS alcohol additively showed strong stepwise increases in EAA. Replication analyses showed robust association between MS stress and EAA in the Generation Scotland and Grady Trauma Project cohorts.CONCLUSIONS: A methylation-derived score tracking stress exposure is associated with various stress-related phenotypes and EAA. Stress and alcohol have additive effects on aging, offering new insights into the pathophysiology of premature aging in AUD and, potentially, other aspects of gene dysregulation in this disorder.

U2 - 10.1016/j.biopsych.2022.06.036

DO - 10.1016/j.biopsych.2022.06.036

M3 - Article

C2 - 36182531

SN - 0006-3223

JO - Biological Psychiatry

JF - Biological Psychiatry

ER -

Additive effects of stress and alcohol exposure on accelerated epigenetic aging in alcohol use disorder

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