DNA methylome-wide association study of genetic risk for depression implicates antigen processing and immune responses

Xueyi Shen; Doretta Caramaschi; Josine L Min; Gibran Hemani; Caroline L Relton; Andrew M. McIntosh

doi:10.1186/s13073-022-01039-5

DNA methylome-wide association study of genetic risk for depression implicates antigen processing and immune responses

Xueyi Shen^*
, Doretta Caramaschi
, Josine L Min
, Gibran Hemani
, Caroline L Relton
, Andrew M. McIntosh^*

^*Corresponding author for this work

Research output: Contribution to journal › Article (Academic Journal) › peer-review

24 Citations (Scopus)

114 Downloads (Pure)

Abstract

Background
Depression is a disabling and highly prevalent condition where genetic and epigenetic, such as DNA methylation (DNAm), differences contribute to disease risk. DNA methylation is influenced by genetic variation but the association between polygenic risk of depression and DNA methylation is unknown.

Methods
We investigated the association between polygenic risk scores (PRS) for depression and DNAm by conducting a methylome-wide association study (MWAS) in Generation Scotland (N = 8898, mean age = 49.8 years) with replication in the Lothian Birth Cohorts of 1921 and 1936 and adults in the Avon Longitudinal Study of Parents and Children (ALSPAC) (Ncombined = 2049, mean age = 79.1, 69.6 and 47.2 years, respectively). We also conducted a replication MWAS in the ALSPAC children (N = 423, mean age = 17.1 years). Gene ontology analysis was conducted for the cytosine-guanine dinucleotide (CpG) probes significantly associated with depression PRS, followed by Mendelian randomisation (MR) analysis to infer the causal relationship between depression and DNAm.

Results
Widespread associations (NCpG = 71, pBonferroni < 0.05, p < 6.3 × 10−8) were found between PRS constructed using genetic risk variants for depression and DNAm in CpG probes that localised to genes involved in immune responses and neural development. The effect sizes for the significant associations were highly correlated between the discovery and replication samples in adults (r = 0.79) and in adolescents (r = 0.82). Gene Ontology analysis showed that significant CpG probes are enriched in immunological processes in the human leukocyte antigen system. Additional MWAS was conducted for each lead genetic risk variant. Over 47.9% of the independent genetic risk variants included in the PRS showed associations with DNAm in CpG probes located in both the same (cis) and distal (trans) locations to the genetic loci (pBonferroni < 0.045). Subsequent MR analysis showed that there are a greater number of causal effects found from DNAm to depression than vice versa (DNAm to depression: pFDR ranged from 0.024 to 7.45 × 10−30; depression to DNAm: pFDR ranged from 0.028 to 0.003).

Conclusions
PRS for depression, especially those constructed from genome-wide significant genetic risk variants, showed methylome-wide differences associated with immune responses. Findings from MR analysis provided evidence for causal effect of DNAm to depression.

Original language	English
Article number	36
Number of pages	1
Journal	Genome Medicine
Volume	14
Issue number	1
DOIs	https://doi.org/10.1186/s13073-022-01039-5
Publication status	Published - 31 Mar 2022

Bibliographical note

Funding Information:
The LBC1921 was supported by the United Kingdom’s Biotechnology and Biological Sciences Research Council (BBSRC), The Royal Society and The Chief Scientist Office of the Scottish Government. The LBC1936 is supported by Age UK (Disconnected Mind project, which supports SEH), the Medical Research Council (G0701120, G1001245, MR/M013111/1, MR/R024065/1) and the University of Edinburgh. Methylation typing of LBC1921 and LBC1936 was supported by Centre for Cognitive Ageing and Cognitive Epidemiology (Pilot Fund award), Age UK, The Wellcome Trust Institutional Strategic Support Fund, The University of Edinburgh, and The University of Queensland. SRC and IJD were supported by a National Institutes of Health (NIH) research grant R01AG054628, and SRC is supported by a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (Grant Number 221890/Z/20/Z).

Funding Information:
The UK Medical Research Council and Wellcome (Grant Ref: 217065/Z/19/Z) and the University of Bristol provide core support for ALSPAC. A comprehensive list of grants funding is available on the ALSPAC website ( http://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf ). GWAS data was generated by Sample Logistics and Genotyping Facilities at Wellcome Sanger Institute and LabCorp (Laboratory Corporation of America) using support from 23andMe. Part of this data was collected using REDCap, see the REDCap website for details https://projectredcap.org/resources/citations/ ). CLR, DC, JLM and GH are supported by the MRC Integrative Epidemiology Unit at the University of Bristol (MC_UU_00011/5).

Funding Information:
This work is supported by two Wellcome Trust grants to AMM ( Investigator Award in Science: 220857/Z/20/Z and Strategic Award 104036/Z/14/Z). For the purpose of open access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. In addition, DNAm profiling was supported by funding from NARSAD (Ref 27404, DMH) and the Royal College of Physicians of Edinburgh (SIM Fellowship, HCW). Genotyping of the GS samples was funded by the MRC and Wellcome Trust [104036/Z/14/Z]. GS also receives support from the Chief Scientist Office of the Scottish Government Health Directorates [CZD/16/6] and the Scottish Funding Council [HR03006].

Publisher Copyright:
© 2022, The Author(s).

Keywords

DNA methylation
Polygenic risk score
Depression
Methylome-wide association study
Mendelian randomisation

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Additional file 3 of DNA methylome-wide association study of genetic risk for depression implicates antigen processing and immune responses
Shen, X. (Creator), Caramaschi, D. (Creator), Adams, M. J. (Creator), Walker, R. M. (Creator), Min, J. L. (Creator), Kwong, A. (Creator), Hemani, G. (Creator), Barbu, M. C. (Creator), Whalley, H. C. (Creator), Harris, S. E. (Creator), Deary, I. J. (Creator), Morris, S. W. (Creator), Cox, S. R. (Creator), Relton, C. L. (Creator), Marioni, R. E. (Creator), Evans, K. L. (Creator) & McIntosh, A. M. (Creator), figshare, 31 Mar 2022
DOI: 10.6084/m9.figshare.19470515.v1, https://springernature.figshare.com/articles/dataset/Additional_file_3_of_DNA_methylome-wide_association_study_of_genetic_risk_for_depression_implicates_antigen_processing_and_immune_responses/19470515/1
Dataset
Additional file 2 of DNA methylome-wide association study of genetic risk for depression implicates antigen processing and immune responses
Shen, X. (Creator), Caramaschi, D. (Creator), Adams, M. J. (Creator), Walker, R. M. (Creator), Min, J. L. (Creator), Kwong, A. (Creator), Hemani, G. (Creator), Barbu, M. C. (Creator), Whalley, H. C. (Creator), Harris, S. E. (Creator), Deary, I. J. (Creator), Morris, S. W. (Creator), Cox, S. R. (Creator), Relton, C. L. (Creator), Marioni, R. E. (Creator), Evans, K. L. (Creator) & McIntosh, A. M. (Creator), figshare, 31 Mar 2022
DOI: 10.6084/m9.figshare.19470512.v1, https://springernature.figshare.com/articles/dataset/Additional_file_2_of_DNA_methylome-wide_association_study_of_genetic_risk_for_depression_implicates_antigen_processing_and_immune_responses/19470512/1
Dataset

Cite this

@article{a4476485779b4941abfdc348fc0e55f0,

title = "DNA methylome-wide association study of genetic risk for depression implicates antigen processing and immune responses",

abstract = "Background Depression is a disabling and highly prevalent condition where genetic and epigenetic, such as DNA methylation (DNAm), differences contribute to disease risk. DNA methylation is influenced by genetic variation but the association between polygenic risk of depression and DNA methylation is unknown. Methods We investigated the association between polygenic risk scores (PRS) for depression and DNAm by conducting a methylome-wide association study (MWAS) in Generation Scotland (N = 8898, mean age = 49.8 years) with replication in the Lothian Birth Cohorts of 1921 and 1936 and adults in the Avon Longitudinal Study of Parents and Children (ALSPAC) (Ncombined = 2049, mean age = 79.1, 69.6 and 47.2 years, respectively). We also conducted a replication MWAS in the ALSPAC children (N = 423, mean age = 17.1 years). Gene ontology analysis was conducted for the cytosine-guanine dinucleotide (CpG) probes significantly associated with depression PRS, followed by Mendelian randomisation (MR) analysis to infer the causal relationship between depression and DNAm. Results Widespread associations (NCpG = 71, pBonferroni < 0.05, p < 6.3 × 10−8) were found between PRS constructed using genetic risk variants for depression and DNAm in CpG probes that localised to genes involved in immune responses and neural development. The effect sizes for the significant associations were highly correlated between the discovery and replication samples in adults (r = 0.79) and in adolescents (r = 0.82). Gene Ontology analysis showed that significant CpG probes are enriched in immunological processes in the human leukocyte antigen system. Additional MWAS was conducted for each lead genetic risk variant. Over 47.9\% of the independent genetic risk variants included in the PRS showed associations with DNAm in CpG probes located in both the same (cis) and distal (trans) locations to the genetic loci (pBonferroni < 0.045). Subsequent MR analysis showed that there are a greater number of causal effects found from DNAm to depression than vice versa (DNAm to depression: pFDR ranged from 0.024 to 7.45 × 10−30; depression to DNAm: pFDR ranged from 0.028 to 0.003). Conclusions PRS for depression, especially those constructed from genome-wide significant genetic risk variants, showed methylome-wide differences associated with immune responses. Findings from MR analysis provided evidence for causal effect of DNAm to depression.",

keywords = "DNA methylation, Polygenic risk score, Depression, Methylome-wide association study, Mendelian randomisation",

author = "Xueyi Shen and Doretta Caramaschi and Min, \{Josine L\} and Gibran Hemani and Relton, \{Caroline L\} and McIntosh, \{Andrew M.\}",

note = "Funding Information: The LBC1921 was supported by the United Kingdom{\textquoteright}s Biotechnology and Biological Sciences Research Council (BBSRC), The Royal Society and The Chief Scientist Office of the Scottish Government. The LBC1936 is supported by Age UK (Disconnected Mind project, which supports SEH), the Medical Research Council (G0701120, G1001245, MR/M013111/1, MR/R024065/1) and the University of Edinburgh. Methylation typing of LBC1921 and LBC1936 was supported by Centre for Cognitive Ageing and Cognitive Epidemiology (Pilot Fund award), Age UK, The Wellcome Trust Institutional Strategic Support Fund, The University of Edinburgh, and The University of Queensland. SRC and IJD were supported by a National Institutes of Health (NIH) research grant R01AG054628, and SRC is supported by a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (Grant Number 221890/Z/20/Z). Funding Information: The UK Medical Research Council and Wellcome (Grant Ref: 217065/Z/19/Z) and the University of Bristol provide core support for ALSPAC. A comprehensive list of grants funding is available on the ALSPAC website ( http://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf ). GWAS data was generated by Sample Logistics and Genotyping Facilities at Wellcome Sanger Institute and LabCorp (Laboratory Corporation of America) using support from 23andMe. Part of this data was collected using REDCap, see the REDCap website for details https://projectredcap.org/resources/citations/ ). CLR, DC, JLM and GH are supported by the MRC Integrative Epidemiology Unit at the University of Bristol (MC\_UU\_00011/5). Funding Information: This work is supported by two Wellcome Trust grants to AMM ( Investigator Award in Science: 220857/Z/20/Z and Strategic Award 104036/Z/14/Z). For the purpose of open access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. In addition, DNAm profiling was supported by funding from NARSAD (Ref 27404, DMH) and the Royal College of Physicians of Edinburgh (SIM Fellowship, HCW). Genotyping of the GS samples was funded by the MRC and Wellcome Trust [104036/Z/14/Z]. GS also receives support from the Chief Scientist Office of the Scottish Government Health Directorates [CZD/16/6] and the Scottish Funding Council [HR03006]. Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = mar,

day = "31",

doi = "10.1186/s13073-022-01039-5",

language = "English",

volume = "14",

journal = "Genome Medicine",

issn = "1756-994X",

publisher = "BioMed Central Ltd",

number = "1",

}

TY - JOUR

T1 - DNA methylome-wide association study of genetic risk for depression implicates antigen processing and immune responses

AU - Shen, Xueyi

AU - Caramaschi, Doretta

AU - Min, Josine L

AU - Hemani, Gibran

AU - Relton, Caroline L

AU - McIntosh, Andrew M.

N1 - Funding Information: The LBC1921 was supported by the United Kingdom’s Biotechnology and Biological Sciences Research Council (BBSRC), The Royal Society and The Chief Scientist Office of the Scottish Government. The LBC1936 is supported by Age UK (Disconnected Mind project, which supports SEH), the Medical Research Council (G0701120, G1001245, MR/M013111/1, MR/R024065/1) and the University of Edinburgh. Methylation typing of LBC1921 and LBC1936 was supported by Centre for Cognitive Ageing and Cognitive Epidemiology (Pilot Fund award), Age UK, The Wellcome Trust Institutional Strategic Support Fund, The University of Edinburgh, and The University of Queensland. SRC and IJD were supported by a National Institutes of Health (NIH) research grant R01AG054628, and SRC is supported by a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (Grant Number 221890/Z/20/Z). Funding Information: The UK Medical Research Council and Wellcome (Grant Ref: 217065/Z/19/Z) and the University of Bristol provide core support for ALSPAC. A comprehensive list of grants funding is available on the ALSPAC website ( http://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf ). GWAS data was generated by Sample Logistics and Genotyping Facilities at Wellcome Sanger Institute and LabCorp (Laboratory Corporation of America) using support from 23andMe. Part of this data was collected using REDCap, see the REDCap website for details https://projectredcap.org/resources/citations/ ). CLR, DC, JLM and GH are supported by the MRC Integrative Epidemiology Unit at the University of Bristol (MC_UU_00011/5). Funding Information: This work is supported by two Wellcome Trust grants to AMM ( Investigator Award in Science: 220857/Z/20/Z and Strategic Award 104036/Z/14/Z). For the purpose of open access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. In addition, DNAm profiling was supported by funding from NARSAD (Ref 27404, DMH) and the Royal College of Physicians of Edinburgh (SIM Fellowship, HCW). Genotyping of the GS samples was funded by the MRC and Wellcome Trust [104036/Z/14/Z]. GS also receives support from the Chief Scientist Office of the Scottish Government Health Directorates [CZD/16/6] and the Scottish Funding Council [HR03006]. Publisher Copyright: © 2022, The Author(s).

PY - 2022/3/31

Y1 - 2022/3/31

N2 - Background Depression is a disabling and highly prevalent condition where genetic and epigenetic, such as DNA methylation (DNAm), differences contribute to disease risk. DNA methylation is influenced by genetic variation but the association between polygenic risk of depression and DNA methylation is unknown. Methods We investigated the association between polygenic risk scores (PRS) for depression and DNAm by conducting a methylome-wide association study (MWAS) in Generation Scotland (N = 8898, mean age = 49.8 years) with replication in the Lothian Birth Cohorts of 1921 and 1936 and adults in the Avon Longitudinal Study of Parents and Children (ALSPAC) (Ncombined = 2049, mean age = 79.1, 69.6 and 47.2 years, respectively). We also conducted a replication MWAS in the ALSPAC children (N = 423, mean age = 17.1 years). Gene ontology analysis was conducted for the cytosine-guanine dinucleotide (CpG) probes significantly associated with depression PRS, followed by Mendelian randomisation (MR) analysis to infer the causal relationship between depression and DNAm. Results Widespread associations (NCpG = 71, pBonferroni < 0.05, p < 6.3 × 10−8) were found between PRS constructed using genetic risk variants for depression and DNAm in CpG probes that localised to genes involved in immune responses and neural development. The effect sizes for the significant associations were highly correlated between the discovery and replication samples in adults (r = 0.79) and in adolescents (r = 0.82). Gene Ontology analysis showed that significant CpG probes are enriched in immunological processes in the human leukocyte antigen system. Additional MWAS was conducted for each lead genetic risk variant. Over 47.9% of the independent genetic risk variants included in the PRS showed associations with DNAm in CpG probes located in both the same (cis) and distal (trans) locations to the genetic loci (pBonferroni < 0.045). Subsequent MR analysis showed that there are a greater number of causal effects found from DNAm to depression than vice versa (DNAm to depression: pFDR ranged from 0.024 to 7.45 × 10−30; depression to DNAm: pFDR ranged from 0.028 to 0.003). Conclusions PRS for depression, especially those constructed from genome-wide significant genetic risk variants, showed methylome-wide differences associated with immune responses. Findings from MR analysis provided evidence for causal effect of DNAm to depression.

AB - Background Depression is a disabling and highly prevalent condition where genetic and epigenetic, such as DNA methylation (DNAm), differences contribute to disease risk. DNA methylation is influenced by genetic variation but the association between polygenic risk of depression and DNA methylation is unknown. Methods We investigated the association between polygenic risk scores (PRS) for depression and DNAm by conducting a methylome-wide association study (MWAS) in Generation Scotland (N = 8898, mean age = 49.8 years) with replication in the Lothian Birth Cohorts of 1921 and 1936 and adults in the Avon Longitudinal Study of Parents and Children (ALSPAC) (Ncombined = 2049, mean age = 79.1, 69.6 and 47.2 years, respectively). We also conducted a replication MWAS in the ALSPAC children (N = 423, mean age = 17.1 years). Gene ontology analysis was conducted for the cytosine-guanine dinucleotide (CpG) probes significantly associated with depression PRS, followed by Mendelian randomisation (MR) analysis to infer the causal relationship between depression and DNAm. Results Widespread associations (NCpG = 71, pBonferroni < 0.05, p < 6.3 × 10−8) were found between PRS constructed using genetic risk variants for depression and DNAm in CpG probes that localised to genes involved in immune responses and neural development. The effect sizes for the significant associations were highly correlated between the discovery and replication samples in adults (r = 0.79) and in adolescents (r = 0.82). Gene Ontology analysis showed that significant CpG probes are enriched in immunological processes in the human leukocyte antigen system. Additional MWAS was conducted for each lead genetic risk variant. Over 47.9% of the independent genetic risk variants included in the PRS showed associations with DNAm in CpG probes located in both the same (cis) and distal (trans) locations to the genetic loci (pBonferroni < 0.045). Subsequent MR analysis showed that there are a greater number of causal effects found from DNAm to depression than vice versa (DNAm to depression: pFDR ranged from 0.024 to 7.45 × 10−30; depression to DNAm: pFDR ranged from 0.028 to 0.003). Conclusions PRS for depression, especially those constructed from genome-wide significant genetic risk variants, showed methylome-wide differences associated with immune responses. Findings from MR analysis provided evidence for causal effect of DNAm to depression.

KW - DNA methylation

KW - Polygenic risk score

KW - Depression

KW - Methylome-wide association study

KW - Mendelian randomisation

U2 - 10.1186/s13073-022-01039-5

DO - 10.1186/s13073-022-01039-5

M3 - Article (Academic Journal)

C2 - 35354486

SN - 1756-994X

VL - 14

JO - Genome Medicine

JF - Genome Medicine

IS - 1

M1 - 36

ER -

DNA methylome-wide association study of genetic risk for depression implicates antigen processing and immune responses

Abstract

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Additional file 3 of DNA methylome-wide association study of genetic risk for depression implicates antigen processing and immune responses

Additional file 2 of DNA methylome-wide association study of genetic risk for depression implicates antigen processing and immune responses

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