{"doi":"10.1038/s41398-019-0548-9","title":"Epigenome-wide association study of depression symptomatology in elderly monozygotic twins","abstract":"<jats:title>Abstract</jats:title><jats:p>Depression is a severe and debilitating mental disorder diagnosed by evaluation of affective, cognitive and physical depression symptoms. Severity of these symptoms strongly impacts individual’s quality of life and is influenced by a combination of genetic and environmental factors. One of the molecular mechanisms allowing for an interplay between these factors is DNA methylation, an epigenetic modification playing a pivotal role in regulation of brain functioning across lifespan. The aim of this study was to investigate if there are DNA methylation signatures associated with depression symptomatology in order to identify molecular mechanisms contributing to pathophysiology of depression. We performed an epigenome-wide association study (EWAS) of continuous depression symptomatology score measured in a cohort of 724 monozygotic Danish twins (346 males, 378 females). Through EWAS analyses adjusted for sex, age, flow-cytometry based blood cell composition, and twin relatedness structure in the data we identified depression symptomatology score to be associated with blood DNA methylation levels in promoter regions of neuropsin (<jats:italic>KLK8</jats:italic>, <jats:italic>p</jats:italic>-value = 4.7 × 10<jats:sup>−7</jats:sup>) and DAZ associated protein 2 (<jats:italic>DAZAP2</jats:italic>, <jats:italic>p</jats:italic>-value = 3.13 × 10<jats:sup>−8</jats:sup>) genes. Other top associated probes were located in gene bodies of <jats:italic>MAD1L1</jats:italic> (<jats:italic>p</jats:italic>-value = 5.16 × 10<jats:sup>−6</jats:sup>), <jats:italic>SLC29A2</jats:italic> (<jats:italic>p</jats:italic>-value = 6.15 × 10<jats:sup>−6</jats:sup>) and <jats:italic>AKT1</jats:italic> (<jats:italic>p</jats:italic>-value = 4.47 × 10<jats:sup>−6</jats:sup>), all genes associated before with development of depression. Additionally, the following three measures (a) DNAmAge (calculated with Horvath and Hannum epigenetic clock estimators) adjusted for chronological age, (b) difference between DNAmAge and chronological age, and (c) DNAmAge acceleration were not associated with depression symptomatology score in our cohort. In conclusion, our data suggests that depression symptomatology score is associated with DNA methylation levels of genes implicated in response to stress, depressive-like behaviors, and recurrent depression in patients, but not with global DNA methylation changes across the genome.</jats:p>","journal":"Translational Psychiatry","year":2019,"id":594419,"datarank":0.6414999178524083,"base_score":4.276666119016055,"endowment":4.276666119016055,"self_citation_contribution":0.6414999178524083,"citation_network_contribution":0.0,"self_endowment_contribution":0.6414999178524083,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":71,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1306591,"name":"Q. Tan","orcid":"0000-0003-2012-1603","position":1,"is_corresponding":false},{"id":1348755,"name":"M. Soerensen","orcid":null,"position":2,"is_corresponding":false},{"id":835485,"name":"M. McGue","orcid":null,"position":3,"is_corresponding":false},{"id":1521640,"name":"O. Mors","orcid":null,"position":4,"is_corresponding":false},{"id":5363,"name":"Anders D. Børglum","orcid":"0000-0001-8627-7219","position":5,"is_corresponding":false},{"id":38571,"name":"Kaare Christensen","orcid":"0000-0002-5429-5292","position":6,"is_corresponding":false},{"id":369378,"name":"Mette Nyegaard","orcid":"0000-0003-4973-8543","position":7,"is_corresponding":false},{"id":1521641,"name":"L. 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The aim of this study was to investigate if there are DNA methylation signatures associated with depression symptomatology in order to identify molecular mechanisms contributing to pathophysiology of depression. We performed an epigenome-wide association study (EWAS) of continuous depression symptomatology score measured in a cohort of 724 monozygotic Danish twins (346 males, 378 females). Through EWAS analyses adjusted for sex, age, flow-cytometry based blood cell composition, and twin relatedness structure in the data we identified depression symptomatology score to be associated with blood DNA methylation levels in promoter regions of neuropsin (<jats:italic>KLK8</jats:italic>, <jats:italic>p</jats:italic>-value = 4.7 × 10<jats:sup>−7</jats:sup>) and DAZ associated protein 2 (<jats:italic>DAZAP2</jats:italic>, <jats:italic>p</jats:italic>-value = 3.13 × 10<jats:sup>−8</jats:sup>) genes. Other top associated probes were located in gene bodies of <jats:italic>MAD1L1</jats:italic> (<jats:italic>p</jats:italic>-value = 5.16 × 10<jats:sup>−6</jats:sup>), <jats:italic>SLC29A2</jats:italic> (<jats:italic>p</jats:italic>-value = 6.15 × 10<jats:sup>−6</jats:sup>) and <jats:italic>AKT1</jats:italic> (<jats:italic>p</jats:italic>-value = 4.47 × 10<jats:sup>−6</jats:sup>), all genes associated before with development of depression. Additionally, the following three measures (a) DNAmAge (calculated with Horvath and Hannum epigenetic clock estimators) adjusted for chronological age, (b) difference between DNAmAge and chronological age, and (c) DNAmAge acceleration were not associated with depression symptomatology score in our cohort. In conclusion, our data suggests that depression symptomatology score is associated with DNA methylation levels of genes implicated in response to stress, depressive-like behaviors, and recurrent depression in patients, but not with global DNA methylation changes across the genome.</jats:p>","is_dataset_classified":null,"base_score":4.276666119016055,"endowment":4.276666119016055,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"31477683","pmcid":"PMC6718679","openalex_id":"https://openalex.org/W2971873523","authors":[],"funders":[{"funder_name":"Lundbeck Foundation","grant_id":"R248-2017-2003","title":null},{"funder_name":"National Institutes of Health","grant_id":"5P01AG008761-08","title":"OLDEST-OLD MORTALITY AND DISABILITY AMONG DANISH TWINS"},{"funder_name":"European Commission","grant_id":"259679","title":"Integrated research on DEvelopmental determinants of Aging and Longevity"}],"total_grants":3,"fwci":3.1114,"citation_percentile":0.92947392,"influential_citations":0,"citation_trend":[{"year":2019,"count":1},{"year":2020,"count":11},{"year":2021,"count":16},{"year":2022,"count":13},{"year":2023,"count":11},{"year":2024,"count":6},{"year":2025,"count":10},{"year":2026,"count":3}],"oa_status":"gold","license":"cc-by","oa_locations":[{"url":"https://www.nature.com/articles/s41398-019-0548-9.pdf","host_type":"journal"},{"url":"https://www.nature.com/articles/s41398-019-0548-9.pdf","host_type":"publisher"},{"url":"https://www.nature.com/articles/s41398-019-0548-9","host_type":"publisher"},{"url":"https://doi.org/10.1038/s41398-019-0548-9","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/31477683","host_type":"repository"},{"url":"https://pure.au.dk/portal/en/publications/929928e9-9b67-45a7-89fe-ad89987a4b91","host_type":""},{"url":"https://portal.findresearcher.sdu.dk/da/publications/3f9ce405-dc95-4595-9b0b-0ec95e416894","host_type":"repository"},{"url":"https://doaj.org/article/2fd2cab7f66a4760a6373cbbcb76a066","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/6718679","host_type":"repository"},{"url":"https://europepmc.org/articles/PMC6718679","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/PMC6718679?pdf=render","host_type":"Europe_PMC"},{"url":"http://dx.doi.org/10.1038/s41398-019-0548-9","host_type":""},{"url":"https://dx.doi.org/10.1038/s41398-019-0548-9","host_type":""},{"url":"https://findresearcher.sdu.dk/ws/files/154340512/Epigenome_wide_association_study_of_depression_symptomatology_in_elderly_monozygotic_twins.pdf","host_type":""},{"url":"https://www.scopus.com/pages/publications/85071778058","host_type":""}],"fields_of_study":["Epigenetics and DNA Methylation","Intergenerational Family Dynamics and Caregiving","Family Support in Illness","0301 basic medicine","0303 health sciences","03 medical and health sciences","Aged","DNA Methylation","Denmark","Depression","Epigenesis, Genetic","Epigenome","Female","Gene-Environment Interaction","Genome-Wide Association Study","Humans","Male","Middle Aged","Quality of Life","Twins, Monozygotic"],"mesh_terms":["Epigenome","Aged","Denmark","Depression","Female","Humans","Male","Middle Aged","Quality of Life","Twins, Monozygotic","DNA Methylation","Epigenesis, Genetic","Genome-Wide Association Study","Gene-Environment Interaction"],"keywords":["DNA methylation","Epigenetics","Depression (economics)","Epigenome","Twin study","Monozygotic twin","Cohort","Internal medicine","Medicine","Bioinformatics","Genetics","Oncology","Gene","Biology","Heritability","Gene expression","Male","Depression","Denmark","Twins, Monozygotic","Middle Aged","Article","Epigenesis, Genetic","Quality of Life","Humans","Female","Gene-Environment Interaction","Aged","Genome-Wide Association Study"],"sdg_mappings":[{"sdg_number":3,"sdg_label":"3. 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