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Bi-ancestral depression GWAS in the Million Veteran Program and meta-analysis in >1.2 million individuals highlight new therapeutic directions
Major depressive disorder is the most common neuropsychiatric disorder, affecting 11% of veterans. Here we report results of a large meta-analysis of depression using data from the Million Veteran Program, 23andMe, UK Biobank and FinnGen, including individuals of European ancestry ( n = 1,154,267;...
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| Published in: | Nature neuroscience 2021-07, Vol.24 (7), p.954-963 |
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| creator | Levey, Daniel F. Stein, Murray B. Wendt, Frank R. Pathak, Gita A. Zhou, Hang Aslan, Mihaela Quaden, Rachel Harrington, Kelly M. Nuñez, Yaira Z. Overstreet, Cassie Radhakrishnan, Krishnan Sanacora, Gerard McIntosh, Andrew M. Shi, Jingchunzi Shringarpure, Suyash S. Concato, John Polimanti, Renato Gelernter, Joel |
| description | Major depressive disorder is the most common neuropsychiatric disorder, affecting 11% of veterans. Here we report results of a large meta-analysis of depression using data from the Million Veteran Program, 23andMe, UK Biobank and FinnGen, including individuals of European ancestry (
n
= 1,154,267; 340,591 cases) and African ancestry (
n
= 59,600; 25,843 cases). Transcriptome-wide association study analyses revealed significant associations with expression of
NEGR1
in the hypothalamus and
DRD2
in the nucleus accumbens, among others. We fine-mapped 178 genomic risk loci, and we identified likely pathogenicity in these variants and overlapping gene expression for 17 genes from our transcriptome-wide association study, including
TRAF3
. Finally, we were able to show substantial replications of our findings in a large independent cohort (
n
= 1,342,778) provided by 23andMe. This study sheds light on the genetic architecture of depression and provides new insight into the interrelatedness of complex psychiatric traits.
This bi-ancestral genome-wide association study of major depressive disorder (MDD) identified 178 risk variants. The results advance understanding of the biology of MDD and hint at new treatment possibilities. |
| doi_str_mv | 10.1038/s41593-021-00860-2 |
| format | article |
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n
= 1,154,267; 340,591 cases) and African ancestry (
n
= 59,600; 25,843 cases). Transcriptome-wide association study analyses revealed significant associations with expression of
NEGR1
in the hypothalamus and
DRD2
in the nucleus accumbens, among others. We fine-mapped 178 genomic risk loci, and we identified likely pathogenicity in these variants and overlapping gene expression for 17 genes from our transcriptome-wide association study, including
TRAF3
. Finally, we were able to show substantial replications of our findings in a large independent cohort (
n
= 1,342,778) provided by 23andMe. This study sheds light on the genetic architecture of depression and provides new insight into the interrelatedness of complex psychiatric traits.
This bi-ancestral genome-wide association study of major depressive disorder (MDD) identified 178 risk variants. The results advance understanding of the biology of MDD and hint at new treatment possibilities.</description><identifier>ISSN: 1097-6256</identifier><identifier>ISSN: 1546-1726</identifier><identifier>EISSN: 1546-1726</identifier><identifier>DOI: 10.1038/s41593-021-00860-2</identifier><identifier>PMID: 34045744</identifier><language>eng</language><publisher>New York: Nature Publishing Group US</publisher><subject>631/208/1515 ; 631/208/205/2138 ; 692/699/476/1414 ; Animal Genetics and Genomics ; Behavioral Sciences ; Biological Techniques ; Biomedical and Life Sciences ; Biomedicine ; Depressive Disorder, Major - genetics ; Dopamine D2 receptors ; Female ; Gene expression ; Genetic aspects ; Genetic Predisposition to Disease - genetics ; Genome-wide association studies ; Genome-Wide Association Study ; Health aspects ; Humans ; Hypothalamus ; Major depressive disorder ; Male ; Mental depression ; Mental disorders ; Meta-analysis ; Neurobiology ; Neurosciences ; Nucleus accumbens ; Pathogenicity ; Pathogens ; Psychiatric research ; Psychological aspects ; Risk factors ; Statistics ; Systematic review ; Transcriptomes ; Veterans</subject><ispartof>Nature neuroscience, 2021-07, Vol.24 (7), p.954-963</ispartof><rights>The Author(s), under exclusive licence to Springer Nature America, Inc. 2021</rights><rights>COPYRIGHT 2021 Nature Publishing Group</rights><rights>The Author(s), under exclusive licence to Springer Nature America, Inc. 2021.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c520t-65fb940e512444a5e3f32a826826da3b2adaf7348ab6c70f411faa23145a9eb43</citedby><cites>FETCH-LOGICAL-c520t-65fb940e512444a5e3f32a826826da3b2adaf7348ab6c70f411faa23145a9eb43</cites><orcidid>0000-0003-0745-6046 ; 0000-0002-2108-6822 ; 0000-0002-7694-6391 ; 0000-0001-9564-2871 ; 0000-0001-8431-9569 ; 0000-0002-0198-4588 ; 0000-0002-4067-1859</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27923,27924</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34045744$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Levey, Daniel F.</creatorcontrib><creatorcontrib>Stein, Murray B.</creatorcontrib><creatorcontrib>Wendt, Frank R.</creatorcontrib><creatorcontrib>Pathak, Gita A.</creatorcontrib><creatorcontrib>Zhou, Hang</creatorcontrib><creatorcontrib>Aslan, Mihaela</creatorcontrib><creatorcontrib>Quaden, Rachel</creatorcontrib><creatorcontrib>Harrington, Kelly M.</creatorcontrib><creatorcontrib>Nuñez, Yaira Z.</creatorcontrib><creatorcontrib>Overstreet, Cassie</creatorcontrib><creatorcontrib>Radhakrishnan, Krishnan</creatorcontrib><creatorcontrib>Sanacora, Gerard</creatorcontrib><creatorcontrib>McIntosh, Andrew M.</creatorcontrib><creatorcontrib>Shi, Jingchunzi</creatorcontrib><creatorcontrib>Shringarpure, Suyash S.</creatorcontrib><creatorcontrib>Concato, John</creatorcontrib><creatorcontrib>Polimanti, Renato</creatorcontrib><creatorcontrib>Gelernter, Joel</creatorcontrib><creatorcontrib>23andMe Research Team</creatorcontrib><creatorcontrib>Million Veteran Program</creatorcontrib><creatorcontrib>the Million Veteran Program</creatorcontrib><creatorcontrib>23andMe Research Team</creatorcontrib><title>Bi-ancestral depression GWAS in the Million Veteran Program and meta-analysis in >1.2 million individuals highlight new therapeutic directions</title><title>Nature neuroscience</title><addtitle>Nat Neurosci</addtitle><addtitle>Nat Neurosci</addtitle><description>Major depressive disorder is the most common neuropsychiatric disorder, affecting 11% of veterans. Here we report results of a large meta-analysis of depression using data from the Million Veteran Program, 23andMe, UK Biobank and FinnGen, including individuals of European ancestry (
n
= 1,154,267; 340,591 cases) and African ancestry (
n
= 59,600; 25,843 cases). Transcriptome-wide association study analyses revealed significant associations with expression of
NEGR1
in the hypothalamus and
DRD2
in the nucleus accumbens, among others. We fine-mapped 178 genomic risk loci, and we identified likely pathogenicity in these variants and overlapping gene expression for 17 genes from our transcriptome-wide association study, including
TRAF3
. Finally, we were able to show substantial replications of our findings in a large independent cohort (
n
= 1,342,778) provided by 23andMe. This study sheds light on the genetic architecture of depression and provides new insight into the interrelatedness of complex psychiatric traits.
This bi-ancestral genome-wide association study of major depressive disorder (MDD) identified 178 risk variants. The results advance understanding of the biology of MDD and hint at new treatment possibilities.</description><subject>631/208/1515</subject><subject>631/208/205/2138</subject><subject>692/699/476/1414</subject><subject>Animal Genetics and Genomics</subject><subject>Behavioral Sciences</subject><subject>Biological Techniques</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Depressive Disorder, Major - genetics</subject><subject>Dopamine D2 receptors</subject><subject>Female</subject><subject>Gene expression</subject><subject>Genetic aspects</subject><subject>Genetic Predisposition to Disease - genetics</subject><subject>Genome-wide association studies</subject><subject>Genome-Wide Association Study</subject><subject>Health aspects</subject><subject>Humans</subject><subject>Hypothalamus</subject><subject>Major depressive disorder</subject><subject>Male</subject><subject>Mental depression</subject><subject>Mental disorders</subject><subject>Meta-analysis</subject><subject>Neurobiology</subject><subject>Neurosciences</subject><subject>Nucleus accumbens</subject><subject>Pathogenicity</subject><subject>Pathogens</subject><subject>Psychiatric research</subject><subject>Psychological aspects</subject><subject>Risk factors</subject><subject>Statistics</subject><subject>Systematic 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Program</aucorp><aucorp>23andMe Research Team</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Bi-ancestral depression GWAS in the Million Veteran Program and meta-analysis in >1.2 million individuals highlight new therapeutic directions</atitle><jtitle>Nature neuroscience</jtitle><stitle>Nat Neurosci</stitle><addtitle>Nat Neurosci</addtitle><date>2021-07-01</date><risdate>2021</risdate><volume>24</volume><issue>7</issue><spage>954</spage><epage>963</epage><pages>954-963</pages><issn>1097-6256</issn><issn>1546-1726</issn><eissn>1546-1726</eissn><abstract>Major depressive disorder is the most common neuropsychiatric disorder, affecting 11% of veterans. Here we report results of a large meta-analysis of depression using data from the Million Veteran Program, 23andMe, UK Biobank and FinnGen, including individuals of European ancestry (
n
= 1,154,267; 340,591 cases) and African ancestry (
n
= 59,600; 25,843 cases). Transcriptome-wide association study analyses revealed significant associations with expression of
NEGR1
in the hypothalamus and
DRD2
in the nucleus accumbens, among others. We fine-mapped 178 genomic risk loci, and we identified likely pathogenicity in these variants and overlapping gene expression for 17 genes from our transcriptome-wide association study, including
TRAF3
. Finally, we were able to show substantial replications of our findings in a large independent cohort (
n
= 1,342,778) provided by 23andMe. This study sheds light on the genetic architecture of depression and provides new insight into the interrelatedness of complex psychiatric traits.
This bi-ancestral genome-wide association study of major depressive disorder (MDD) identified 178 risk variants. The results advance understanding of the biology of MDD and hint at new treatment possibilities.</abstract><cop>New York</cop><pub>Nature Publishing Group US</pub><pmid>34045744</pmid><doi>10.1038/s41593-021-00860-2</doi><tpages>10</tpages><orcidid>https://orcid.org/0000-0003-0745-6046</orcidid><orcidid>https://orcid.org/0000-0002-2108-6822</orcidid><orcidid>https://orcid.org/0000-0002-7694-6391</orcidid><orcidid>https://orcid.org/0000-0001-9564-2871</orcidid><orcidid>https://orcid.org/0000-0001-8431-9569</orcidid><orcidid>https://orcid.org/0000-0002-0198-4588</orcidid><orcidid>https://orcid.org/0000-0002-4067-1859</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1097-6256 |
| ispartof | Nature neuroscience, 2021-07, Vol.24 (7), p.954-963 |
| issn | 1097-6256 1546-1726 1546-1726 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_2534612789 |
| source | Nature |
| subjects | 631/208/1515 631/208/205/2138 692/699/476/1414 Animal Genetics and Genomics Behavioral Sciences Biological Techniques Biomedical and Life Sciences Biomedicine Depressive Disorder, Major - genetics Dopamine D2 receptors Female Gene expression Genetic aspects Genetic Predisposition to Disease - genetics Genome-wide association studies Genome-Wide Association Study Health aspects Humans Hypothalamus Major depressive disorder Male Mental depression Mental disorders Meta-analysis Neurobiology Neurosciences Nucleus accumbens Pathogenicity Pathogens Psychiatric research Psychological aspects Risk factors Statistics Systematic review Transcriptomes Veterans |
| title | Bi-ancestral depression GWAS in the Million Veteran Program and meta-analysis in >1.2 million individuals highlight new therapeutic directions |
| url | http://sfxeu10.hosted.exlibrisgroup.com/loughborough?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-12T20%3A40%3A05IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_proqu&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Bi-ancestral%20depression%20GWAS%20in%20the%20Million%20Veteran%20Program%20and%20meta-analysis%20in%20%3E1.2%20million%20individuals%20highlight%20new%20therapeutic%20directions&rft.jtitle=Nature%20neuroscience&rft.au=Levey,%20Daniel%20F.&rft.aucorp=23andMe%20Research%20Team&rft.date=2021-07-01&rft.volume=24&rft.issue=7&rft.spage=954&rft.epage=963&rft.pages=954-963&rft.issn=1097-6256&rft.eissn=1546-1726&rft_id=info:doi/10.1038/s41593-021-00860-2&rft_dat=%3Cgale_proqu%3EA667092986%3C/gale_proqu%3E%3Cgrp_id%3Ecdi_FETCH-LOGICAL-c520t-65fb940e512444a5e3f32a826826da3b2adaf7348ab6c70f411faa23145a9eb43%3C/grp_id%3E%3Coa%3E%3C/oa%3E%3Curl%3E%3C/url%3E&rft_id=info:oai/&rft_pqid=2547168085&rft_id=info:pmid/34045744&rft_galeid=A667092986&rfr_iscdi=true |