Complex genetic signatures in immune cells underlie autoimmunity and inform therapy
We report on the influence of ~22 million variants on 731 immune cell traits in a cohort of 3,757 Sardinians. We detected 122 significant ( P
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| Veröffentlicht in: | Nature genetics 2020-10, Vol.52 (10), p.1036-1045 |
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| creator | Orrù, Valeria Steri, Maristella Sidore, Carlo Marongiu, Michele Serra, Valentina Olla, Stefania Sole, Gabriella Lai, Sandra Dei, Mariano Mulas, Antonella Virdis, Francesca Piras, Maria Grazia Lobina, Monia Marongiu, Mara Pitzalis, Maristella Deidda, Francesca Loizedda, Annalisa Onano, Stefano Zoledziewska, Magdalena Sawcer, Stephen Devoto, Marcella Gorospe, Myriam Abecasis, Gonçalo R. Floris, Matteo Pala, Mauro Schlessinger, David Fiorillo, Edoardo Cucca, Francesco |
| description | We report on the influence of ~22 million variants on 731 immune cell traits in a cohort of 3,757 Sardinians. We detected 122 significant (
P
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| doi_str_mv | 10.1038/s41588-020-0684-4 |
| format | Article |
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P
< 1.28 × 10
−11
) independent association signals for 459 cell traits at 70 loci (53 of them novel) identifying several molecules and mechanisms involved in cell regulation. Furthermore, 53 signals at 36 loci overlapped with previously reported disease-associated signals, predominantly for autoimmune disorders, highlighting intermediate phenotypes in pathogenesis. Collectively, our findings illustrate complex genetic regulation of immune cells with highly selective effects on autoimmune disease risk at the cell-subtype level. These results identify drug-targetable pathways informing the design of more specific treatments for autoimmune diseases.
An analysis of 3,757 Sardinian genomes identifies 122 association signals for 459 immune cell traits at 69 loci. Some variants are associated with autoimmune disorders.</description><identifier>ISSN: 1061-4036</identifier><identifier>EISSN: 1546-1718</identifier><identifier>DOI: 10.1038/s41588-020-0684-4</identifier><identifier>PMID: 32929287</identifier><language>eng</language><publisher>New York: Nature Publishing Group US</publisher><subject>631/208 ; 631/250 ; 692/699/249/1313 ; Adaptive immunity ; Agriculture ; Analysis ; Animal Genetics and Genomics ; Antigens ; Autoimmune diseases ; Autoimmune Diseases - drug therapy ; Autoimmune Diseases - epidemiology ; Autoimmune Diseases - genetics ; Autoimmune Diseases - pathology ; Autoimmunity ; Autoimmunity - genetics ; B cells ; Biomedical and Life Sciences ; Biomedicine ; Cancer Research ; Disease ; Drug development ; Flow cytometry ; Gene Function ; Genetic Predisposition to Disease ; Genome-Wide Association Study ; Genomes ; Genomics ; Health risks ; Human Genetics ; Humans ; Immune system ; Italy - epidemiology ; Loci ; Lymphocytes ; Pathogenesis ; Phenotype ; Phenotypes ; Polymorphism, Single Nucleotide - genetics ; Population ; Therapeutic targets</subject><ispartof>Nature genetics, 2020-10, Vol.52 (10), p.1036-1045</ispartof><rights>The Author(s), under exclusive licence to Springer Nature America, Inc. 2020</rights><rights>COPYRIGHT 2020 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group Oct 2020</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c653t-5203b6bad052832c63bcab3e7d1c167347b4e11a6fd072df876212dbd1a2b2033</citedby><cites>FETCH-LOGICAL-c653t-5203b6bad052832c63bcab3e7d1c167347b4e11a6fd072df876212dbd1a2b2033</cites><orcidid>0000-0002-7414-1995 ; 0000-0003-3620-3160 ; 0000-0002-6047-4625 ; 0000-0001-7504-7477 ; 0000-0003-1509-1825 ; 0000-0002-7289-9815 ; 0000-0001-5869-3872 ; 0000-0003-4385-9336</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/s41588-020-0684-4$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/s41588-020-0684-4$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>230,314,780,784,885,27924,27925,41488,42557,51319</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32929287$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Orrù, Valeria</creatorcontrib><creatorcontrib>Steri, Maristella</creatorcontrib><creatorcontrib>Sidore, Carlo</creatorcontrib><creatorcontrib>Marongiu, Michele</creatorcontrib><creatorcontrib>Serra, Valentina</creatorcontrib><creatorcontrib>Olla, Stefania</creatorcontrib><creatorcontrib>Sole, Gabriella</creatorcontrib><creatorcontrib>Lai, Sandra</creatorcontrib><creatorcontrib>Dei, Mariano</creatorcontrib><creatorcontrib>Mulas, Antonella</creatorcontrib><creatorcontrib>Virdis, Francesca</creatorcontrib><creatorcontrib>Piras, Maria Grazia</creatorcontrib><creatorcontrib>Lobina, Monia</creatorcontrib><creatorcontrib>Marongiu, Mara</creatorcontrib><creatorcontrib>Pitzalis, Maristella</creatorcontrib><creatorcontrib>Deidda, Francesca</creatorcontrib><creatorcontrib>Loizedda, Annalisa</creatorcontrib><creatorcontrib>Onano, Stefano</creatorcontrib><creatorcontrib>Zoledziewska, Magdalena</creatorcontrib><creatorcontrib>Sawcer, Stephen</creatorcontrib><creatorcontrib>Devoto, Marcella</creatorcontrib><creatorcontrib>Gorospe, Myriam</creatorcontrib><creatorcontrib>Abecasis, Gonçalo R.</creatorcontrib><creatorcontrib>Floris, Matteo</creatorcontrib><creatorcontrib>Pala, Mauro</creatorcontrib><creatorcontrib>Schlessinger, David</creatorcontrib><creatorcontrib>Fiorillo, Edoardo</creatorcontrib><creatorcontrib>Cucca, Francesco</creatorcontrib><title>Complex genetic signatures in immune cells underlie autoimmunity and inform therapy</title><title>Nature genetics</title><addtitle>Nat Genet</addtitle><addtitle>Nat Genet</addtitle><description>We report on the influence of ~22 million variants on 731 immune cell traits in a cohort of 3,757 Sardinians. We detected 122 significant (
P
< 1.28 × 10
−11
) independent association signals for 459 cell traits at 70 loci (53 of them novel) identifying several molecules and mechanisms involved in cell regulation. Furthermore, 53 signals at 36 loci overlapped with previously reported disease-associated signals, predominantly for autoimmune disorders, highlighting intermediate phenotypes in pathogenesis. Collectively, our findings illustrate complex genetic regulation of immune cells with highly selective effects on autoimmune disease risk at the cell-subtype level. These results identify drug-targetable pathways informing the design of more specific treatments for autoimmune diseases.
An analysis of 3,757 Sardinian genomes identifies 122 association signals for 459 immune cell traits at 69 loci. Some variants are associated with autoimmune disorders.</description><subject>631/208</subject><subject>631/250</subject><subject>692/699/249/1313</subject><subject>Adaptive immunity</subject><subject>Agriculture</subject><subject>Analysis</subject><subject>Animal Genetics and Genomics</subject><subject>Antigens</subject><subject>Autoimmune diseases</subject><subject>Autoimmune Diseases - drug therapy</subject><subject>Autoimmune Diseases - epidemiology</subject><subject>Autoimmune Diseases - genetics</subject><subject>Autoimmune Diseases - pathology</subject><subject>Autoimmunity</subject><subject>Autoimmunity - genetics</subject><subject>B cells</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Cancer Research</subject><subject>Disease</subject><subject>Drug development</subject><subject>Flow cytometry</subject><subject>Gene Function</subject><subject>Genetic Predisposition to Disease</subject><subject>Genome-Wide Association Study</subject><subject>Genomes</subject><subject>Genomics</subject><subject>Health risks</subject><subject>Human Genetics</subject><subject>Humans</subject><subject>Immune system</subject><subject>Italy - epidemiology</subject><subject>Loci</subject><subject>Lymphocytes</subject><subject>Pathogenesis</subject><subject>Phenotype</subject><subject>Phenotypes</subject><subject>Polymorphism, Single Nucleotide - genetics</subject><subject>Population</subject><subject>Therapeutic 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Francesco</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Complex genetic signatures in immune cells underlie autoimmunity and inform therapy</atitle><jtitle>Nature genetics</jtitle><stitle>Nat Genet</stitle><addtitle>Nat Genet</addtitle><date>2020-10-01</date><risdate>2020</risdate><volume>52</volume><issue>10</issue><spage>1036</spage><epage>1045</epage><pages>1036-1045</pages><issn>1061-4036</issn><eissn>1546-1718</eissn><abstract>We report on the influence of ~22 million variants on 731 immune cell traits in a cohort of 3,757 Sardinians. We detected 122 significant (
P
< 1.28 × 10
−11
) independent association signals for 459 cell traits at 70 loci (53 of them novel) identifying several molecules and mechanisms involved in cell regulation. Furthermore, 53 signals at 36 loci overlapped with previously reported disease-associated signals, predominantly for autoimmune disorders, highlighting intermediate phenotypes in pathogenesis. Collectively, our findings illustrate complex genetic regulation of immune cells with highly selective effects on autoimmune disease risk at the cell-subtype level. These results identify drug-targetable pathways informing the design of more specific treatments for autoimmune diseases.
An analysis of 3,757 Sardinian genomes identifies 122 association signals for 459 immune cell traits at 69 loci. Some variants are associated with autoimmune disorders.</abstract><cop>New York</cop><pub>Nature Publishing Group US</pub><pmid>32929287</pmid><doi>10.1038/s41588-020-0684-4</doi><tpages>10</tpages><orcidid>https://orcid.org/0000-0002-7414-1995</orcidid><orcidid>https://orcid.org/0000-0003-3620-3160</orcidid><orcidid>https://orcid.org/0000-0002-6047-4625</orcidid><orcidid>https://orcid.org/0000-0001-7504-7477</orcidid><orcidid>https://orcid.org/0000-0003-1509-1825</orcidid><orcidid>https://orcid.org/0000-0002-7289-9815</orcidid><orcidid>https://orcid.org/0000-0001-5869-3872</orcidid><orcidid>https://orcid.org/0000-0003-4385-9336</orcidid><oa>free_for_read</oa></addata></record> |
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| identifier | ISSN: 1061-4036 |
| ispartof | Nature genetics, 2020-10, Vol.52 (10), p.1036-1045 |
| issn | 1061-4036 1546-1718 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_8517961 |
| source | MEDLINE; Nature; SpringerLink Journals - AutoHoldings |
| subjects | 631/208 631/250 692/699/249/1313 Adaptive immunity Agriculture Analysis Animal Genetics and Genomics Antigens Autoimmune diseases Autoimmune Diseases - drug therapy Autoimmune Diseases - epidemiology Autoimmune Diseases - genetics Autoimmune Diseases - pathology Autoimmunity Autoimmunity - genetics B cells Biomedical and Life Sciences Biomedicine Cancer Research Disease Drug development Flow cytometry Gene Function Genetic Predisposition to Disease Genome-Wide Association Study Genomes Genomics Health risks Human Genetics Humans Immune system Italy - epidemiology Loci Lymphocytes Pathogenesis Phenotype Phenotypes Polymorphism, Single Nucleotide - genetics Population Therapeutic targets |
| title | Complex genetic signatures in immune cells underlie autoimmunity and inform therapy |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-05T10%3A04%3A46IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Complex%20genetic%20signatures%20in%20immune%20cells%20underlie%20autoimmunity%20and%20inform%20therapy&rft.jtitle=Nature%20genetics&rft.au=Orr%C3%B9,%20Valeria&rft.date=2020-10-01&rft.volume=52&rft.issue=10&rft.spage=1036&rft.epage=1045&rft.pages=1036-1045&rft.issn=1061-4036&rft.eissn=1546-1718&rft_id=info:doi/10.1038/s41588-020-0684-4&rft_dat=%3Cgale_pubme%3EA637083493%3C/gale_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2450658758&rft_id=info:pmid/32929287&rft_galeid=A637083493&rfr_iscdi=true |