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  < 1.28 × 10 −11 ) independent association signals for 459 cell traits at 70 loci (53 of them novel) identifying several molecules and mechanisms involved...

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Veröffentlicht in:Nature genetics Jg. 52; H. 10; S. 1036 - 1045
Hauptverfasser: 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
Format: Journal Article
Sprache:Englisch
Veröffentlicht: New York Nature Publishing Group US 01.10.2020
Nature Publishing Group
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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
Italy
ISSN:1061-4036, 1546-1718, 1546-1718
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Beschreibung
Zusammenfassung: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.
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F.C. conceived and supervised the study. F.C., V.O., M.S. and C.S. drafted the manuscript; M. Pala, S. Olla and M.F. contributed to the writing of specific sections; D.S., M.G., M. Devoto, M.Z. and G.R.A. revised the manuscript; V.O., E.F. and F.C. designed flow cytometric panels; M. Dei., S.L., V.S. and F.V. measured immunophenotypes; V.O., V.S. and E.F. analyzed raw immunophenotype data; A.M., S.L., M. Dei, M.L., M.G.P., M. Pitzalis, F.D. and A.L. isolated DNA; M.Z. and A.M. performed array genotyping; M.S., C.S., Michele Marongiu and G.S. carried out genetic analysis; M. Pala, S. Onano and Mara Marongiu performed RNA data analyses; M.F. and S. Olla carried out bioinformatics and drug target analyses; Michele Marongiu managed the SardiNIA project database; S.S. shared genetic data on MS; F.C., G.R.A. and D.S. provided funds and reagents. All authors read the paper and contributed to its final form.
Author contributions
ISSN:1061-4036
1546-1718
1546-1718
DOI:10.1038/s41588-020-0684-4