Genetic variants regulating immune cell levels in health and disease.
The complex network of specialized cells and molecules in the immune system has evolved to defend against pathogens, but inadvertent immune system attacks on "self" result in autoimmune disease. Both genetic regulation of immune cell levels and their relationships with autoimmunity are largely undetermined. Here, we report genetic contributions to quantitative levels of 95 cell types encompassing 272 immune traits, in a cohort of 1,629 individuals from four clustered Sardinian villages. We first estimated trait heritability, showing that it can be substantial, accounting for up to 87% of the variance (mean 41%). Next, by assessing ∼8.2 million variants that we identified and confirmed in an extended set of 2,870 individuals, 23 independent variants at 13 loci associated with at least one trait. Notably, variants at three loci (HLA, IL2RA, and SH2B3/ATXN2) overlap with known autoimmune disease associations. These results connect specific cellular phenotypes to specific genetic variants, helping to explicate their involvement in disease.
Istituto di Ricerca Genetica e Biomedica (IRGB), CNR, Monserrato 09042, Italy.
Valeria
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Orrù
Maristella
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Steri
Gabriella
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Sole
Carlo
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Sidore
Francesca
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Virdis
Mariano
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Dei
Sandra
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Lai
Magdalena
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Zoledziewska
Fabio
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Busonero
Antonella
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Mulas
Matteo
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Floris
Wieslawa I
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Mentzen
Silvana A M
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Urru
Stefania
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Olla
Michele
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Marongiu
Maria G
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Piras
Monia
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Lobina
Andrea
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Maschio
Maristella
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Pitzalis
Maria F
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Urru
Marco
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Marcelli
Roberto
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Cusano
Francesca
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Deidda
Valentina
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Serra
Manuela
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Oppo
Rosella
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Pilu
Frederic
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Reinier
Riccardo
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Berutti
Luca
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Pireddu
Ilenia
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Zara
Eleonora
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Porcu
Alan
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Kwong
Christine
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Brennan
Brendan
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Tarrier
Robert
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Lyons
Hyun M
HM
Kang
Sergio
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Uzzau
Rossano
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Atzeni
Maria
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Valentini
Davide
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Firinu
Lidia
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Leoni
Gianluca
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Rotta
Silvia
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Naitza
Andrea
A
Angius
Mauro
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Congia
Michael B
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Whalen
Chris M
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Jones
David
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Schlessinger
Gonçalo R
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Abecasis
Edoardo
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Fiorillo
Serena
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Sanna
Francesco
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Cucca
D005434:Flow Cytometry / Q000379:methods*; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D007154:Immune System Diseases / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide