Common Genetic Variants Modulate Pathogen-Sensing Responses in Human Dendritic Cells

Little is known about how human genetic variation affects the responses to environmental stimuli in the context of complex diseases. Experimental and computational approaches were applied to determine the effects of genetic variation on the induction of pathogen-responsive genes in human dendritic cells. We identified 121 common genetic variants associated in cis with variation in expression responses to Escherichia coli lipopolysaccharide, influenza, or interferon-β (IFN-β). We localized and validated causal variants to binding sites of pathogen-activated STAT (signal transducer and activator of transcription) and IRF (IFN-regulatory factor) transcription factors. We also identified a common variant in IRF7 that is associated in trans with type I IFN induction in response to influenza infection. Our results reveal common alleles that explain interindividual variation in pathogen sensing and provide functional annotation for genetic variants that alter susceptibility to inflammatory diseases.National Human Genome Research Institute (U.S.) (Grant P50 HG006193)National Institutes of Health (U.S.). Pioneer Award (DP1 CA174427)Howard Hughes Medical InstituteNational Institutes of Health (U.S.) (Grant HG004037)National Institutes of Health (U.S.). Pioneer Award (DP1 MH100706)National Institutes of Health (U.S.) (Transformative R01 Grant R01 DK097768)W. M. Keck FoundationMcKnight FoundationMerkin, Richard N.Damon Runyon Cancer Research FoundationSearle Scholars ProgramSimons Foundatio

Polarization of the Effects of Autoimmune and Neurodegenerative Risk Alleles in Leukocytes

To extend our understanding of the genetic basis of human immune function and dysfunction, we performed an expression quantitative trait locus (eQTL) study of purified CD4[superscript +] T cells and monocytes, representing adaptive and innate immunity, in a multi-ethnic cohort of 461 healthy individuals. Context-specific cis- and trans-eQTLs were identified, and cross-population mapping allowed, in some cases, putative functional assignment of candidate causal regulatory variants for disease-associated loci. We note an over-representation of T cell–specific eQTLs among susceptibility alleles for autoimmune diseases and of monocyte-specific eQTLs among Alzheimer’s and Parkinson’s disease variants. This polarization implicates specific immune cell types in these diseases and points to the need to identify the cell-autonomous effects of disease susceptibility variants