Genetic analysis of isoform usage in the human anti-viral response reveals influenza-specific regulation of ERAP2 transcripts under balancing selection.

While genetic variants are known to be associated with overall gene abundance in stimulated immune cells, less is known about their effects on alternative isoform usage. By analyzing RNA-seq profiles of monocyte-derived dendritic cells from 243 individuals, we uncovered thousands of unannotated isoforms synthesized in response to influenza infection and type 1 interferon stimulation. We identified more than a thousand quantitative trait loci (QTLs) associated with alternate isoform usage (isoQTLs), many of which are independent of expression QTLs (eQTLs) for the same gene. Compared with eQTLs, isoQTLs are enriched for splice sites and untranslated regions, but depleted of sequences upstream of annotated transcription start sites. Both eQTLs and isoQTLs explain a significant proportion of the disease heritability attributed to common genetic variants. At the ERAP2 locus, we shed light on the function of the gene and how two frequent, highly differentiated haplotypes with intermediate frequencies could be maintained by balancing selection. At baseline and following type 1 interferon stimulation, the major haplotype is associated with low ERAP2 expression caused by nonsense-mediated decay, while the minor haplotype, known to increase Crohn's disease risk, is associated with high ERAP2 expression. In response to influenza infection, we found two uncharacterized isoforms expressed from the major haplotype, likely the result of multiple perfectly linked variants affecting the transcription and splicing at the locus. Thus, genetic variants at a single locus could modulate independent gene regulatory processes in innate immune responses and, in the case of ERAP2, may confer a historical fitness advantage in response to virus.

Dissecting the role of non-coding RNAs in the accumulation of amyloid and tau neuropathologies in Alzheimer's disease.

BACKGROUND: Given multiple studies of brain microRNA (miRNA) in relation to Alzheimer's disease (AD) with few consistent results and the heterogeneity of this disease, the objective of this study was to explore their mechanism by evaluating their relation to different elements of Alzheimer's disease pathology, confounding factors and mRNA expression data from the same subjects in the same brain region. METHODS: We report analyses of expression profiling of miRNA (n = 700 subjects) and lincRNA (n = 540 subjects) from the dorsolateral prefrontal cortex of individuals participating in two longitudinal cohort studies of aging. RESULTS: We confirm the association of two well-established miRNA (miR-132, miR-129) with pathologic AD in our dataset and then further characterize this association in terms of its component neuritic ß-amyloid plaques and neurofibrillary tangle pathologies. Additionally, we identify one new miRNA (miR-99) and four lincRNA that are associated with these traits. Many other previously reported associations of microRNA with AD are associated with the confounders quantified in our longitudinal cohort. Finally, by performing analyses integrating both miRNA and RNA sequence data from the same individuals (525 samples), we characterize the impact of AD associated miRNA on human brain expression: we show that the effects of miR-132 and miR-129-5b converge on certain genes such as EP300 and find a role for miR200 and its target genes in AD using an integrated miRNA/mRNA analysis. CONCLUSIONS: Overall, miRNAs play a modest role in human AD, but we observe robust evidence that a small number of miRNAs are responsible for specific alterations in the cortical transcriptome that are associated with AD.

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-ß (IFN-ß). 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.