Functional genomics bridges the gap between quantitative genetics and molecular biology

Lappalainen, Tuuli

doi:10.1101/gr.190983.115

Cited by 60 publications

(53 citation statements)

References 57 publications

(51 reference statements)

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“…Use of eQTL mapping studies to interpret GWAS findings have proved fundamental in our progression towards this goal—through prioritization of candidate genes, refinement of causal variants, and illumination of mechanistic relationships between disease-associated genetic variants and gene expression (69,70). However, there is often a disparity between disease-associated genetic variation and phenotypic alteration, which historically may be due to the use of microarray-based technologies to profile genome-wide gene expression.…”

Section: Discussionmentioning

confidence: 99%

Mapping eQTLs with RNA-seq reveals novel susceptibility genes, non-coding RNAs and alternative-splicing events in systemic lupus erythematosus

et al. 2017

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Studies attempting to functionally interpret complex-disease susceptibility loci by GWAS and eQTL integration have predominantly employed microarrays to quantify gene-expression. RNA-Seq has the potential to discover a more comprehensive set of eQTLs and illuminate the underlying molecular consequence. We examine the functional outcome of 39 variants associated with Systemic Lupus Erythematosus (SLE) through the integration of GWAS and eQTL data from the TwinsUK microarray and RNA-Seq cohort in lymphoblastoid cell lines. We use conditional analysis and a Bayesian colocalisation method to provide evidence of a shared causal-variant, then compare the ability of each quantification type to detect disease relevant eQTLs and eGenes. We discovered the greatest frequency of candidate-causal eQTLs using exon-level RNA-Seq, and identified novel SLE susceptibility genes (e.g. NADSYN1 and TCF7) that were concealed using microarrays, including four non-coding RNAs. Many of these eQTLs were found to influence the expression of several genes, supporting the notion that risk haplotypes may harbour multiple functional effects. Novel SLE associated splicing events were identified in the T-reg restricted transcription factor, IKZF2, and other candidate genes (e.g. WDFY4) through asQTL mapping using the Geuvadis cohort. We have significantly increased our understanding of the genetic control of gene-expression in SLE by maximising the leverage of RNA-Seq and performing integrative GWAS-eQTL analysis against gene, exon, and splice-junction quantifications. We conclude that to better understand the true functional consequence of regulatory variants, quantification by RNA-Seq should be performed at the exon-level as a minimum, and run in parallel with gene and splice-junction level quantification.

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Section: Discussionmentioning

confidence: 99%

Mapping eQTLs with RNA-seq reveals novel susceptibility genes, non-coding RNAs and alternative-splicing events in systemic lupus erythematosus

et al. 2017

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“…Molecular and sub-cellular traits like gene expression, epigenetic modifications, and chromatin state form the foundation upon which tissue and organism level phenotypes are built [1]. Examination of the co-variation between genetic variation and these molecular traits, as is done in genome-wide association tests, can facilitate a mechanistic understanding of how complex traits arise, including disease risks [2–4].…”

Section: Introductionmentioning

confidence: 99%

Global variation in gene expression and the value of diverse sampling

Kelly

Hansen

Tishkoff

2017

Current Opinion in Systems Biology

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The genomics era has accelerated our understanding of how genetic and epigenetic factors influence both normal variable traits and disease risk in humans. However, the majority of “omics” studies have focused on individuals living in urban centers, primarily from Europe and Asia, neglecting much of the genetic and environmental variation that exists across worldwide populations. Comparative studies of gene regulation in ethnically diverse populations are informing our understanding of how evolutionary forces have shaped the genetic and molecular mechanisms underlying complex traits, and studying gene expression in different environmental contexts is enabling the dissection of disease-related pathways such as immune response. Such approaches are vital to the equitable application of genomics and medicine.

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“…To achieve this goal, different molecular approaches such as analysis of genome, transcriptome, metablome and proteome were developed (Carpentier, 2007;Lappalainen, 2015).…”

Section: Molecular Approachesmentioning

confidence: 99%