A gene-based association method for mapping traits using reference transcriptome data

Gamazon, Eric R.; Wheeler, Heather E.; Shah, Kaanan P.; Mozaffari, Sahar V.; Aquino‐Michaels, Keston; Carroll, Robert J.; Eyler, Anne E.; Denny, Joshua C.; Nicolae, Dan L.; Cox, Nancy J.; Im, Hae Kyung

doi:10.1038/ng.3367

Cited by 1,570 publications

(2,348 citation statements)

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“…Therefore, it does not prove causality, similarly to all current methods. [7][8][9][10][11][12] In fact, if gene functions are often pleiotropic, for which we found some evidence in the current study, the assumption of independence between the instrument variable and the outcome of Mendelian randomization approaches is more likely to be violated. 34 Still, the inferences made here can potentially guide phenotypic studies of gene functions in model systems.…”

Section: Discussionmentioning

confidence: 77%

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Large-Scale Identification of Common Trait and Disease Variants Affecting Gene Expression

Hauberg

Zhang

Giambartolomei

et al. 2017

The American Journal of Human Genetics

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Genome-wide association studies (GWASs) have identified a multitude of genetic loci involved with traits and diseases. However, it is often unclear which genes are affected in such loci and whether the associated genetic variants lead to increased or decreased gene function. To mitigate this, we integrated associations of common genetic variants in 57 GWASs with 24 studies of expression quantitative trait loci (eQTLs) from a broad range of tissues by using a Mendelian randomization approach. We discovered a total of 3,484 instances of gene-trait-associated changes in expression at a false-discovery rate < 0.05. These genes were often not closest to the genetic variant and were primarily identified in eQTLs derived from pathophysiologically relevant tissues. For instance, genes with expression changes associated with lipid traits were mostly identified in the liver, and those associated with cardiovascular disease were identified in arterial tissue. The affected genes additionally point to biological processes implicated in the interrogated traits, such as the interleukin-27 pathway in rheumatoid arthritis. Further, comparing trait-associated gene expression changes across traits suggests that pleiotropy is a widespread phenomenon and points to specific instances of both agonistic and antagonistic pleiotropy. For instance, expression of SNX19 and ABCB9 is positively correlated with both the risk of schizophrenia and educational attainment. To facilitate interpretation, we provide this lexicon of how common trait-associated genetic variants alter gene expression in various tissues as the online database GWAS2Genes.

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Section: Discussionmentioning

confidence: 77%

“…From a study using SMR, 13 we found support for 69.1% (47/68) of the reported gene-trait associations, and for a study using PrediXcan, 7 this number was 66.7% (6/9) ( Table S4).…”

Section: Resultsmentioning

confidence: 99%

Large-Scale Identification of Common Trait and Disease Variants Affecting Gene Expression

Hauberg

Zhang

Giambartolomei

et al. 2017

The American Journal of Human Genetics

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“…These spatiotemporal maps of gene activity and gene regulation will be instrumental in pinpointing the specific brain region(s) and critical periods where susceptibility genes influence GTS pathophysiology at the molecular level 198,199 . In parallel, collaborations in the field of neuro-imaging genetics (the largest example of which is the ENIGMA Consortium) will facilitate integration of GTS genetics with systems neuroscience to uncover underlying GTS biology at the neural circuit level 200,201 .…”

Section: Thoughts For Dougmentioning

confidence: 99%

Gilles de la Tourette syndrome

Robertson

Eapen

Singer

et al. 2017

Nat Rev Dis Primers

284

244

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The unstructured abstract of 200 words maximum should summarize the main points of the article. All information mentioned in the abstract must be addressed somewhere in the main article. The abstract should not contain references or display item citations. Gilles de la Tourette Syndrome (GTS), a reasonably common disorder, has had a long, tortuous and somewhat controversial history. First and well described in the 18th century 1,2 , the main features of GTS have, however, remained fairly constant. The core diagnostic features are multiple motor and one or more vocal (phonic) tics lasting for over a year. In addition, almost pathognomic, but not necessary, features described in the early documentations include coprolalia (involuntary, inappropriate swearing), and echophenomena (copying behaviours), as well as many co-morbidities and psychopathologies 3 . Introduction [suggested 500 words, is 544 words -8 refs] Mary Robertson Thoughts for Mary -Your word count when combining sections 1 and 2 is 1001 (1000 limit)-so OKGTS was originally described in France and the majority of early literature came from and standardised schedules such as diagnostic confidence, measurement of severity, QoL, and assessment of both co-morbidities and co-existent psychopathologies are currently available.Large international collaborative consortia are engaged in studies exploring aetiological factors in particular, and some international treatment studies are also underway. Perhaps as a result of earlier small patient numbers, the treatment trials have given good clues to management, but unsurprisingly systematic reviews and meta-analyses have been hampered, giving disappointing, if not unexpected, results. Intriguingly medications from the typical NRDP -Gilles de la Tourette Syndrome 3 antipsychotic family including haloperidol, which first had documented success in 1961 6,7 are still being used, although successive generations of "atypicals" are currently more in vogue,as are medications such as alpha-2-adrenergic agonists. Interestingly, haloperidol remains the only medication prescribed on licence in many parts of the world. In contrast to disorders such as ADHD, in which it is clear which treatments work and which do not require further study 8 , a variety of treatment studies in GTS are still being undertaken, including using other medications (trying to improve efficacy and reduce side effects), behavioural therapies, deep brain stimulation (for refractory cases), and other more "alternative" methods such as "orthotics" (teeth braces). The GTS community has to first agree on how common GTS is and then seek funding for research in the areas of major importance.2. Epidemiology [suggested 500 words, is 444 words, 6 additional refs] Mary Robertson GTS was for many years thought to be not only very rare, but a bizarre curiosity, with sporadic case reports peppering the literature. The belief that GTS was uncommon at the very least was held by many until Comings 9 controversially suggested that GTS occurred in between 0.66% and...

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“…[3][4][5][6][7][8][9][10][11][12] In parallel, large-scale expression quantitative trail locus (eQTL) mapping studies in multiple human tissues have revealed a large number of genetic variants that affect gene expression [13][14][15][16][17][18][19] (reviewed by Albert and Kruglyak 20 ). Gene expression serves as an important intermediate cellular phenotype that affects complex diseases and traits, [21][22][23][24] and the functional effects of eQTLs provide another lens through which researchers can investigate molecular mechanisms. 9,[13][14][15][16][17][18][19][20][25][26][27] However, the underlying functional mechanisms of eQTLs are still largely unclear.…”

Section: Introductionmentioning

confidence: 99%

Functional Architectures of Local and Distal Regulation of Gene Expression in Multiple Human Tissues

Liu

Finucane

Gusev

et al. 2017

The American Journal of Human Genetics

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Genetic variants that modulate gene expression levels play an important role in the etiology of human diseases and complex traits. Although large-scale eQTL mapping studies routinely identify many local eQTLs, the molecular mechanisms by which genetic variants regulate expression remain unclear, particularly for distal eQTLs, which these studies are not well powered to detect. Here, we leveraged all variants (not just those that pass stringent significance thresholds) to analyze the functional architecture of local and distal regulation of gene expression in 15 human tissues by employing an extension of stratified LD-score regression that produces robust results in simulations. The top enriched functional categories in local regulation of peripheral-blood gene expression included coding regions (11.413), conserved regions (4.673), and four histone marks (p < 5 3 10 À5 for all enrichments); local enrichments were similar across the 15 tissues.We also observed substantial enrichments for distal regulation of peripheral-blood gene expression: coding regions (4.473), conserved regions (4.513), and two histone marks (p < 3 3 10 À7 for all enrichments). Analyses of the genetic correlation of gene expression across tissues confirmed that local regulation of gene expression is largely shared across tissues but that distal regulation is highly tissue specific. Our results elucidate the functional components of the genetic architecture of local and distal regulation of gene expression.

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A gene-based association method for mapping traits using reference transcriptome data

Cited by 1,570 publications

References 52 publications

Large-Scale Identification of Common Trait and Disease Variants Affecting Gene Expression

Large-Scale Identification of Common Trait and Disease Variants Affecting Gene Expression

Gilles de la Tourette syndrome

Functional Architectures of Local and Distal Regulation of Gene Expression in Multiple Human Tissues

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