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Integrative approaches for large-scale transcriptome-wide association studies

Authors: Alexander Gusev; Arthur Ko; Huwenbo Shi; Gaurav Bhatia; Wonil Chung; Brenda W J H Penninx; Rick Jansen; +18 Authors

Integrative approaches for large-scale transcriptome-wide association studies

Abstract

Abstract Many genetic variants influence complex traits by modulating gene expression, thus altering the abundance levels of one or multiple proteins. In this work we introduce a powerful strategy that integrates gene expression measurements with large-scale genome-wide association data to identify genes whose cis-regulated expression is associated to complex traits. We use a relatively small reference panel of individuals for which both genetic variation and gene expression have been measured to impute gene expression into large cohorts of individuals and identify expression-trait associations. We extend our methods to allow for indirect imputation of the expression-trait association from summary association statistics of large-scale GWAS 1-3 . We applied our approaches to expression data from blood and adipose tissue measured in ∼3,000 individuals overall. We then imputed gene expression into GWAS data from over 900,000 phenotype measurements 4-6 to identify 69 novel genes significantly associated to obesity-related traits (BMI, lipids, and height). Many of the novel genes were associated with relevant phenotypes in the Hybrid Mouse Diversity Panel. Overall our results showcase the power of integrating genotype, gene expression and phenotype to gain insights into the genetic basis of complex traits.

Countries
United States, Netherlands
Keywords

Gene Expression Regulation (mesh), Netherlands Twin Register (NTR), 3102 Bioinformatics and computational biology (for-2020), 3001 Agricultural biotechnology (for-2020), 11 Medical and Health Sciences (for), Medical and Health Sciences, 3105 Genetics (for-2020), Mice, Obesity (mesh), Animals (mesh), Genetic Predisposition to Disease (mesh), Cancer, Developmental Biology (science-metrix), Humans (mesh), Generic health relevance (hrcs-hc), Mice (mesh), Biological Sciences, Bioinformatics and computational biology, Phenotype (mesh), 06 Biological Sciences (for), Phenotype, Genome-Wide Association Study (mesh), Quantitative Trait Loci (mesh), 570, Genotype, Agricultural biotechnology, Quantitative Trait Loci, 610, SDG 3 - Good Health and Well-being, Genetics, Animals, Humans, Genetic Predisposition to Disease, Obesity, Obesity (rcdc), 31 Biological Sciences (for-2020), Genetics (rcdc), Genotype (mesh), Human Genome, Cancer (hrcs-hc), ta3121, Transcriptome (mesh), Human Genome (rcdc), Gene Expression Regulation, Generic health relevance, Transcriptome, Developmental Biology, Genome-Wide Association Study

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    This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
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selected citations
These citations are derived from selected sources.
This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
BIP!Citations provided by BIP!
popularity
This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.
BIP!Popularity provided by BIP!
influence
This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
BIP!Influence provided by BIP!
impulse
This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.
BIP!Impulse provided by BIP!
2K
Top 0.01%
Top 0.1%
Top 0.1%
Green
hybrid