@article {99, title = {Cell type-specific genetic regulation of gene expression across human tissues.}, journal = {Science}, volume = {369}, year = {2020}, month = {2020 09 11}, abstract = {

The Genotype-Tissue Expression (GTEx) project has identified expression and splicing quantitative trait loci in cis (QTLs) for the majority of genes across a wide range of human tissues. However, the functional characterization of these QTLs has been limited by the heterogeneous cellular composition of GTEx tissue samples. We mapped interactions between computational estimates of cell type abundance and genotype to identify cell type-interaction QTLs for seven cell types and show that cell type-interaction expression QTLs (eQTLs) provide finer resolution to tissue specificity than bulk tissue cis-eQTLs. Analyses of genetic associations with 87 complex traits show a contribution from cell type-interaction QTLs and enables the discovery of hundreds of previously unidentified colocalized loci that are masked in bulk tissue.

}, keywords = {Cells, Gene Expression Regulation, Humans, Organ Specificity, Quantitative Trait Loci, RNA, Long Noncoding, Transcriptome}, issn = {1095-9203}, doi = {10.1126/science.aaz8528}, author = {Kim-Hellmuth, Sarah and Aguet, Fran{\c c}ois and Oliva, Meritxell and Mu{\~n}oz-Aguirre, Manuel and Kasela, Silva and Wucher, Valentin and Castel, Stephane E and Hamel, Andrew R and Vi{\~n}uela, Ana and Roberts, Amy L and Mangul, Serghei and Wen, Xiaoquan and Wang, Gao and Barbeira, Alvaro N and Garrido-Mart{\'\i}n, Diego and Nadel, Brian B and Zou, Yuxin and Bonazzola, Rodrigo and Quan, Jie and Brown, Andrew and Martinez-Perez, Angel and Soria, Jos{\'e} Manuel and Getz, Gad and Dermitzakis, Emmanouil T and Small, Kerrin S and Stephens, Matthew and Xi, Hualin S and Im, Hae Kyung and Guigo, Roderic and Segr{\`e}, Ayellet V and Stranger, Barbara E and Ardlie, Kristin G and Lappalainen, Tuuli} } @article {102, title = {The impact of sex on gene expression across human tissues.}, journal = {Science}, volume = {369}, year = {2020}, month = {2020 09 11}, abstract = {

Many complex human phenotypes exhibit sex-differentiated characteristics. However, the molecular mechanisms underlying these differences remain largely unknown. We generated a catalog of sex differences in gene expression and in the genetic regulation of gene expression across 44 human tissue sources surveyed by the Genotype-Tissue Expression project (GTEx, v8 release). We demonstrate that sex influences gene expression levels and cellular composition of tissue samples across the human body. A total of 37\% of all genes exhibit sex-biased expression in at least one tissue. We identify cis expression quantitative trait loci (eQTLs) with sex-differentiated effects and characterize their cellular origin. By integrating sex-biased eQTLs with genome-wide association study data, we identify 58 gene-trait associations that are driven by genetic regulation of gene expression in a single sex. These findings provide an extensive characterization of sex differences in the human transcriptome and its genetic regulation.

}, keywords = {Chromosomes, Human, X, Disease, Epigenesis, Genetic, Female, Gene Expression, Gene Expression Regulation, Genetic Variation, Genome-Wide Association Study, Humans, Male, Organ Specificity, Promoter Regions, Genetic, Quantitative Trait Loci, Sex Characteristics, Sex Factors}, issn = {1095-9203}, doi = {10.1126/science.aba3066}, author = {Oliva, Meritxell and Mu{\~n}oz-Aguirre, Manuel and Kim-Hellmuth, Sarah and Wucher, Valentin and Gewirtz, Ariel D H and Cotter, Daniel J and Parsana, Princy and Kasela, Silva and Balliu, Brunilda and Vi{\~n}uela, Ana and Castel, Stephane E and Mohammadi, Pejman and Aguet, Fran{\c c}ois and Zou, Yuxin and Khramtsova, Ekaterina A and Skol, Andrew D and Garrido-Mart{\'\i}n, Diego and Reverter, Ferran and Brown, Andrew and Evans, Patrick and Gamazon, Eric R and Payne, Anthony and Bonazzola, Rodrigo and Barbeira, Alvaro N and Hamel, Andrew R and Martinez-Perez, Angel and Soria, Jos{\'e} Manuel and Pierce, Brandon L and Stephens, Matthew and Eskin, Eleazar and Dermitzakis, Emmanouil T and Segr{\`e}, Ayellet V and Im, Hae Kyung and Engelhardt, Barbara E and Ardlie, Kristin G and Montgomery, Stephen B and Battle, Alexis J and Lappalainen, Tuuli and Guigo, Roderic and Stranger, Barbara E} } @article {46, title = {Modified penetrance of coding variants by cis-regulatory variation contributes to disease risk.}, journal = {Nat Genet}, volume = {50}, year = {2018}, month = {2018 Sep}, pages = {1327-1334}, abstract = {

Coding variants represent many of the strongest associations between genotype and phenotype; however, they exhibit inter-individual differences in effect, termed {\textquoteright}variable penetrance{\textquoteright}. Here, we study how cis-regulatory variation modifies the penetrance of coding variants. Using functional genomic and genetic data from the Genotype-Tissue Expression Project (GTEx), we observed that in the general population, purifying selection has depleted haplotype combinations predicted to increase pathogenic coding variant penetrance. Conversely, in cancer and autism patients, we observed an enrichment of penetrance increasing haplotype configurations for pathogenic variants in disease-implicated genes, providing evidence that regulatory haplotype configuration of coding variants affects disease risk. Finally, we experimentally validated this model by editing a Mendelian single-nucleotide polymorphism (SNP) using CRISPR/Cas9 on distinct expression haplotypes with the transcriptome as a phenotypic readout. Our results demonstrate that joint regulatory and coding variant effects are an important part of the genetic architecture of human traits and contribute to modified penetrance of disease-causing variants.

}, issn = {1546-1718}, doi = {10.1038/s41588-018-0192-y}, author = {Castel, Stephane E and Cervera, Alejandra and Mohammadi, Pejman and Aguet, Fran{\c c}ois and Reverter, Ferran and Wolman, Aaron and Guigo, Roderic and Iossifov, Ivan and Vasileva, Ana and Lappalainen, Tuuli} }