Discovery and quality analysis of a comprehensive set of structural variants and short tandem repeats.

Structural variants (SVs) and short tandem repeats (STRs) are important sources of genetic diversity but are not routinely analyzed in genetic studies because they are difficult to accurately identify and genotype. Because SVs and STRs range in size and type, it is necessary to apply multiple algorithms that incorporate different types of evidence from sequencing data and employ complex filtering strategies to discover a comprehensive set of high-quality and reproducible variants. Here we assemble a set of 719 deep whole genome sequencing (WGS) samples (mean 42×) from 477 distinct individuals which we use to discover and genotype a wide spectrum of SV and STR variants using five algorithms. We use 177 unique pairs of genetic replicates to identify factors that affect variant call reproducibility and develop a systematic filtering strategy to create of one of the most complete and well characterized maps of SVs and STRs to date

Properties of structural variants and short tandem repeats associated with gene expression and complex traits.

Structural variants (SVs) and short tandem repeats (STRs) comprise a broad group of diverse DNA variants which vastly differ in their sizes and distributions across the genome. Here, we identify genomic features of SV classes and STRs that are associated with gene expression and complex traits, including their locations relative to eGenes, likelihood of being associated with multiple eGenes, associated eGene types (e.g., coding, noncoding, level of evolutionary constraint), effect sizes, linkage disequilibrium with tagging single nucleotide variants used in GWAS, and likelihood of being associated with GWAS traits. We identify a set of high-impact SVs/STRs associated with the expression of three or more eGenes via chromatin loops and show that they are highly enriched for being associated with GWAS traits. Our study provides insights into the genomic properties of structural variant classes and short tandem repeats that are associated with gene expression and human traits

Discovery and quality analysis of a comprehensive set of structural variants and short tandem repeats.

Structural variants (SVs) and short tandem repeats (STRs) are important sources of genetic diversity but are not routinely analyzed in genetic studies because they are difficult to accurately identify and genotype. Because SVs and STRs range in size and type, it is necessary to apply multiple algorithms that incorporate different types of evidence from sequencing data and employ complex filtering strategies to discover a comprehensive set of high-quality and reproducible variants. Here we assemble a set of 719 deep whole genome sequencing (WGS) samples (mean 42×) from 477 distinct individuals which we use to discover and genotype a wide spectrum of SV and STR variants using five algorithms. We use 177 unique pairs of genetic replicates to identify factors that affect variant call reproducibility and develop a systematic filtering strategy to create of one of the most complete and well characterized maps of SVs and STRs to date

Properties of structural variants and short tandem repeats associated with gene expression and complex traits.

Structural variants (SVs) and short tandem repeats (STRs) comprise a broad group of diverse DNA variants which vastly differ in their sizes and distributions across the genome. Here, we identify genomic features of SV classes and STRs that are associated with gene expression and complex traits, including their locations relative to eGenes, likelihood of being associated with multiple eGenes, associated eGene types (e.g., coding, noncoding, level of evolutionary constraint), effect sizes, linkage disequilibrium with tagging single nucleotide variants used in GWAS, and likelihood of being associated with GWAS traits. We identify a set of high-impact SVs/STRs associated with the expression of three or more eGenes via chromatin loops and show that they are highly enriched for being associated with GWAS traits. Our study provides insights into the genomic properties of structural variant classes and short tandem repeats that are associated with gene expression and human traits

Properties of structural variants and short tandem repeats associated with gene expression and complex traits.

Structural variants (SVs) and short tandem repeats (STRs) comprise a broad group of diverse DNA variants which vastly differ in their sizes and distributions across the genome. Here, we identify genomic features of SV classes and STRs that are associated with gene expression and complex traits, including their locations relative to eGenes, likelihood of being associated with multiple eGenes, associated eGene types (e.g., coding, noncoding, level of evolutionary constraint), effect sizes, linkage disequilibrium with tagging single nucleotide variants used in GWAS, and likelihood of being associated with GWAS traits. We identify a set of high-impact SVs/STRs associated with the expression of three or more eGenes via chromatin loops and show that they are highly enriched for being associated with GWAS traits. Our study provides insights into the genomic properties of structural variant classes and short tandem repeats that are associated with gene expression and human traits

Large-scale cis- and trans-eQTL analyses identify thousands of genetic loci and polygenic scores that regulate blood gene expression

Trait-associated genetic variants affect complex phenotypes primarily via regulatory mechanisms on the transcriptome. To investigate the genetics of gene expression, we performed cis- and trans-expression quantitative trait locus (eQTL) analyses using blood-derived expression from 31,684 individuals through the eQTLGen Consortium. We detected cis-eQTL for 88% of genes, and these were replicable in numerous tissues. Distal trans-eQTL (detected for 37% of 10,317 trait-associated variants tested) showed lower replication rates, partially due to low replication power and confounding by cell type composition. However, replication analyses in single-cell RNA-seq data prioritized intracellular trans-eQTL. Trans-eQTL exerted their effects via several mechanisms, primarily through regulation by transcription factors. Expression of 13% of the genes correlated with polygenic scores for 1,263 phenotypes, pinpointing potential drivers for those traits. In summary, this work represents a large eQTL resource, and its results serve as a starting point for in-depth interpretation of complex phenotypes.This article is freely available online. Click on the 'Additional Link' above to access the full-text via the publisher's site.Accepted version (6 months embargo), submitted versio