Genomic properties of structural variants and short tandem repeats that impact gene expression and complex traits in humans

Jakubosky, David; D’Antonio, Matteo; Bonder, Marc Jan; Smail, Craig; Donovan, Maureen D.; Greenwald, William W.; D’Antonio‐Chronowska, Agnieszka; Matsui, Hiroko; Stegle, Oliver; Smith, Erin N.; Montgomery, Stephen B.; DeBoever, Christopher; Frazer, Kelly A.

doi:10.1101/714477

Cited by 4 publications

(6 citation statements)

References 50 publications

(30 reference statements)

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“…For structural variants (SVs), a 9-fold increase in rare (study MAF 0<=MAF<1%) duplications, and 18fold increase in rare multi-allelic copy number variants (mCNVs), was observed in overexpression outliers compared with non-outliers ( Fig 2B) ( Table S8). The findings for SVs agrees with recent consortium findings detailed previously 20 .…”

Section: Mapping Large-effect Rare Variants Impacting Gene Expressionsupporting

confidence: 92%

Systematic assessment of regulatory effects of human disease variants in pluripotent cells

Bonder

Smail

Gloudemans

et al. 2019

Preprint

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Identifying regulatory genetic effects in pluripotent cells provides important insights into disease variants with potentially transient or developmental origins. Combining existing and newlygenerated data, we established a population-scale resource of 1,367 induced pluripotent stem cell lines derived from 948 unique donors, with matched RNA-sequencing (RNA-seq) and genetic information. The sample size of our study allowed us to significantly expand our knowledge of quantitative trait loci (QTL) in pluripotent human cells and their broad trait and disease relevance.We identified cis-QTL for conventional gene expression levels but also transcript-ratio, exon expression levels, alternative-splicing and alternative polyadenylation usage, cumulatively yielding cis regulatory effects for 18,556 genes. We assessed the effects of rare variants identified from whole-genome sequencing data, by relating these to gene expression outliers, observing an enrichment for rare, deleterious variants in iPSCs with outlying expression profiles, which exceeds previous observations in differentiated tissues. Finally, we assessed distal QTL on a genomewide scale, identifying 193 trans-eQTL, linked to 191 trans-eGenes (FDR <10%), 38% of which were replicated in independent samples.By linking our regulatory map of rare and common QTL to comprehensive GWAS data, we identified high-confidence colocalization events for 4,336 individual GWAS loci, which includes physical traits such as height and coronary artery disease. In addition, we identify rare variant associations for metabolic rate and trans-eQTL linked to both cancer and height. Collectively, our data greatly expand the regulatory landscape in human pluripotent cells, and catalogues traitassociated variants that have potential developmental or transient contexts.

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Section: Mapping Large-effect Rare Variants Impacting Gene Expressionsupporting

confidence: 92%

Systematic assessment of regulatory effects of human disease variants in pluripotent cells

Bonder

Smail

Gloudemans

et al. 2019

Preprint

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“…This was true across variant classes in both studies, with the exception of duplications in 1KGP, which were less correlated (r=0.74), likely as a result of limited genotyping sensitivity in 1KGP due to the use of low coverage WGS data ( Figure S15,S16). These results support that the i2QTL SV call set is accurate and contains most common SVs discoverable using short read sequencing data as well as novel, rare SVs, making it a valuable resource for examining functional differences between the SV classes (Jakubosky et al, 2019).…”

Section: Comparison Between Svs In I2qtl Gtex and 1kgpsupporting

confidence: 70%

“…Overall, this study provides a roadmap for discovering and genotyping SVs from WGS data and establishes a high-quality catalog of SVs and STRs that can be used in future genotyping efforts. A companion paper (Jakubosky et al, 2019)examines how the i2QTL SVs and STRs characterized here influence gene expression and contribute to disease risk. These studies demonstrate that SVs and STrs can be reliably identified and genotyped for hundreds of samples and used to study the impact of this class of genetic variation on human health.…”

Section: Discussionmentioning

confidence: 98%

“…For each of the 42,921 total non-redundant SVs and STRs that were within 1MB of an expressed gene in iPSCs ( (Jakubosky et al, 2019), we used bcftools to extract all SNPs 50 kb upstream and downstream. For each SV or STR, we calculated LD as the correlation (Pearson R 2 ) with the genotypes of each surrounding SNV or indel genotyped in i2QTL WGS and selected the variant with the strongest LD.…”

Section: Ld Taggingmentioning

confidence: 99%

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Discovery and Quality Analysis of a Comprehensive Set of Structural Variants and Short Tandem Repeats

Jakubosky

Smith

D’Antonio

et al. 2019

Preprint

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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 assembled a set of 719 deep whole genome sequencing (WGS) samples (mean 42x) from 477 distinct individuals which we used to discover and genotype a wide spectrum of SV and STR variants using five algorithms. We used 177 unique pairs of genetic replicates to identify factors that affect variant call reproducibility and developed a systematic filtering strategy to create of one of the most complete and well characterized maps of SVs and STRs to date.

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“…To address this gap, we developed a comprehensive map of regulatory variation in the MHC region using deep WGS from 419 individuals and RNA-seq data from matched iPSCs. We have previously shown that iPSCs are well-powered for eQTL mapping (Bonder et al, 2019; Jakubosky et al, 2019a; Jakubosky et al, 2019b), have a distinct regulatory landscape relative to somatic tissues (DeBoever et al, 2017), and thereby provide insights into regulatory variants that exert their effects during early development. While we demonstrate the feasibility of generating a map of regulatory variation for the MHC region and its utility for examining molecular mechanisms underlying disease associations in the interval, future studies using eQTLs from other cell types could increase the number of complex trait loci in the interval that are functionally annotated.…”

Section: Discussionmentioning

confidence: 99%

Systematic genetic analysis of the MHC region reveals mechanistic underpinnings of HLA type associations with disease

D’Antonio

Reyna

Jakubosky

et al. 2019

eLife

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The MHC region is highly associated with autoimmune and infectious diseases. Here we conduct an in-depth interrogation of associations between genetic variation, gene expression and disease. We create a comprehensive map of regulatory variation in the MHC region using WGS from 419 individuals to call eight-digit HLA types and RNA-seq data from matched iPSCs. Building on this regulatory map, we explored GWAS signals for 4083 traits, detecting colocalization for 180 disease loci with eQTLs. We show that eQTL analyses taking HLA type haplotypes into account have substantially greater power compared with only using single variants. We examined the association between the 8.1 ancestral haplotype and delayed colonization in Cystic Fibrosis, postulating that downregulation of RNF5 expression is the likely causal mechanism. Our study provides insights into the genetic architecture of the MHC region and pinpoints disease associations that are due to differential expression of HLA genes and non-HLA genes.

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Genomic properties of structural variants and short tandem repeats that impact gene expression and complex traits in humans

Abstract: S t r u c t

Cited by 4 publications

References 50 publications

Systematic assessment of regulatory effects of human disease variants in pluripotent cells

Systematic assessment of regulatory effects of human disease variants in pluripotent cells

Discovery and Quality Analysis of a Comprehensive Set of Structural Variants and Short Tandem Repeats

Systematic genetic analysis of the MHC region reveals mechanistic underpinnings of HLA type associations with disease

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