Deep-coverage whole genome sequences and blood lipids among 16,324 individuals

Natarajan, Pradeep; Peloso, Gina M.; Zekavat, Seyedeh M.; Montasser, May E.; Ganna, Andrea; Chaffin, Mark; Khera, Amit V.; Zhou, Wei; Bloom, Jonathan M.; Engreitz, Jesse M.; Ernst, Jason; O’Connell, Jeffrey R.; Ruotsalainen, Sanni; Alver, Maris; Manichaikul, Ani; Johnson, W. Craig; Perry, James A.; Poterba, Timothy; Seed, Cotton; Surakka, Ida; Esko, Tõnu; Ripatti, Samuli; Salomaa, Veikko; Correa, Adolfo; Vasan, Ramachandran S.; Kellis, M; Neale, Benjamin M.; Lander, Eric S.; Abecasis, Gonçalo R.; Mitchell, Braxton D.; Rich, Stephen S.; Wilson, James G.; Cupples, L. Adrienne; Rotter, Jerome I.; Willer, Cristen J.; Kathiresan, Sekar

doi:10.1038/s41467-018-05747-8

Cited by 157 publications

(108 citation statements)

References 62 publications

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“…Human genetic research and clinical diagnostics are becoming increasingly invested in defining the complete landscape of variation in individual genomes. Ambitious international initiatives to generate short-read WGS in hundreds of thousands of individuals from complex disease cohorts have underwritten this goal, [56][57][58][59] and millions of genomes from unselected individuals will be sequenced in the coming years from national biobanks. 60,61 A central challenge to these efforts will be the uniform analysis and interpretation of all variation accessible to short-read WGS, particularly SVs, which are frequently cited as a source of added value offered by WGS over conventional technologies.…”

Section: Discussionmentioning

confidence: 99%

“…62 Indeed, early efforts to deploy WGS in cardiovascular disease, autism, and type 2 diabetes were largely consistent in their analyses of SNVs using GATK, but all studies have differed in their analyses of SVs. 25,37,50,[57][58][59]63,64 Thus, while ExAC and gno-mAD have catalyzed remarkable advances in medical and population genetics, the same opportunities for new discovery and translational impact have not yet been realized for SVs. Although gnomAD-SV is by no means comprehensive, the nearly half-million SVs it contains were derived from WGS methods and a reference genome that match those currently used in many research and clinical settings.…”

Section: Discussionmentioning

confidence: 99%

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An open resource of structural variation for medical and population genetics

Team¹

2019

Preprint

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Structural variants (SVs) rearrange large segments of the genome and can have profound consequences for evolution and human diseases. As national biobanks, disease association studies, and clinical genetic testing grow increasingly reliant on genome sequencing, population references such as the Genome Aggregation Database (gnomAD) have become integral for interpreting genetic variation.To date, no large-scale reference maps of SVs exist from high-coverage sequencing comparable to those available for point mutations in protein-coding genes. Here, we constructed a reference atlas of SVs across 14,891 genomes from diverse global populations (54% non-European) as a component of gnomAD. We discovered a rich landscape of 433,371 distinct SVs, including 5,295 multi-breakpoint complex SVs across 11 mutational subclasses, and examples of localized chromosome shattering, as in chromothripsis. The average individual harbored 7,439 SVs, which accounted for 25-29% of all rare protein-truncating events per genome. We found strong correlations between constraint against damaging point mutations and rare SVs that both disrupt and duplicate protein-coding sequence, suggesting intolerance to reciprocal dosage alterations for a subset of tightly regulated genes. We also uncovered modest selection against noncoding SVs in cis-regulatory elements, although selection against protein-truncating SVs was stronger than any effect on noncoding SVs. Finally, we benchmarked carrier rates for medically relevant SVs, finding very large (≥1Mb) rare SVs in 3.8% of genomes (~1:26 individuals) and clinically reportable incidental SVs in 0.18% of genomes (~1:556 individuals). These data have been integrated directly into the gnomAD browser (https://gnomad.broadinstitute. org) and will have broad utility for population genetics, disease association, and diagnostic screening.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

An open resource of structural variation for medical and population genetics

Team¹

2019

Preprint

Self Cite

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“…Third, SKAT‐O is computationally demanding, especially for WGS studies. Indeed, only the burden and SKAT tests have been used in recent publications on WGS studies (e.g., Natarajan et al, ; Zekavat et al, ).…”

Section: Discussionmentioning

confidence: 99%

A simple and accurate method to determine genomewide significance for association tests in sequencing studies

Lin

2019

Genetic Epidemiology

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Whole‐exome sequencing (WES) and whole‐genome sequencing (WGS) studies are underway to investigate the impact of genetic variants on complex diseases and traits. It is customary to perform single‐variant association tests for common variants and region‐based association tests for rare variants. The latter may target variants with similar or opposite effects, interrogate variants with different frequencies or different functional annotations, and examine a variety of regions. The large number of tests that are performed necessitates adjustment for multiple testing. The conventional Bonferroni correction is overly conservative as the test statistics are correlated. To address this challenge, we propose a simple and accurate method based on parametric bootstrap to assess genomewide significance. We show that the correlations of the test statistics are determined primarily by the genotypes, such that the same significance threshold can be used in different studies that share a common sequencing platform. We demonstrate the usefulness of the proposed method with WES data from the National Heart, Lung, and Blood Institute Exome Sequencing Project and WGS data from the 1000 Genomes Project. We recommend the p value of 5 × 1 0 − 9 as the genomewide significance threshold for testing all common and low‐frequency variants (MAFs ≥ 0.1%) in the human genome.

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“…Additionally, HNF4A was observed to interplay with this area through either DNA-binding at the PPP2CA/CDKL3/PPP2CA-AS shared promoter, or LIR-specific co-expression (PCC=0.68, FDR=1.1e-4). We conclude that suggestive variants could be significantly disease-associated (Natarajan, Peloso et al, 2018, Onengut-Gumuscu, Chen et al, 2015, van der Harst & Verweij, 2018 and NPS contributes to the hunting.…”

Section: Clinical Relevance Of the Identified Neuroblastoma Ctssmentioning

confidence: 75%

Tipping-point analysis uncovers critical transition signals from gene expression profiles

Yang

Wang

Goldstein

et al. 2019

Preprint

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Highlights: We adopt 'tipping-point' theory to identify distribution-transition in disease regulatory states  Critical transcriptional transition happens between low-risk and a high-risk neuroblastoma states  A critical transition signal (CTS) based on coherent expression of genes and lncRNAs shows prognostic significance  GWAS-scans with the CTS unveiled five overlooked genes and four lncRNAs with promising clinical implications  We propose a CTS-amplifier model that unveils complex but mastering transregulation in disease AbstractTipping-point models have had success identifying transcriptional critical-transition signal (CTS) in tumor phenotypes using time-course data. Can these mathematical models be adopted to cross-sectional transcriptome profiles? Furthermore, can the 2 CTS analysis that characterizes tumor progression be applied to lncRNA-expression patterns? This study introduces a novel network-perturbation signature (NPS) scoring scheme to model a phenotype-defined tumor regulatory system. Applying NPS to neuroblastoma transcriptome of two patient populations yielded two CTSs that reproducibly identified a critical system transition between the low-risk and a high-risk state. The coherent expression pattern of one specific CTS, consisting of mRNA and lncRNA components, showed prognostic significance. Associating GWAS-scans with the CTS unveiled four overlooked intergenic loci and five genes with promising clinical significance. Additionally, a new mechanism of 'CTS-amplifier' is proposed, modeling how CTS-transcript fluctuation response to complex master regulators such as c-MYC and HNF4A uniquely in the transition state. Overall, NPS is a powerful computational approach that provides a breakthrough in phenomenological analysis of collective regulatory trajectory by applying 'tipping-point' theory to '-omics' data.

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Deep-coverage whole genome sequences and blood lipids among 16,324 individuals

Cited by 157 publications

References 62 publications

An open resource of structural variation for medical and population genetics

An open resource of structural variation for medical and population genetics

A simple and accurate method to determine genomewide significance for association tests in sequencing studies

Tipping-point analysis uncovers critical transition signals from gene expression profiles

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