ArticleAmerican journal of human genetics2016
A Burden of Rare Variants Associated with Extremes of Gene Expression in Human Peripheral Blood.
Article in American journal of human genetics, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 51 papers.
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Who cites it
51 citing papers in PubMed, 93 citations in OpenAlex.
- Machine learning and statistical methods for molecular quantitative trait loci.Nature reviews. Genetics · 2026Review
- Cis-regulation of gene expression between sexes and life stages in Rumex hastatulus.Molecular biology and evolution · 2026Article
- Targeted long-read RNA sequencing for rare disease diagnosis and variant interpretation.Science advances · 2026Article
- Geography, Ancestry, Age and Sex Shape Somatic Autosomal Mosaic Chromosomal Alterations in Blood.medRxiv : the preprint server for health sciences · 2025Article
- Transcriptome-wide outlier approach identifies individuals with minor spliceopathies.American journal of human genetics · 2025Article
- In silico prediction of variant effects: promises and limitations for precision plant breeding.TAG. Theoretical and applied genetics. Theoretische und angewandte Genetik · 2025Review
- Genetic Regulatory Perturbation of Gene Expression Impacted by Genomic Introgression in Fiber Development of Allotetraploid Cotton.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
- Next-Generation Sequencing Data-Based Association Testing of a Group of Genetic Markers for Complex Responses Using a Generalized Linear Model Framework.Mathematics (Basel, Switzerland) · 2023Article
- Rare genetic variants underlie outlying levels of DNA methylation and gene-expression.Human molecular genetics · 2023Article
- Schizophrenia risk conferred by rare protein-truncating variants is conserved across diverse human populations.Nature genetics · 2023Article
- Targeted Genome Sequencing Identifies Multiple Rare Variants in Caveolin-1 Associated with Obstructive Sleep Apnea.American journal of respiratory and critical care medicine · 2022Article
- Article
- Deleterious Mutations and the Rare Allele Burden on Rice Gene Expression.Molecular biology and evolution · 2022Article
- Integration of rare expression outlier-associated variants improves polygenic risk prediction.American journal of human genetics · 2022Article
- Variation in upstream open reading frames contributes to allelic diversity in maize protein abundance.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Toward transcriptomics as a primary tool for rare disease investigation.Cold Spring Harbor molecular case studies · 2022Article
- Combinatorial patterns of gene expression changes contribute to variable expressivity of the developmental delay-associated 16p12.1 deletion.Genome medicine · 2021Article
- Rare variants regulate expression of nearby individual genes in multiple tissues.PLoS genetics · 2021Article
- Article
- Identification of rare and common regulatory variants in pluripotent cells using population-scale transcriptomics.Nature genetics · 2021Article
Corrections and comments
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Authors and funding
9 authors at 1 institution in 1 country.
Funding
Abstract
In order to evaluate whether rare regulatory variants in the vicinity of promoters are likely to impact gene expression, we conducted a novel burden test for enrichment of rare variants at the extremes of expression. After sequencing 2-kb promoter regions of 472 genes in 410 healthy adults, we performed a quadratic regression of rare variant count on bins of peripheral blood transcript abundance from microarrays, summing over ranks of all genes. After adjusting for common eQTLs and the major axes of gene expression covariance, a highly significant excess of variants with minor allele frequency less than 0.05 at both high and low extremes across individuals was observed. Further enrichment was seen in sites annotated as potentially regulatory by RegulomeDB, but a deficit of effects was associated with known metabolic disease genes. The main result replicates in an independent sample of 75 individuals with RNA-seq and whole-genome sequence information. Three of four predicted large-effect sites were validated by CRISPR/Cas9 knockdown in K562 cells, but simulations indicate that effect sizes need not be unusually large to produce the observed burden. Unusually divergent low-frequency promoter haplotypes were observed at 31 loci, at least 9 of which appear to be derived from Neandertal admixture, but these were not associated with divergent gene expression in blood. The overall burden test results are consistent with rare and private regulatory variants driving high or low transcription at specific loci, potentially contributing to disease.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.