ArticleNature genetics2019
Ultrarare variants drive substantial cis heritability of human gene expression.
Article in Nature genetics, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 81 papers, 1 of them a synthesis that pooled it.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
81 citing papers in PubMed, 1 synthesis or guideline pooled it.
- Multi-ancestry sequencing-based genome-wide association study of C-reactive protein in 513,273 genomes.Nature communications · 2025Pooled it
- Trial
- Identification of novel loci regulating circulating melatonin and its causal relationship with hypertension.Human genetics · 2026Article
- Massively parallel characterization and predictive modelling of neuronal regulatory variation.bioRxiv : the preprint server for biology · 2026Article
- UK Biobank whole-genome sequencing reveals robust contributions of rare variants to complex-trait heritability.Genome biology · 2026Article
- An empirical Bayes framework for burden and dispersion association tests helps prioritize rare variants associated with Alzheimer's disease.medRxiv : the preprint server for health sciences · 2026Article
- Fine-tuning sequence-to-expression models on personal genome and transcriptome data.Genome biology · 2026Article
- Integrated mapping of human meniscus and cartilage eQTLs reveals shared and distinct osteoarthritis genetic drivers.medRxiv : the preprint server for health sciences · 2026Article
- Pitfalls in estimating and interpreting the contribution of ultra-rare genetic variants to the heritability of complex traits.medRxiv : the preprint server for health sciences · 2026Article
- Massive-scale single-nucleus multi-omics identifies novel rare noncoding drivers of Parkinson's disease.bioRxiv : the preprint server for biology · 2026Article
- Farm animal evolution demonstrates hidden molecular basis of human traits.bioRxiv : the preprint server for biology · 2026Article
- Tracing the evolutionary histories of ultra-rare variants using variational dating of large ancestral recombination graphs.bioRxiv : the preprint server for biology · 2026Article
- Deep-learning prediction of gene expression from personal genomes.Genome biology · 2026Article
- Article
- A combined genomic arrhythmia propensity score delineates cumulative risk.Cell reports. Medicine · 2025Article
- Comprehensive gene heritability estimation reveals the genetic architecture of rare coding variants underlying complex traits.bioRxiv : the preprint server for biology · 2025Article
- A Differential Depth Sequencing Method, SPRE-Seq, for Enhancing Targeted Region Coverage in Hybridization Capture-Based NGS.Engineering in life sciences · 2025Article
- Article
- Impact of rare non-coding variants on human diseases through alternative polyadenylation outliers.Nature communications · 2025Article
- Systems genomics of salinity stress response in rice.bioRxiv : the preprint server for biology · 2024Article
21 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
6 authors.
Funding
Abstract
The vast majority of human mutations have minor allele frequencies under 1%, with the plurality observed only once (that is, 'singletons'). While Mendelian diseases are predominantly caused by rare alleles, their cumulative contribution to complex phenotypes is largely unknown. We develop and rigorously validate an approach to jointly estimate the contribution of all alleles, including singletons, to phenotypic variation. We apply our approach to transcriptional regulation, an intermediate between genetic variation and complex disease. Using whole-genome DNA and lymphoblastoid cell line RNA sequencing data from 360 European individuals, we conservatively estimate that singletons contribute approximately 25% of cis heritability across genes (dwarfing the contributions of other frequencies). The majority (approximately 76%) of singleton heritability derives from ultrarare variants absent from thousands of additional samples. We develop an inference procedure to demonstrate that our results are consistent with pervasive purifying selection shaping the regulatory architecture of most human genes.
Indexed as
Identifiers
What OpenQuestion holds
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.