ArticleGenome research2016
Selection and explosive growth alter genetic architecture and hamper the detection of causal rare variants.
Article in Genome research, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 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
35 citing papers in PubMed, 1 synthesis or guideline pooled it.
- Genome-wide association analyses identify 143 risk variants and putative regulatory mechanisms for type 2 diabetes.Nature communications · 2018Pooled it
- MKado: a toolkit for McDonald-Kreitman tests of natural selection.G3 (Bethesda, Md.) · 2026Article
- Inference of population demographic history captures differing evolutionary signals based on the number of individuals in the dataset.bioRxiv : the preprint server for biology · 2026Article
- The effect of long-range linkage disequilibrium on allele-frequency dynamics under stabilizing selection.PLoS genetics · 2026Article
- Multi-ancestry GWAS of age-related hearing loss identifies 140 loci and key cellular mechanisms.Nature communications · 2026Article
- The Influence of Demographic History and Genetic Architecture on Complex Traits via Runs of Homozygosity.bioRxiv : the preprint server for biology · 2025Article
- A likelihood-based framework for demographic inference from genealogical trees.Nature genetics · 2025Article
- Using Computational Simulations to Model Deleterious Variation and Genetic Load in Natural Populations.The American naturalist · 2023Review
- A general framework for identifying oligogenic combinations of rare variants in complex disorders.Genome research · 2022Article
- Assessing the contribution of rare variants to complex trait heritability from whole-genome sequence data.Nature genetics · 2022Article
- Populations, Traits, and Their Spatial Structure in Humans.Genome biology and evolution · 2021Review
- The population frequency of human mitochondrial DNA variants is highly dependent upon mutational bias.Biology open · 2021Article
- The influence of evolutionary history on human health and disease.Nature reviews. Genetics · 2021Review
- A Large-Scale Association Study Detects Novel Rare Variants, Risk Genes, Functional Elements, and Polygenic Architecture of Prostate Cancer Susceptibility.Cancer research · 2021Article
- How Machine Learning and Statistical Models Advance Molecular Diagnostics of Rare Disorders Via Analysis of RNA Sequencing Data.Frontiers in molecular biosciences · 2021Review
- Article
- Evaluation of genetic diversity, agronomic traits, and anthracnose resistance in the NPGS Sudan Sorghum Core collection.BMC genomics · 2020Article
- Evolutionary perspectives on polygenic selection, missing heritability, and GWAS.Human genetics · 2020Review
- Population genetic simulation study of power in association testing across genetic architectures and study designs.Genetic epidemiology · 2020Article
- Ultrarare variants drive substantial cis heritability of human gene expression.Nature genetics · 2019Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
5 authors.
Funding
Abstract
The role of rare alleles in complex phenotypes has been hotly debated, but most rare variant association tests (RVATs) do not account for the evolutionary forces that affect genetic architecture. Here, we use simulation and numerical algorithms to show that explosive population growth, as experienced by human populations, can dramatically increase the impact of very rare alleles on trait variance. We then assess the ability of RVATs to detect causal loci using simulations and human RNA-seq data. Surprisingly, we find that statistical performance is worst for phenotypes in which genetic variance is due mainly to rare alleles, and explosive population growth decreases power. Although many studies have attempted to identify causal rare variants, few have reported novel associations. This has sometimes been interpreted to mean that rare variants make negligible contributions to complex trait heritability. Our work shows that RVATs are not robust to realistic human evolutionary forces, so general conclusions about the impact of rare variants on complex traits may be premature.
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.