ArticleProceedings of the National Academy of Sciences of the United States of America2010
Evolution in health and medicine Sackler colloquium: Genetic architecture of a complex trait and its implications for fitness and genome-wide association studies.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 137 papers.
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137 citing papers in PubMed.
- Genetic architectures of brain-related traits are shaped by strong selective constraints.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- The distribution of fitness effects of nonsynonymous mutations varies phylogenetically across animals.PLoS biology · 2026Article
- Allele frequency trajectories across age groups reveal ongoing natural selection shaping disease susceptibility.American journal of human genetics · 2026Article
- Methods to detect selection history in a population under ongoing directional selection.Genetics · 2026Article
- Unravelling the genetic architecture of cerebral small vessel disease in the context of stroke.Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism · 2026Review
- Genetic architectures of brain-related traits are shaped by strong selective constraints.bioRxiv : the preprint server for biology · 2026Article
- A new perspective on population genetics: Deciphering the relationship between genetic variants and disease prevalence in Psoriasis.PloS one · 2026Article
- Determining the driving factors shaping genetic architecture of complex traits in recently admixed populations.bioRxiv : the preprint server for biology · 2025Article
- Cost-effective non-additive GWAS across 2329 diseases in 500,349 individuals.Nature communications · 2025Article
- The impact of non-neutral synonymous mutations when inferring selection on nonsynonymous mutations.Genetics · 2025Article
- Article
- Rare-variant association studies: When are aggregation tests more powerful than single-variant tests?American journal of human genetics · 2025Article
- Contribution of Range-Wide and Short-Scale Chemical Soil Variation to Local Adaptation in a Tropical Montane Forest Tree.Evolutionary applications · 2025Article
- Neanderthal introgressed ancestry reveals human genomic regions enriched with recessive deleterious mutations.bioRxiv : the preprint server for biology · 2025Article
- Article
- Evaluation of genomic selection models using whole genome sequence data and functional annotation in Belgian Blue cattle.Genetics, selection, evolution : GSE · 2025Article
- Impacts of limits to adaptation on population and community persistence in a changing environment.Philosophical transactions of the Royal Society of London. Series B, Biological sciences · 2025Review
- Integrative genetic and epigenetic control of skeletal muscle fiber traits in agricultural animals.Frontiers in genetics · 2025Review
- Evolutionary consequences of domestication on the selective effects of new amino acid changing mutations in canids.bioRxiv : the preprint server for biology · 2024Article
- Life history in Caenorhabditis elegans: from molecular genetics to evolutionary ecology.Genetics · 2024Review
77 more citing papers are in PubMed but not listed here.
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Abstract
A model is investigated in which mutations that affect a complex trait (e.g., heart disease) also affect fitness because the trait is a component of fitness or because the mutations have pleiotropic effects on fitness. The model predicts that the genetic variance, and hence the heritability, in the trait is contributed by mutations at low frequency in the population, unless the mean strength of selection of mutations that affect the trait is very small or weakly selected mutations tend to contribute disproportionately to the trait compared with strongly selected mutations. Furthermore, it is shown that each rare mutation tends to contribute more to the variance than each common mutation. These results may explain why most genome-wide association studies have failed to find associations that explain much of the variance. It is also shown that most of the variance in fitness contributed by new nonsynonymous mutations is caused by mutations at very low frequency in the population. This implies that most low-frequency SNPs, which are observed in current resequencing studies of, for example, 100 chromosomes, probably have little impact on the variance in fitness or traits. Finally, it is shown that the variance contributed by a category of mutations (e.g., coding or regulatory) depends largely upon the mean strength of selection; this has implications for understanding which types of mutations are likely to be responsible for the variance in fitness and inherited disease.
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