ArticleAmerican journal of human genetics2001
Are rare variants responsible for susceptibility to complex diseases?
Article in American journal of human genetics, 2001. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 507 papers, 2 of them syntheses that pooled it.
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Who cites it
507 citing papers in PubMed, 2 syntheses or guidelines pooled it.
- Correcting for Genomic Inflation Leads to Loss of Power in Large-Scale Genome-Wide Association Study Meta-Analysis.Genetic epidemiology · 2025Pooled it
- Exome Sequencing of Familial Bipolar Disorder.JAMA psychiatry · 2016Pooled it
- Exome sequencing-based identification of novel type 2 diabetes risk allele loci in the Qatari population.PloS one · 2018Trial
- Implementation of genome-wide complex trait analysis to quantify the heritability in multiple myeloma.Scientific reports · 2015Trial
- 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
- NATURAL VARIATION IN RADIOTOLERANCE IS ASSOCIATED WITH DIFFERENCES IN INNATE IMMUNE ACTIVITY AND S-PHASE TRANSCRIPTION IN DROSOPHILA MELANOGASTER.bioRxiv : the preprint server for biology · 2026Article
- Polygenic backgrounds influence phenotypic consequences of variants in cells, individuals, and populations.Cell genomics · 2026Review
- Leveraging ancestral recombination graphs for scalable mixed-model analysis of complex traits.Cell genomics · 2026Article
- Leveraging low-cost short-read sequencing: revolutionizing complex trait genetics.Molecular biology and evolution · 2026Article
- A new perspective on population genetics: Deciphering the relationship between genetic variants and disease prevalence in Psoriasis.PloS one · 2026Article
- Article
- Forward and reverse genomic screens enhance the understanding of phenotypic variation in a large Chinese rhesus macaque cohort.Nature communications · 2025Article
- Truncated variant rs373056577 confers increased risk of type 2 diabetes and missense variant rs121912717 is associated with hypertriglyceridemia in Bangladeshi population.Metabolism open · 2025Article
- Article
- The Abundance of Harmful Rare Homozygous Variants in Children of Consanguineous Parents.Biology · 2025Article
- Germline predisposition in multiple myeloma.iScience · 2025Article
- Winner's curse in rare variant analysis: effect size estimation bias depends on effect direction and the association method used.Frontiers in genetics · 2025Article
- Prequalification of genome-based newborn screening for severe childhood genetic diseases through federated training based on purifying hyperselection.American journal of human genetics · 2024Article
- Too big to purge: persistence of deleterious Mutations in Island populations of the European Barn Owl (Tyto alba).Heredity · 2024Article
447 more citing papers are in PubMed but not listed here.
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Abstract
Little is known about the nature of genetic variation underlying complex diseases in humans. One popular view proposes that mapping efforts should focus on identification of susceptibility mutations that are relatively old and at high frequency. It is generally assumed-at least for modeling purposes-that selection against complex disease mutations is so weak that it can be ignored. In this article, I propose an explicit model for the evolution of complex disease loci, incorporating mutation, random genetic drift, and the possibility of purifying selection against susceptibility mutations. I show that, for the most plausible range of mutation rates, neutral susceptibility alleles are unlikely to be at intermediate frequencies and contribute little to the overall genetic variance for the disease. Instead, it seems likely that the bulk of genetic variance underlying diseases is due to loci where susceptibility mutations are mildly deleterious and where there is a high overall mutation rate to the susceptible class. At such loci, the total frequency of susceptibility mutations may be quite high, but there is likely to be extensive allelic heterogeneity at many of these loci. I discuss some practical implications of these results for gene mapping efforts.
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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.