Abstract
Linkage disequilibrium (LD) plays a central role in current and proposed methods for mapping complex disease genes. LD-based methods work best when there is a single susceptibility allele at any given disease locus, and generally perform very poorly if there is substantial allelic heterogeneity. The extent of allelic heterogeneity at typical complex disease loci is not yet known, but predictions about allelic heterogeneity have important implications for the design of future mapping studies, including the proposed genome-wide association studies. In this article, we review the available data and models relating to the number and frequencies of susceptibility alleles at complex disease loci-the 'allelic architecture' of human disease genes. We also show that the predicted frequency spectrum of disease variants at a gene depends crucially on the method of ascertainment, for example from prior linkage scans or from surveys of functional candidate loci.
Keywords
BiologyGeneticsAlleleLinkage disequilibriumLocus (genetics)Allelic heterogeneityGenetic associationGeneGenetic architectureAllele frequencyDiseaseGenetic linkageHuman genomeGenomeSingle-nucleotide polymorphismGenotypeHaplotypeQuantitative trait locus
Affiliated Institutions
Related Publications
Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls
There is increasing evidence that genome-wide association (GWA) studies represent a powerful approach to the identification of genes involved in common human diseases. We descri...
Genetic Dissection of Transcriptional Regulation in Budding Yeast
To begin to understand the genetic architecture of natural variation in gene expression, we carried out genetic linkage analysis of genomewide expression patterns in a cross bet...
On the inference of ancestries in admixed populations
Inference of ancestral information in recently admixed populations, in which every individual is composed of a mixed ancestry (e.g., African Americans in the United States), is ...
Worldwide Human Relationships Inferred from Genome-Wide Patterns of Variation
Human genetic diversity is shaped by both demographic and biological factors and has fundamental implications for understanding the genetic basis of diseases. We studied 938 unr...
The Genotype-Tissue Expression (GTEx) project.
Genome-wide association studies have identified thousands of loci for common diseases, but, for the majority of these, the mechanisms underlying disease susceptibility remain un...
Publication Info
- Year
- 2002
- Type
- review
- Volume
- 11
- Issue
- 20
- Pages
- 2417-2423
- Citations
- 712
- Access
- Closed
External Links
Social Impact
Altmetric
PlumX Metrics
Social media, news, blog, policy document mentions
Citation Metrics
712
OpenAlex
Cite This
Jonathan K. Pritchard
(2002).
The allelic architecture of human disease genes: common disease-common variant... or not?.
Human Molecular Genetics
, 11
(20)
, 2417-2423.
https://doi.org/10.1093/hmg/11.20.2417
Identifiers
- DOI
- 10.1093/hmg/11.20.2417