Genotype-Specific Recurrence Risks as Indicators of the Genetic Architecture of Complex Diseases
Open accessAbstract
A statistic is introduced that relates discoveries made in genome-wide association (GWA) studies to patterns of disease risks among relatives. The genotype-specific recurrence risk (GSR) is the genotype-specific risk to relatives of known relationship to affected probands. The GSRs can be used for three purposes. (1) They can provide an independent test of whether an allele identified in a GWA study is associated with the disease. (2) They can provide a test of whether interactions among loci affecting the disease are multiplicative. (3) They can be used by genetic counselors to incorporate information from GWA studies for predicting the risk to relatives of known genotype. Under a multiplicative model of disease causation, the GSRs for a locus are the genotypic risks in probands for that locus multiplied by lambda(R)/lambda(jR), where lambda(R) is Risch's recurrence risk ratio and lambda(jR) is the contribution to lambda(R) from the locus of interest. If there is saturation of risk with increasing numbers of causative alleles, then observed GSRs for individuals with high-risk genotypes will be lower than predicted by the multiplicative model.
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The rare allele model must explain population association data and fit demographic distributions within and among families, and there is little theory supporting that it can do both.
“Nevertheless, the rare allele model must not only explain association data in populations, but also fit demographic distributions of disease within and among families, and there is little theory supporting the claim that they can do both55–57.”
From Rare and common variants: twenty arguments (2012) · cites this paper as [56]
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Rare and common variants: twenty arguments
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- Authors
- Slatkin, M.
- Affiliations
- University of California, Berkeley (US)
- Corresponding author
- Slatkin, Montgomery
- ORCID
- Slatkin, Montgomery
- Venue
- The American Journal of Human Genetics
- Publisher
- Elsevier BV
- Published
- 2008-07
- Volume
- 83
- Issue
- 1
- Pages
- 120-126
- ISSN
- 0002-9297 (ISSN-L)
- PMC
- PMC2443843
- OpenAlex
- W2152781144
- Cited by
- 9
- References
- 13
- Citations by year
- 2018: 1 · 2014: 1 · 2013: 1 · 2012: 2
- FWCI
- 0.75
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- The American Journal of Human Genetics (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of General Medical Sciences (R01GM040282)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Mapping and Diversity in Plants and Animals
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and phenotypic traits in livestock
- Keywords
- genome-wide association study, genetic counseling
- MeSH terms
- Aged, Aged, 80 and over, Alleles, Chromosome Mapping, Chromosomes, Human, Pair 10, Computer Simulation, Gene Frequency, Genes, Genetics, Population, Genotype, Humans, Macular Degeneration, Mathematics, Models, Genetic, Netherlands, Recurrence, Risk, Prevalence, Case-Control Studies, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Siblings
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