Implications of multilocus inheritance for gene-disease association studies
Abstract
The impact of multilocus inheritance on the power of candidate gene association studies and the parameters derived therefrom is considered. Both case-control and family-based control designs are included. When the background heritability H (i.e., residual correlation) among sibs for the disease in question is high, the power of multiplex affected sibships versus singletons is diminished compared with the situation when background heritability is low. Thus, multiplex families for association studies are most advantageous for low heritability disorders. Estimates of genotype relative risk (GRR) are also distorted in multiplex sibships compared with singletons based on background heritability. In a case-control study, GRR is inflated in multiplex families, with the degree of inflation decreasing with background heritability. By contrast, in a TDT (parental control) study, GRR is deflated in multiplex families, with the degree of deflation increasing with background heritability (and no deflation when H is 0). Considering identical twins, the difference in genotype frequencies between concordant versus discordant MZ twin pairs for the candidate gene is large when the heritability is low, but modest when the heritability is high.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
An excess of multiplex families relative to population frequencies could substantially diminish the estimated Vm.
“Various factors could skew this distribution and thus bias downwards the estimated Vm, a notable one being an excess of multiplex families relative to population frequencies (35,36).”
From Individual common variants exert weak effects on the risk for autism spectrum disorders (2012) · cites this paper as [35]
Cites
Initial sequencing and analysis of the human genome
International Human Genome Sequencing Consortium, Whitehead Institute for Biomedical Research, C. F. G. R., Lander, E. S., Linton, L. M., Birren, B., Nusbaum, C., Zody, M. C., Baldwin, J., Devon, K., Dewar, K., et al. (2001) · Nature · doi:10.1038/35057062 · Cited by 24,216 · see citing works
The sequence of the human genome
Venter, J. C., Adams, M. D., Myers, E. W., Li, P. W., Mural, R. J., Sutton, G. G., Smith, H. O., Yandell, M., Evans, C. A., Holt, R. A., et al. (2001) · Science · doi:10.1126/science.1058040 · Cited by 13,909 · see citing works
The Future of Genetic Studies of Complex Human Diseases
Risch, N., & Merikangas, K. (1996) · Science · doi:10.1126/science.273.5281.1516 · Cited by 5,355 · see citing works
Self-citationSpielman, R. S., McGinnis, R. E., & Ewens, W. J. (1993) · PubMed · Cited by 3,679 · see citing works
Prospects for whole-genome linkage disequilibrium mapping of common disease genes
Kruglyak, L. (1999) · Nature Genetics · doi:10.1038/9642 · Cited by 1,416 · see citing works
The New Genomics: Global Views of Biology
Lander, E. S. (1996) · Science · doi:10.1126/science.274.5287.536 · Cited by 1,174 · see citing works
Variations on a Theme: Cataloging Human DNA Sequence Variation
Collins, F. S., Guyer, M. S., & Chakravarti, A. (1997) · Science · doi:10.1126/science.278.5343.1580 · Cited by 1,062 · see citing works
Fundamentals of Genetic Epidemiology
Khoury, M. J., Beaty, T. H., & Cohen, B. H. (1993) · doi:10.1093/oso/9780195052886.001.0001 · Cited by 699 · see citing works
Wacholder, S. (2000) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/92.14.1151 · Cited by 442 · see citing works
Population choice in mapping genes for complex diseases
Wright, A., Carothers, A., & Pirastu, M. (1999) · Nature Genetics · doi:10.1038/70501 · Cited by 377 · see citing works
Risch, N., & Teng, J. (1998) · Genome Research · doi:10.1101/gr.8.12.1273 · Cited by 366 · see citing works
Self-citationGenotype relative risks: methods for design and analysis of candidate-gene association studies.
Schaid, D. J., & Sommer, S. S. (1993) · PubMed · Cited by 292 · see citing works
Demographic history and linkage disequilibrium in human populations
Laan, M., & Pääbo, S. (1997) · Nature Genetics · doi:10.1038/ng1297-435 · Cited by 199 · see citing works
Teng, J., & RISCH, N. J. (1999) · Genome Research · doi:10.1101/gr.9.3.234 · Cited by 123 · see citing works
Self-citationFundamentals of Genetic Epidemiology
Bishop, D. T. (1994) · Journal of Medical Genetics · doi:10.1136/jmg.31.11.900 · Cited by 92 · see citing works
Allelic association between marker loci.
Lonjou, C., Collins, A., & Morton, N. (1999) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.96.4.1621 · Cited by 67 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Common genetic variants, acting additively, are a major source of risk for autism
Klei, L., Sanders, S. J., Murtha, M. T., Hus, V., Lowe, J. K., Willsey, A. J., Moreno-De-Luca, D., Yu, T. W., Fombonne, E., Geschwind, D., et al. (2012) · Molecular Autism · doi:10.1186/2040-2392-3-9 · Cited by 418 · see citing works
A genetic variant that disrupts <i>MET</i> transcription is associated with autism
Campbell, D. B., Sutcliffe, J. S., Ebert, P. J., Militerni, R., Bravaccio, C., Trillo, S., Elia, M., Schneider, C., Melmed, R., Sacco, R., et al. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0605296103 · Cited by 401 · see citing works
Individual common variants exert weak effects on the risk for autism spectrum disorders
Anney, R., Klei, L., Pinto, D., Almeida, J., Bacchelli, E., Baird, G., Bolshakova, N., Bölte, S., Bolton, P. F., Bourgeron, T., et al. (2012) · Human Molecular Genetics · doi:10.1093/hmg/dds301 · Cited by 375 · see citing works
Conley, Y. P., Jakobsdottir, J., Mah, T., Weeks, D. E., Klein, R., Kuller, L., Ferrell, R. E., & Gorin, M. B. (2006) · Human Molecular Genetics · doi:10.1093/hmg/ddl396 · Cited by 157 · see citing works
Epi4K: Gene discovery in 4,000 genomes
The Epi4K Consortium (2012) · Epilepsia · doi:10.1111/j.1528-1167.2012.03511.x · Cited by 85 · see citing works
Peyrot, W. J., Boomsma, D. I., Penninx, B. W. J. H., & Wray, N. R. (2016) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2015.12.017 · Cited by 42 · see citing works
A new synaptic player leading to autism risk: Met receptor tyrosine kinase
Judson, M. C., Eagleson, K. L., & Levitt, P. (2011) · Journal of Neurodevelopmental Disorders · doi:10.1007/s11689-011-9081-8 · Cited by 43 · see citing works
Ferreira, M. A. R., Sham, P., Daly, M. J., & Purcell, S. (2007) · Behavior Genetics · doi:10.1007/s10519-007-9149-0 · Cited by 15 · see citing works
- Authors
- Risch, N.
- Affiliations
- Kaiser Permanente (US)
- Corresponding author
- Risch, Neil
- ORCID
- Risch, Neil
- Venue
- Theoretical Population Biology
- Publisher
- Elsevier BV
- Published
- 2001-11
- Volume
- 60
- Issue
- 3
- Pages
- 215-220
- ISSN
- 0040-5809 (ISSN-L)
- OpenAlex
- W2006356781
- Cited by
- 52
- References
- 16
- Citations by year
- 2018: 1 · 2017: 2 · 2016: 2 · 2015: 1 · 2013: 1 · 2012: 4
- FWCI
- 1.99
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Theoretical Population Biology (publishedVersion)
- PubMed (publishedVersion)
- 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 diversity and population structure
- Keywords
- gene-disease association, candidate gene association, statistical power, genotype relative risk, case-control study, transmission disequilibrium test, monozygotic twin concordance
- MeSH terms
- Alleles, Chromosome Mapping, Genetic Markers, Genotype, Humans, Genetic Linkage, Models, Genetic, Pedigree, Risk, Genetic Predisposition to Disease
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
