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A General Test of Association for Quantitative Traits in Nuclear Families
Open accessAbstract
High-resolution mapping is an important step in the identification of complex disease genes. In outbred populations, linkage disequilibrium is expected to operate over short distances and could provide a powerful fine-mapping tool. Here we build on recently developed methods for linkage-disequilibrium mapping of quantitative traits to construct a general approach that can accommodate nuclear families of any size, with or without parental information. Variance components are used to construct a test that utilizes information from all available offspring but that is not biased in the presence of linkage or familiality. A permutation test is described for situations in which maximum-likelihood estimates of the variance components are biased. Simulation studies are used to investigate power and error rates of this approach and to highlight situations in which violations of multivariate normality assumptions warrant the permutation test. The relationship between power and the level of linkage disequilibrium for this test suggests that the method is well suited to the analysis of dense maps. The relationship between power and family structure is investigated, and these results are applicable to study design in complex disease, especially for late-onset conditions for which parents are usually not available. When parental genotypes are available, power does not depend greatly on the number of offspring in each family. Power decreases when parental genotypes are not available, but the loss in power is negligible when four or more offspring per family are genotyped. Finally, it is shown that, when siblings are available, the total number of genotypes required in order to achieve comparable power is smaller if parents are not genotyped.
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“Within-family genetic association estimates, such as those obtained from samples of siblings, can provide less biased estimates of direct genetic effects because they are unlikely to be affected by demographic and indirect genetic effects of parents7,17,30–34.”
From Within-sibship genome-wide association analyses decrease bias in estimates of direct genetic effects (2022) · cites this paper as [31]
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A Powerful and Flexible Multilocus Association Test for Quantitative Traits
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Genetics of human gene expression: mapping DNA variants that influence gene expression
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“Marker-trait association was assessed using the “totalassociation” option of the package QTDT (Abecasis et al. 2000).”
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“The orthogonal model (OM) (31), which applies to general pedigrees, was used to test allelic association between each SNP and age-at-onset.”
MethodSCAN: SNP and copy number annotation
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Investigation of Dyslexia and SLI Risk Variants in Reading- and Language-Impaired Subjects
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“Since each cohort applied different measures of language and reading ability, the QTDT tests were performed independently within the SLI and dyslexia families.”
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“This approach is analagous to permutation strategies for TDT-like tests for testing the null hypothesis of no association [McIntyre et al., 2000; Abecasis et al., 2000b].”
MethodFilaggrin Mutations in Children with Severe Atopic Dermatitis
Morar, N., Cookson, W., Harper, J. I., & Moffatt, M. F. (2007) · Journal of Investigative Dermatology · doi:10.1038/sj.jid.5700739 · Cited by 220
Self-citationGenetic Advances in the Study of Speech and Language Disorders
Newbury, D. F., & Monaco, A. P. (2010) · Neuron · doi:10.1016/j.neuron.2010.10.001 · Cited by 231
“However, it is possible to apply such methods to genetic data collected from families by using parents or unaffected siblings as controls (Lunetta et al., 2000) or by applying quasi-association extensions (Abecasis et al., 2000).”
Genetic analysis of radiation-induced changes in human gene expression
Smirnov, D., Morley, M., Shin, E., Spielman, R., & Cheung, V. (2009) · Nature · doi:10.1038/nature07940 · Cited by 221
FOXP2 Is Not a Major Susceptibility Gene for Autism or Specific Language Impairment
Newbury, D. F., Bonora, E., Lamb, J. A., Fisher, S. E., Lai, C. S. L., Baird, G., Jannoun, L., Slonims, V., Stott, C., Merricks, M. J., et al. (2002) · The American Journal of Human Genetics · doi:10.1086/339931 · Cited by 223
Willis‐Owen, S. A. G., Turri, M. G., Munafo, M. R., Surtees, P. G., Wainwright, N. W. J., Brixey, R. D., & Flint, J. (2005) · Biological Psychiatry · doi:10.1016/j.biopsych.2005.04.050 · Cited by 212
Methods for Handling Multiple Testing
Rice, T., Schork, N. J., & Rao, D. C. (2008) · Advances in genetics · doi:10.1016/s0065-2660(07)00412-9 · Cited by 202
Addington, A. M., Gornick, M., Duckworth, J., Sporn, A. L., Gogtay, N., Bobb, A., GREENSTEIN, D. K., Lenane, M., Gochman, P., Baker, N., et al. (2004) · Molecular Psychiatry · doi:10.1038/sj.mp.4001599 · Cited by 207
GWAS of epigenetic aging rates in blood reveals a critical role for TERT
Lu, A. T.-H., Xue, L., Salfati, E., Chen, B. H., Ferrucci, L., Levy, D. A., Joehanes, R., Murabito, J. M., Kiel, D. P., Tsai, P.-C., et al. (2018) · Nature Communications · doi:10.1038/s41467-017-02697-5 · Cited by 208
Hammond, C. J., Andrew, T., Mak, Y. T., & Spector, T. D. (2004) · The American Journal of Human Genetics · doi:10.1086/423148 · Cited by 202
Sobel, E. M., Sengul, H., & Weeks, D. E. (2001) · Human Heredity · doi:10.1159/000053366 · Cited by 201
“For example, the quantitative analysis package QTDT [30] reads in the results of a SimWalk2 MPMC IBD analysis as a prelude to its main computations.”
MethodGenetic variation in the 22q11 locus and susceptibility to schizophrenia
Liu, H., Abecasis, G. R., Heath, S. C., Knowles, A., Demars, S., Chen, Y., Roos, J. L., Rapoport, J. L., Gogos, J. A., & Karayiorgou, M. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.232186099 · Cited by 201
Self-citationEvaluation of Genetic Variation Contributing to Differences in Gene Expression between Populations
Zhang, W., Duan, S., Kistner, E. O., Bleibel, W. K., Huang, R. S., Clark, T. A., Chen, T. X., Schweitzer, A. C., Blume, J. E., Cox, N. J., et al. (2008) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2007.12.015 · Cited by 201
Seshadri, S. S., DeStefano, A. L., Au, R., Massaro, J. M., Beiser, A., Kelly‐Hayes, M., Kase, C. S., D’Agostino, R. B., DeCarli, C. S., Atwood, L. D., et al. (2007) · BMC Medical Genetics · doi:10.1186/1471-2350-8-s1-s15 · Cited by 201
“For the linkage analyses, we used Merlin software to compute multipoint identity-by-descent utilizing 10,592 informative SNPs and 613 short tandem repeats selected to minimize LD [29,30]; we then used maximum variance component analyses in SOLAR to compute LOD scores as a measure of linkage [31].”
A multivariate family-based association test using generalized estimating equations: FBAT-GEE
Lange, C. (2003) · Biostatistics · doi:10.1093/biostatistics/4.2.195 · Cited by 198
Huang, R. S., Duan, S., Bleibel, W. K., Kistner, E. O., Zhang, W., Clark, T. A., Chen, T. X., Schweitzer, A. C., Blume, J. E., Cox, N. J., et al. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0703736104 · Cited by 197
Support for involvement of neuregulin 1 in schizophrenia pathophysiology
Petryshen, T. L., Middleton, F. A., Kirby, A. W., Aldinger, K. A., Purcell, S., Tahl, A. R., Morley, C. P., McGann, L., Gentile, K. L., Rockwell, G. N., et al. (2004) · Molecular Psychiatry · doi:10.1038/sj.mp.4001608 · Cited by 196
Tepper, B. J., Koelliker, Y., Zhao, L., Ullrich, N. V., Lanzara, C., D’Adamo, P., Ferrara, A., Ulivi, S., Esposito, L., & Gasparini, P. (2008) · Obesity · doi:10.1038/oby.2008.357 · Cited by 194
MacGregor, S., Lind, P. A., Bucholz, K. K., Hansell, N. K., Madden, P. A. F., Richter, M. M., Montgomery, G. W., Martin, N. G., Heath, A. C., & Whitfield, J. B. (2008) · Human Molecular Genetics · doi:10.1093/hmg/ddn372 · Cited by 194
“Secondary analyses robust to population stratification were conducted using the orthogonal ‘within’ test in QTDT.”
MethodCorrelated genotypes in friendship networks
Fowler, J. H., Settle, J. E., & Christakis, N. A. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1011687108 · Cited by 188
Loss-of-function variants in endothelial lipase are a cause of elevated HDL cholesterol in humans
Edmondson, A. C., Brown, R., Kathiresan, S., Cupples, L. A., Demissie, S., Manning, A. K., Jensen, M. K., Rimm, E. B., Wang, J., Rodrigues, A., et al. (2009) · Journal of Clinical Investigation · doi:10.1172/jci37176 · Cited by 194
“The QTDT (55, 56) was used to test association of LIPG variants with”
MethodInfluentialGenomics and Genetics in the Biology of Adaptation to Exercise
Bouchard, C., Rankinen, T., & Timmons, J. A. (2011) · Comprehensive physiology · doi:10.1002/cphy.c100059 · Cited by 222
“The TDT models were later extended to families with multiple offspring and to quantitative traits (1, 254).”
CMIP and ATP2C2 Modulate Phonological Short-Term Memory in Language Impairment
Newbury, D. F., Winchester, L. M., Addis, L., Paracchini, S., Buckingham, L.-L., Clark, A., Cohen, W., Cowie, H., Dworzynski, K., Everitt, A., et al. (2009) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2009.07.004 · Cited by 188
“Our principal analysis involved the variance-components modeling of 28-item nonword repetition scores(8) within 211 SLIC families (ao option) as a quantitative trait and was performed within QTDT.(19) In”
MethodInfluentialMorales, F., Couto, J. M., Higham, C. F., Hogg, G., Cuenca, P., Braida, C., Wilson, R. H., Adam, B., Valle, G. D., Brian, R., et al. (2012) · Human Molecular Genetics · doi:10.1093/hmg/dds185 · Cited by 181
“Genetic correlations and heritability estimates were acquired using QTDT, a general test package for the association of quantitative measures in nuclear families (34).”
G enetic F actors in E xternal A pical R oot R esorption and O rthodontic T reatment
Hartsfield, J. K., Everett, E. T., & Al-Qawasmi, R. A. (2004) · Critical Reviews in Oral Biology & Medicine · doi:10.1177/154411130401500205 · Cited by 177
Noguchi, E., Nishimura, F., Fukai, H., Kim, J. K., Ichikawa, K., Shibasaki, M., & Arinami, T. (2004) · Clinical & Experimental Allergy · doi:10.1111/j.1365-2222.2004.01839.x · Cited by 176
Al-Qawasmi, R. A., Hartsfield, J. K., Everett, E. T., Wetherill, L. F., Liu, L., Foroud, T., Macri, J. V., & Roberts, W. E. (2003) · Journal of Dental Research · doi:10.1177/154405910308200506 · Cited by 172
“Second, we evaluated evidence of linkage disequilibrium for TNSALP and TNFa using the quantitative transmission disequilibrium test (Q-TDT) as implemented in the program QTDT (Abecasis et al., 2000).”
MethodRNA-Seq Identifies SNP Markers for Growth Traits in Rainbow Trout
Salem, M., Vallejo, R. L., Leeds, T. D., Palti, Y., Liu, S., Sabbagh, A., Rexroad, C. E., & Yao, J. (2012) · PLoS ONE · doi:10.1371/journal.pone.0036264 · Cited by 170
“Family-based association analysis methods were used to detect association signals that are robust to population stratification [21].”
BackgroundMethodInfluentialVariants in TF and HFE Explain ∼40% of Genetic Variation in Serum-Transferrin Levels
Benyamin, B., McRae, A. F., Zhu, G., Gordon, S. D., Henders, A. K., Palotie, A. V., Peltonen, L., Martin, N. G., Montgomery, G. W., Whitfield, J. B., et al. (2008) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2008.11.011 · Cited by 167
5′ Flanking Variants of Resistin Are Associated With Obesity
Engert, J. C., Vohl, M., Williams, S. M., Lepage, P., Loredo‐Osti, J., Faith, J., Doré, C., Renaud, Y., Burtt, N. P., Villeneuve, A., et al. (2002) · Diabetes · doi:10.2337/diabetes.51.5.1629 · Cited by 169
Metadata
- Authors
- Abecasis, G. R., Cardon, L. R., & Cookson, W. O. C.
- Affiliations
- Centre for Human Genetics (GB)
- Corresponding author
- Abecasis, G.R.
- ORCID
- Abecasis, G.R.
- Venue
- The American Journal of Human Genetics
- Publisher
- Elsevier BV
- Published
- 2000-01
- Volume
- 66
- Issue
- 1
- Pages
- 279-292
- ISSN
- 0002-9297 (ISSN-L)
- PMC
- PMC1288332
- OpenAlex
- W2078625752
- Cited by
- 1,126
- References
- 30
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 7 · 2023: 7 · 2022: 6 · 2021: 13 · 2020: 15 · 2019: 13 · 2018: 18 · 2017: 23 · 2016: 22 · 2015: 26 · 2014: 27 · 2013: 38 · 2012: 51
- FWCI
- 27.12
- 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
- Wellcome Trust
- 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
- association mapping, quantitative traits, nuclear family, variance components, permutation tests, fine mapping, power analysis, family structure, parental genotypes, multivariate normality, research design
- MeSH terms
- Genetics, Population, Humans, Models, Genetic, Nuclear Family, Linkage Disequilibrium, Quantitative Trait, Heritable
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