Cited by 1,126Genetic Associations and EpidemiologyGenetic Mapping and Diversity in Plants and AnimalsGenetic and phenotypic traits in livestock

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A General Test of Association for Quantitative Traits in Nuclear Families

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Abecasis, G.R., Cardon, L.R., Cookson, W.O.C.·2000·The American Journal of Human Genetics

DOI 10.1086/302698PMC PMC1288332

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Abstract

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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Result
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Method
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BackgroundMethod
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Method
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BackgroundMethod
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MethodInfluential
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MethodInfluential
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“The associations between either single SNPs or SLC4A5 haplotypes and hemodynamic and metabolic phenotypes were analyzed using a variance components and likelihood ratio test based procedure in the QTDT software package 17 with details elsewhere 18.”
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Yokley, J. L., Prasad, K. M. R., Chowdari, K. V., Talkowski, M. E., Wood, J. A., Gur, R. C., Gur, R. E., Almasy, L. A., Nimgaonkar, V. L., & Pogue‐Geile, M. F. (2011) · Psychiatric Genetics · doi:10.1097/ypg.0b013e32834f352c · Cited by 25
“SNPs were tested for association with a trait (e.g. cognitive performance or affected status) by the quantitative trait linkage disequilibrium test (QTLD) (Havill et al., 2005), unless there was evidence of significant (Pr 0.05) stratification, in which case, the quantitative transmission disequilibrium test (QTDT) (A…”
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“…values of all individuals for the 335 PCs. Heritabilities were estimated for the PCs generated from data set a, using Quantitative Trait Disequilibrium Test (QTDT), which partitions variance components attributed to additive genetic, environmental, or common family variance (Abecasis et al. 2000).”
BackgroundMethod
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McCrea, S. M. (2008) · Neuropsychiatric Disease and Treatment · doi:10.2147/ndt.s4329 · Cited by 26
CETP genotypes and HDL-cholesterol phenotypes in the HERITAGE Family Study
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“The total association model of the QTDT software utilizes a variance-components framework to combine a phenotypic means model and the estimates of additive genetic, residual genetic, and residual environmental variances from a variance-covariance matrix into a single likelihood model (1).”
Method
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“However, rather than modeling allelic effects based on allelic transmission, we tested the overall additive genetic effect of each polymorphism.(23,24) The presence of a statistical interaction between D4 receptor genotypes and age for diastolic and systolic BP was determined through a general linear model in SPSS 10.”
Method
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“We evaluated the withinand between-family components by phenotypic variability, using the orthogonal model as implemented by Abecasis, Cardon, and Cookson (17) in the QTDT software (version 2.3; http://www.sph. umich.edu/csg/abecasis/QTDT).”
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“…0.052 0.049 0.051 0.051 REC 0.805 0.565 0.067 0.564 0.722 0.750 – 0.766 – 0.572 0.566 ADD 0.563 0.802 0.565 0.802 0.745 0.750 0.753 0.767 0.767 0.814 0.804 DOM 0.063 0.562 0.802 0.562 0.721 – 0.751 – 0.765 0.571 0.563 †the likelihood-based QTDT/orthogonal model proposed by Abecasis et al. (2000).”
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Variation in IL-1β gene expression is a major determinant of genetic differences in arthritis aggressivity in mice
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“A qTDT was performed to correct the rate of malaria episodes for family-based ethnic bias (36).”
Method
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“Combined association and linkage analyses of quantitative traits were carried out using the FBAT program and the QTDT program [32,36].”
Method
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Chen, C., Wickenheisser, J. K., Ewens, K. G., Ankener, W., Legro, R. S., Dunaif, A. E., McAllister, J. M., Spielman, R. S., & Strauss, J. F. (2009) · Molecular Human Reproduction · doi:10.1093/molehr/gap035 · Cited by 24
“The quantitative TDT (QTDT version 2.4.6; Abecasis et al., 2000) was used to test for association of the SNPs in PDE8A with PCOS-related”
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“We used the Quantitative Transmission Disequilibrium Test (QTDT) software package (15) with the polygenic variance component option and performed association analyses of quantitative traits with the total association model assuming no population stratification.”
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“…(TDT) to quantitative traits, was conducted to further evaluate the association between the SNP marker and the phenotype data using the nuclear families since the QTDT was developed to access association in the presence of linkage signal without increasing type I error rate (Abecasis et al., 2000).”
Comprehensive association analysis of APOE regulatory region polymorphisms in Alzheimer disease
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“To assess the effect of the APOE region SNPs on AAO in the families, we used the variance components method implemented in the QTDT package [30].”
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“An orthogonal model in the QTDT analyses [20] decomposes the genotype score into orthogonal between-family (bb) and withinfamily (bw) components.”
Method
Quantitative Similarity-Based Association Tests Using Population Samples
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“This approach has been extended to nuclear families (Abecasis et al. 2000) and general sibship data (Sham et al.”
Background
Two Adaptive Weighting Methods to Test for Rare Variant Associations in Family‐Based Designs
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“We can decompose the children’s genotype score xi j ( j > 2) into between-family x̄i = (xi1 + xi2) /2 and withinfamily xwi j = xi( j+2) − x̄i components [Abecasis et al., 2000].”
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“edu/csg/ abecasis/QTDT), which is based on a variance-components framework [16].”
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“2007) in unrelated individuals and QTDT for families (Abecasis et al. 2000), modelling for an additive effect unless otherwise specified.”
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“Associations between the three SNPs and the traits were investigated in QTDT using the test that models total association with sex included as a fixed effect [Abecasis et al., 2000].”
Method
A nonsynonymous SNP within PCDH15 is associated with lipid traits in familial combined hyperlipidemia
Huertas‐Vázquez, A., Plaisier, C. L., Geng, R., Haas, B. E., Lee, J., van Greevenbroek, M. M. J., Kallen, C., de Bruin, T. W., Taskinen, M., Alagramam, K. N., et al. (2009) · Human Genetics · doi:10.1007/s00439-009-0749-z · Cited by 23
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Method
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Method
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Method
Correcting for relatedness in Bayesian models for genomic data association analysis
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Liao, S., Lin, S., Liu, C., Hsieh, M. H., Hwang, T., Liu, S., Guo, S., Hwu, H., & Chen, W. J. (2008) · Genes Brain & Behavior · doi:10.1111/j.1601-183x.2008.00467.x · Cited by 22
“Next, the WCST or CPT performance scores were treated as quantitative traits and their relations with the COMT SNPs were evaluated using software QTDT V2.4.6 ( Abecasis et al. 2000a, b).”
MethodInfluential

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)
DOI: 10.1086/302698
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: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 4948 d)
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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A General Test of Association for Quantitative Traits in Nuclear Families

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