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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Haberstick, B. C., Smolen, A., & Hewitt, J. K. (2006) · Biological Psychiatry · doi:10.1016/j.biopsych.2005.10.008 · Cited by 112
Evolutionary‐based association analysis using haplotype data
Seltman, H. J., Roeder, K., & Devlin, B. (2003) · Genetic Epidemiology · doi:10.1002/gepi.10246 · Cited by 111
“Incorporating Zir into the model reduces the chance of detecting spurious associations due to population substructure [see Abecasis et al., 2000].”
BackgroundMethodInfluential
What Is Familial About Familial Bipolar Disorder?
Schulze, T. G., Hedeker, D., Zandi, P. P., Rietschel, M., & McMahon, F. J. (2006) · Archives of General Psychiatry · doi:10.1001/archpsyc.63.12.1368 · Cited by 110
Genetic association mapping at the crossroads: Which test and why? Overview and practical guidelines
Schulze, T. G., & McMahon, F. J. (2001) · American Journal of Medical Genetics · doi:10.1002/ajmg.10042 · Cited by 110
“Comprehensive power analyses regarding the impact of missing parental information are given by Abecasis et al. [2000] as well as Monks and Kaplan [2000].”
BackgroundInfluential
BDNF gene effects on brain circuitry replicated in 455 twins
Chiang, M., Marina Barysheva, A., Toga, A. W., Medland, S. E., Hansell, N. K., James, M. R., McMahon, K. L., de Zubicaray, G. I., Martin, N. G., Wright, M. J., et al. (2010) · NeuroImage · doi:10.1016/j.neuroimage.2010.12.053 · Cited by 108
“The above association model was fitted using the maximumlikelihood method (Abecasis et al., 2000).”
Influential
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Addington, A. M., Gornick, M. C., Shaw, P., Seal, J., Gogtay, N., GREENSTEIN, D. K., CLASEN, L. S., Coffey, M., Gochman, P., Long, R. T. L., et al. (2006) · Molecular Psychiatry · doi:10.1038/sj.mp.4001906 · Cited by 110
Associations of HLA alleles with specific language impairment
Nudel, R., Simpson, N. H., Baird, G., O'Hare, A. E., Conti‐Ramsden, G., Bolton, P., Hennessy, E. R., Monaco, A. P., Knight, J. C., WINNEY, B. J., et al. (2014) · Journal of Neurodevelopmental Disorders · doi:10.1186/1866-1955-6-1 · Cited by 108
“Since the imputed HLA types were multi-allelic, quantitative transmission disequilibrium test (QTDT) [40] was used for the family-based quantitative association analyses of these data.”
The metabotropic glutamate receptor 8 gene at 7q31: partial duplication and possible association with autism
Serajee, F., Zhong, H., Nabi, R., & Huq, A. H. M. M. (2003) · Journal of Medical Genetics · doi:10.1136/jmg.40.4.e42 · Cited by 109
SNP Set Association Analysis for Familial Data
Schifano, E. D., Epstein, M. P., Bielak, L. F., Jhun, M. A., Kardia, S. L. R., Peyser, P. A., & Lin, X. (2012) · Genetic Epidemiology · doi:10.1002/gepi.21676 · Cited by 110
“Similar polygenic effects have been considered in the individual-SNP-based framework [Abecasis et al., 2000; Atkinson and Therneau, 2009], as well as in kernel-based regression for estimation and prediction [Gianola and van Kaam, 2008].”
Background
FTO and MC4R Gene Variants Are Associated with Obesity in Polycystic Ovary Syndrome
Ewens, K. G., Jones, M. R., Ankener, W., Stewart, D. R., Urbanek, M., Dunaif, A. E., Legro, R. S., Chua, A. K., Azziz, R., Spielman, R. S., et al. (2011) · PLoS ONE · doi:10.1371/journal.pone.0016390 · Cited by 105
“html [20]) and families with one or more Mendelian discrepancies for a marker were excluded in the analysis of that markerLinkage and association between SNPs and PCOS was tested with the TDT [21].”
Method
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de Maat, M. P. M., Bladbjerg, E., Hjelmborg, J., Bathum, L., Jespersen, J., & Christensen, K. (2004) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/01.atv.0000143856.01669.e7 · Cited by 104
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Baessler, A., Hasinoff, M. J., Fischer, M., Reinhard, W., Sonnenberg, G. E., Olivier, M., Erdmann, J., Schunkert, H., Doering, A., Jacob, H. J., et al. (2005) · Diabetes · doi:10.2337/diabetes.54.1.259 · Cited by 105
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“Marker-trait association was evaluated using the ‘‘total’’ association model with the QTDT package [30].”
Method
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Plomion, C., Bousquet, J., & Kole, C. (2011) · CRC Press eBooks · doi:10.1201/b11075 · Cited by 106
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Mill, J. S., Xu, X., Ronald, A., Curran, S. R., Price, T., Knight, J., Craig, I., Sham, P. C., Plomin, R. J., & Asherson, P. J. (2004) · American Journal of Medical Genetics Part B Neuropsychiatric Genetics · doi:10.1002/ajmg.b.30107 · Cited by 105
“First, the quantitative transmission disequilibrium test (QTDT) was used [Abecasis et al., 2000], which is available online at http://www.hgmp.mrc.ac. uk/Registered/Option/qtdt.html.”
Method
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Wedenoja, J., Loukola, A., Tuulio‐Henriksson, A., Paunio, T., Ekelund, J., Silander, K., Varilo, T., Heikkila, K. V., Suvisaari, J., Partonen, T., et al. (2007) · Molecular Psychiatry · doi:10.1038/sj.mp.4002047 · Cited by 102
“For the quantitative trait analysis, the QTDT softwar”
Method
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Knoblauch, H. (2004) · Human Molecular Genetics · doi:10.1093/hmg/ddh119 · Cited by 102
“The possibility of population admixture was tested by splitting the individual genotype into a between-family and a within-family component (19,20).”
Method
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Won, S., Morris, N. J., Lu, Q. L., & Elston, R. C. (2009) · Statistics in Medicine · doi:10.1002/sim.3569 · Cited by 101
“The methods for multi-phase analysis in genetic epidemiology, for example, have so far not considered the expected genetic effects [7–9, 13, 14], even though the optimal method of combining p-values depends on the magnitude of the genetic effects to be expected and theoretical investigations on detecting genetic assoc…”
MethodResult
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Kébir, O., Tabbane, K., Sengupta, S. M., & Joober, R. (2009) · Journal of Psychiatry and Neuroscience · doi:10.1139/jpn.0913 · Cited by 98
Comparing Linkage Disequilibrium-Based Methods for Fine Mapping Quantitative Trait Loci
Grapes, L., Dekkers, J. C. M., Rothschild, M. F., & Fernando, R. L. (2004) · Genetics · doi:10.1534/genetics.166.3.1561 · Cited by 100
Genomewide Linkage Analysis Identifies Polymorphism in the Human Interferon-γ Receptor Affecting Helicobacter pylori Infection
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“A quantitative transmission/disequilibrium test was performed with the QTDT program as described elsewhere (Abecasis et al. 2000).”
Method
Trans-ethnic fine mapping of a quantitative trait locus for circulating angiotensin I-converting enzyme (ACE)
McKenzie, C. A. (2001) · Human Molecular Genetics · doi:10.1093/hmg/10.10.1077 · Cited by 98
“Briefly, the phenotype model allows for fixed association effects, which are partitioned into a between- and within-family effect, as well as random effects, which are partitioned into environmental, polygenic and major locus linkage variances (27).”
Background
Identification of novel genes significantly affecting growth in catfish through GWAS analysis
Li, N., Zhou, T., Geng, X., Jin, Y., Wang, X., Liu, S., Xu, X., Gao, D., Li, Q., & Liu, Z. (2017) · Molecular Genetics and Genomics · doi:10.1007/s00438-017-1406-1 · Cited by 98
A Search for Variants Associated With Young-Onset Type 2 Diabetes in American Indians in a 100K Genotyping Array
Hanson, R. L., Bogardus, C., Duggan, D. J., Kobes, S., Knowlton, M., Infante, A. M., Marovich, L., Benitez, D. S., Baier, L. J., & Knowler, W. C. (2007) · Diabetes · doi:10.2337/db07-0462 · Cited by 98
On a semiparametric test to detect associations between quantitative traits and candidate genes using unrelated individuals
Zhang, S., Zhu, X., & Zhao, H. (2002) · Genetic Epidemiology · doi:10.1002/gepi.10196 · Cited by 98
“…orthogonal components, a between-family (b) component and a withinfamily (w) component, in the context of familybased association studies [Fulker et al., 1999; Abecasis et al., 2000; Sham et al., 2000], to study associations between candidate markers and traits of interest using population samples.”
BackgroundMethod
A Genome-Wide Search for Quantitative Trait Loci That Influence Antisocial Drug Dependence in Adolescence
Stallings, M. C., Corley, R. P., Dennehey, B. K., Hewitt, J. K., Krauter, K. S., Lessem, J. M., Mikulich‐Gilbertson, S. K., Rhee, S. H., Smolen, A., Young, S. E., et al. (2005) · Archives of General Psychiatry · doi:10.1001/archpsyc.62.9.1042 · Cited by 96
The 5-HT2A −1438G/A polymorphism in anorexia nervosa: a combined analysis of 316 trios from six European centres
Gorwood, P. A. P. M., Adès, J., Bellodi, L., Cellini, E., Collier, D. A., Bella, D. D., Bernardo, M., Estivill, X., Fernández‐Aranda, F., Gratacòs, M., et al. (2002) · Molecular Psychiatry · doi:10.1038/sj.mp.4000938 · Cited by 97
“19 and the related quantitative traits of minimum adult BMI, subtype of diagnosis, and age at onset, using the Q-TDT program”
Method
The Power to Detect Linkage Disequilibrium with Quantitative Traits in Selected Samples
Abecasis, G. R., Cookson, W., & Cardon, L. R. (2001) · The American Journal of Human Genetics · doi:10.1086/320590 · Cited by 99
“Under the null hypothesis of no linkage disequilibrium, , whereas under the b p 0 w alternative hypothesis, , the additive genetic value b p a w at the marker locus (Abecasis et al. 2000a).”
BackgroundMethodResultInfluentialSelf-citation
Overview of techniques to account for confounding due to population stratification and cryptic relatedness in genomic data association analyses
Sillanpää, M. J. (2010) · Heredity · doi:10.1038/hdy.2010.91 · Cited by 94
“TDT has been generalized to quantitative traits (Allison, 1997; Rabinowitz, 1997; Abecasis et al., 2000), multiallelic markers (Sham and Curtis, 1995), marker haplotypes (Clayton, 1999) and to several data structures (Spielman and Ewens, 1998; Abecasis et al., 2000).”
BackgroundMethod
A genome-wide search for quantitative trait loci influencing substance dependence vulnerability in adolescence
Stallings, M. C., Corley, R. P., Hewitt, J. K., Krauter, K. S., Lessem, J. M., Mikulich, S. K., Rhee, S. H., Smolen, A., Young, S. E., & Crowley, T. J. (2003) · Drug and Alcohol Dependence · doi:10.1016/s0376-8716(03)00031-0 · Cited by 94
“, 2001), PEDSTATS (Abecasis et al., 2000), MERLIN (Abecasis et al.”
Binge-eating episodes are not characteristic of carriers of melanocortin-4 receptor gene mutations
Hebebrand, J., Geller, F., Dempfle, A., Heinzel‐Gutenbrunner, M., Raab, M. S., Gerber, G., Wermter, A. ‐., Horro, F. F., Blundell, J. E., Schäfer, H., et al. (2004) · Molecular Psychiatry · doi:10.1038/sj.mp.4001491 · Cited by 96
Variance Component Methods for Analysis of Complex PhenotypesPreprint
Almasy, L. A., & Blangero, J. (2010) · Cold Spring Harbor Protocols · doi:10.1101/pdb.top77 · Cited by 96
“…due to population stratification by separating the genotype score for association with a marker into between- and within-family components and using only the within-family component for the test of association (Fulker et al. 1999; Abecasis et al. 2000a; Abecasis et al. 2000b; Siegmund et al. 2001).”
Method
Estimating effects of parents’ cognitive and non-cognitive skills on offspring education using polygenic scores
Demange, P., Hottenga, J., Abdellaoui, A., Eilertsen, E. M., Malanchini, M., Domingue, B. W., Armstrong‐Carter, E., de Zeeuw, E. L., Rimfeld, K., Boomsma, D. I., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-32003-x · Cited by 103
TCF7L2 Is Not a Major Susceptibility Gene for Type 2 Diabetes in Pima Indians
Guo, T., Hanson, R. L., Traurig, M. T., Muller, Y. L., Ma, L., Mack, J. L., Kobes, S., Knowler, W. C., Bogardus, C., & Baier, L. J. (2007) · Diabetes · doi:10.2337/db07-0621 · Cited by 97
Amino acid variant in the kinase binding domain of dual-specific A kinase-anchoring protein 2: A disease susceptibility polymorphism
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Contribution of the LRP5 Gene to Normal Variation in Peak BMD in Women
Koller, D. L., Ichikawa, S., Johnson, M. L., Lai, D., Xuei, X., Edenberg, H. J., Conneally, P. M., Hui, S. L., Johnston, C. C., Peacock, M., et al. (2005) · Journal of Bone and Mineral Research · doi:10.1359/jbmr.041019 · Cited by 92
“This method, as implemented in the QTDT computer software package,((16)) extends the trio-based TDT((17)) to quantitative trait data and allows for the inclusion of sibling and parental data.”
Method
SNPs, microarrays and pooled DNA: identification of four loci associated with mild mental impairment in a sample of 6000 children
Butcher, L. M., Meaburn, E. L., Knight, J., Sham, P. C., Schalkwyk, L. C., Craig, I., & Plomin, R. J. (2005) · Human Molecular Genetics · doi:10.1093/hmg/ddi142 · Cited by 93
“The negative correlation for SNP rs41284924 indicates lower scores for the G allele of the A/ G SNP. Effect sizes (r2) shown in Table 3 reflect the results of the QTDT analyses.”
MethodInfluential
The Val66Met polymorphism of the brain‐derived neurotrophic factor gene is associated with risk for psychosis: Evidence from a family‐based association study
Rosa, A., Cuesta, M. J., Fatjó‐Vilas, M., Peralta, V., Zarzuela, A., & Fañanás, L. (2006) · American Journal of Medical Genetics Part B Neuropsychiatric Genetics · doi:10.1002/ajmg.b.30266 · Cited by 93
Association Analysis in a Variance Components Framework
Abecasis, G. R., Cardon, L. R., Cookson, W., Sham, P. C., & Cherny, S. S. (2001) · Genetic Epidemiology · doi:10.1002/gepi.2001.21.s1.s341 · Cited by 91
Self-citation
Family Based Association Analyses between the Serotonin Transporter Gene Polymorphism (5-HTTLPR) and Neuroticism, Anxiety and Depression
Middeldorp, C. M., de Geus, E. J. C., Beem, A. L., Lakenberg, N., Hottenga, J., Slagboom, P. E., & Boomsma, D. I. (2007) · Behavior Genetics · doi:10.1007/s10519-006-9139-7 · Cited by 89
Association and linkage of α-2A adrenergic receptor gene polymorphisms with childhood ADHD
Park, L., Nigg, J. T., Waldman, I. D., Nummy, K. A., Huang‐Pollock, C. L., Rappley, M. D., & Friderici, K. H. (2004) · Molecular Psychiatry · doi:10.1038/sj.mp.4001605 · Cited by 95
Hemoglobin C is associated with reduced Plasmodium falciparum parasitemia and low risk of mild malaria attack
Rihet, P. (2003) · Human Molecular Genetics · doi:10.1093/hmg/ddh002 · Cited by 90
The SNAP-25 gene is associated with cognitive ability: evidence from a family-based study in two independent Dutch cohorts
Gosso, M. F., de Geus, E. J. C., van Belzen, M. J., Polderman, T. J. C., Heutink, P., Boomsma, D. I., & Posthuma, D. (2006) · Molecular Psychiatry · doi:10.1038/sj.mp.4001868 · Cited by 90

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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