A unified approach to adjusting association tests for population admixture with arbitrary pedigree structure and arbitrary missing marker information.
Abstract
A general approach to family-based examinations of association between marker alleles and traits is proposed. The approach is based on computing p values by comparing test statistics for association to their conditional distributions given the minimal sufficient statistic under the null hypothesis for the genetic model, sampling plan and population admixture. The approach can be applied with any test statistic, so any kind of phenotype and multi-allelic markers may be examined, and covariates may be included in analyses. By virtue of the conditioning, the approach results in correct type I error probabilities regardless of population admixture, the true genetic model and the sampling strategy. An algorithm for computing the conditional distributions is described, and the results of the algorithm for configurations of nuclear families are presented. The algorithm is applicable with all pedigree structures and all patterns of missing marker allele information.
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This methodology extends readily to scenarios in which the parental genotypes are not known, using the approach of Rabinowitz and Laird.
“This methodology extends readily to scenarios in which the parental genotypes are not known, using the approach of Rabinowitz and Laird [67].”
From The oxytocin receptor (OXTR) contributes to prosocial fund allocations in the dictator game and the social value orientations task (2009) · cites this paper as [67]
The FBAT statistic is robust against population admixture and stratification.
“The FBAT statistic has an additional advantage in that it is robust against population admixture and stratification [67].”
From The oxytocin receptor (OXTR) contributes to prosocial fund allocations in the dictator game and the social value orientations task (2009) · cites this paper as [67]
Cites
Spielman, R. S., McGinnis, R. E., & Ewens, W. J. (1993) · PubMed · Cited by 3,679 · see citing works
A Sibship Test for Linkage in the Presence of Association: The Sib Transmission/Disequilibrium Test
Spielman, R. S., & Ewens, W. J. (1998) · The American Journal of Human Genetics · doi:10.1086/301714 · Cited by 666 · see citing works
Falk, C. T., & Rubinstein, P. G. (1987) · Annals of Human Genetics · doi:10.1111/j.1469-1809.1987.tb00875.x · Cited by 618 · see citing works
The transmission/disequilibrium test: history, subdivision, and admixture.
Ewens, W. J., & Spielman, R. S. (1995) · PubMed Central · Cited by 546 · see citing works
A Haplotype-Based Haplotype Relative Risk’ Approach to Detecting Allelic Associations
Terwilliger, J. D., & Ott, J. (1992) · Human Heredity · doi:10.1159/000154096 · Cited by 486 · see citing works
A Transmission Disequilibrium Test for Quantitative Trait Loci
Rabinowitz, D. (1997) · Human Heredity · doi:10.1159/000154433 · Cited by 230 · see citing works
Self-citationTests for Linkage and Association in Nuclear Families
Martin, E. R., Kaplan, N. L., & Weir, B. S. (1997) · The American Journal of Human Genetics · doi:10.1086/514860 · Cited by 215 · see citing works
Genetic Association Mapping Based on Discordant Sib Pairs: The Discordant-Alleles Test
Boehnke, M., & Langefeld, C. D. (1998) · The American Journal of Human Genetics · doi:10.1086/301787 · Cited by 206 · see citing works
A note on the application of the transmission disequilibrium test when a parent is missing.
Curtis, D., & Sham, P. C. (1995) · PubMed · Cited by 182 · see citing works
Knapp, M. (1999) · The American Journal of Human Genetics · doi:10.1086/302285 · Cited by 165 · see citing works
A Course in Theortical Statistics.
Blackmor, R. W., & Rahman, N. A. (1970) · Journal of the Royal Statistical Society Series D (The Statistician) · doi:10.2307/2987374 · Cited by 153 · see citing works
A Conditional Inference Framework for Extending the Transmission/Disequilibrium Test
Lazzeroni, L. C., & Lange, K. L. (1998) · Human Heredity · doi:10.1159/000022784 · Cited by 138 · see citing works
Power studies for the transmission/disequilibrium tests with multiple alleles.
Kaplan, N. L., Martin, E. R., & Weir, B. S. (1997) · PubMed · Cited by 107 · see citing works
Genetic analysis with hierarchical models
Witte, J. S. (1997) · Genetic Epidemiology · doi:10.1002/(sici)1098-2272(1997)14:6 · Cited by 33 · see citing works
Comparison of methods for analyzing binary data arising from two-sample twin studies
Gao, X., Klar, N. S., & Donner, A. P. (1997) · Genetic Epidemiology · doi:10.1002/(sici)1098-2272(1997)14:4 · Cited by 13 · see citing works
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The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease
Rogaeva, E., Meng, Y., Lee, J. H., Gu, Y., Kawarai, T., Zou, F., Katayama, T., Baldwin, C. T., Cheng, R., Hasegawa, H., et al. (2007) · Nature Genetics · doi:10.1038/ng1943 · Cited by 1,167 · see citing works
Association of the oxytocin receptor gene (OXTR) in Caucasian children and adolescents with autism
Jacob, S., Brune, C. W., Carter, C. S., Leventhal, B. L., Lord, C., & Cook, E. H. (2007) · Neuroscience Letters · doi:10.1016/j.neulet.2007.02.001 · Cited by 425 · see citing works
Deconstructing a Syndrome: Genomic Insights Into PCOS Causal Mechanisms and Classification
Dapas, M., & Dunaif, A. (2022) · Endocrine Reviews · doi:10.1210/endrev/bnac001 · Cited by 300 · see citing works
Israel, S., Lerer, E., Shalev, I., Uzefovsky, F., Riebold, M., Laiba, E., Bachner-Melman, R., Maril, A., Bornstein, G., Knafo, A., et al. (2009) · PLoS ONE · doi:10.1371/journal.pone.0005535 · Cited by 278 · see citing works
Dickel, D. E., Veenstra-VanderWeele, J., Cox, N. J., Wu, X., Fischer, D. J., Van Etten-Lee, M., Himle, J. A., Leventhal, B. L., Cook, E. H., & Hanna, G. L. (2006) · Archives of General Psychiatry · doi:10.1001/archpsyc.63.7.778 · Cited by 274 · see citing works
PBAT: tools for family-based association studies.
Lange, C., DeMeo, D., Silverman, E. K., Weiss, S. T., & Laird, N. M. (2004) · The American Journal of Human Genetics · doi:10.1086/381563 · Cited by 268 · see citing works
Self-citationWang, J. C., Grucza, R., Cruchaga, C., Hinrichs, A. L., Bertelsen, S., Budde, J. P., Fox, L., Goldstein, E., Reyes, O., Saccone, N., et al. (2009) · Molecular Psychiatry · doi:10.1038/mp.2008.42 · Cited by 226 · see citing works
Cordell, H. J., Barratt, B. J., & Clayton, D. G. (2004) · Genetic Epidemiology · doi:10.1002/gepi.10307 · Cited by 223 · see citing works
Lesch, K.-P., Selch, S., Renner, T. J., Jacob, C., Nguyen, T. T., Hahn, T., Romanos, M., Walitza, S., Shoichet, S., Dempfle, A., et al. (2011) · Molecular Psychiatry · doi:10.1038/mp.2010.29 · Cited by 167 · see citing works
Macrophage migration inhibitory factor and autism spectrum disorders
Grigorenko, E. L., Han, S. S., Yrigollen, C. M., Leng, L., Mizue, Y., Anderson, G. M., Mulder, E. J., de Bildt, A., Minderaa, R. B., Volkmar, F. R., et al. (2008) · PEDIATRICS · doi:10.1542/peds.2007-3604 · Cited by 118 · see citing works
Association of GSK3B with Alzheimer disease and frontotemporal dementia
Schaffer, B. A. J., Bertram, L., Miller, B. L., Mullin, K., Weintraub, S., Johnson, N., Bigio, E. H., Mesulam, M., Wiedau-Pazos, M., Jackson, G. R., et al. (2008) · Archives of Neurology · doi:10.1001/archneur.65.10.1368 · Cited by 100 · see citing works
Van Steen, K., & Lange, C. (2005) · Human Genomics · doi:10.1186/1479-7364-2-1-67 · Cited by 73 · see citing works
Genome-wide association studies and the genetic dissection of complex traits
Sebastiani, P., Timofeev, N., Dworkis, D. A., Perls, T. T., & Steinberg, M. H. (2009) · American Journal of Hematology · doi:10.1002/ajh.21440 · Cited by 67 · see citing works
Converging Evidence for an Association of ATP2B2 Allelic Variants with Autism in Male Subjects
Carayol, J., Sacco, R., Tores, F., Rousseau, F., Lewin, P., Hager, J., & Persico, A. M. (2011) · Biological Psychiatry · doi:10.1016/j.biopsych.2011.05.020 · Cited by 59 · see citing works
Heterogeneous association between engrailed‐2 and autism in the CPEA network
Brune, C. W., Korvatska, E., Allen‐Brady, K., Cook, E. H., Dawson, G., Devlin, B., Estes, A., Hennelly, M., Hyman, S. L., McMahon, W. M., et al. (2008) · American Journal of Medical Genetics Part B: Neuropsychiatric Genetics · doi:10.1002/ajmg.b.30585 · Cited by 40 · see citing works
The Evidence for Association of ATP2B2 Polymorphisms with Autism in Chinese Han Population
Yang, W., Liu, J., Zheng, F., Jia, M., Zhao, L., Lu, T., Ruan, Y., Zhang, J., Yue, W., Zhang, D., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0061021 · Cited by 34 · see citing works
- Authors
- Rabinowitz, D., & Laird, N.
- Affiliations
- Columbia University (US)
- Harvard University (US)
- ORCID
- Laird, Nan
- Venue
- Human Heredity
- Publisher
- S. Karger AG
- Published
- 2000
- Volume
- 50
- Issue
- 4
- Pages
- 211-223
- ISSN
- 0001-5652 (ISSN-L)
- 1423-0062
- OpenAlex
- W2052071194
- Cited by
- 627
- References
- 15
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 3 · 2023: 3 · 2022: 1 · 2021: 5 · 2020: 7 · 2019: 11 · 2018: 4 · 2017: 7 · 2016: 13 · 2015: 19 · 2014: 18 · 2013: 22 · 2012: 32
- FWCI
- 15.28
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Human Heredity (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Mental Health (R01MH059532, MH 59532)
- National Institute of General Medical Sciences (GM5597)
- 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 › Forensic and Genetic Research
- Keywords
- family-based association test, population admixture, pedigree structure, conditional distributions, minimal sufficient statistics, type I error control, nuclear family, covariates, genetic association
- MeSH terms
- Algorithms, Alleles, Animals, Female, Genetic Markers, Haplotypes, Male, Models, Genetic, Pedigree, Risk, Models, Statistical, Linkage Disequilibrium
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