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A generalized robust allele‐based genetic association test

The allele‐based association test, comparing allele frequency difference between case and control groups, is locally most powerful. However, application of the classical allelic test is limited in practice, because the method is sensitive to the Hardy–Weinberg equilibrium (HWE) assumption, not appli...

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Autores principales: Zhang, Lin, Sun, Lei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9544499/
https://www.ncbi.nlm.nih.gov/pubmed/33729547
http://dx.doi.org/10.1111/biom.13456
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author Zhang, Lin
Sun, Lei
author_facet Zhang, Lin
Sun, Lei
author_sort Zhang, Lin
collection PubMed
description The allele‐based association test, comparing allele frequency difference between case and control groups, is locally most powerful. However, application of the classical allelic test is limited in practice, because the method is sensitive to the Hardy–Weinberg equilibrium (HWE) assumption, not applicable to continuous traits, and not easy to account for covariate effect or sample correlation. To develop a generalized robust allelic test, we propose a new allele‐based regression model with individual allele as the response variable. We show that the score test statistic derived from this robust and unifying regression framework contains a correction factor that explicitly adjusts for potential departure from HWE and encompasses the classical allelic test as a special case. When the trait of interest is continuous, the corresponding allelic test evaluates a weighted difference between individual‐level allele frequency estimate and sample estimate where the weight is proportional to an individual's trait value, and the test remains valid under Y‐dependent sampling. Finally, the proposed allele‐based method can analyze multiple (continuous or binary) phenotypes simultaneously and multiallelic genetic markers, while accounting for covariate effect, sample correlation, and population heterogeneity. To support our analytical findings, we provide empirical evidence from both simulation and application studies.
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spelling pubmed-95444992022-10-14 A generalized robust allele‐based genetic association test Zhang, Lin Sun, Lei Biometrics Biometric Methodology The allele‐based association test, comparing allele frequency difference between case and control groups, is locally most powerful. However, application of the classical allelic test is limited in practice, because the method is sensitive to the Hardy–Weinberg equilibrium (HWE) assumption, not applicable to continuous traits, and not easy to account for covariate effect or sample correlation. To develop a generalized robust allelic test, we propose a new allele‐based regression model with individual allele as the response variable. We show that the score test statistic derived from this robust and unifying regression framework contains a correction factor that explicitly adjusts for potential departure from HWE and encompasses the classical allelic test as a special case. When the trait of interest is continuous, the corresponding allelic test evaluates a weighted difference between individual‐level allele frequency estimate and sample estimate where the weight is proportional to an individual's trait value, and the test remains valid under Y‐dependent sampling. Finally, the proposed allele‐based method can analyze multiple (continuous or binary) phenotypes simultaneously and multiallelic genetic markers, while accounting for covariate effect, sample correlation, and population heterogeneity. To support our analytical findings, we provide empirical evidence from both simulation and application studies. John Wiley and Sons Inc. 2021-05-04 2022-06 /pmc/articles/PMC9544499/ /pubmed/33729547 http://dx.doi.org/10.1111/biom.13456 Text en © 2021 The Authors. Biometrics published by Wiley Periodicals LLC on behalf of International Biometric Society. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
spellingShingle Biometric Methodology
Zhang, Lin
Sun, Lei
A generalized robust allele‐based genetic association test
title A generalized robust allele‐based genetic association test
title_full A generalized robust allele‐based genetic association test
title_fullStr A generalized robust allele‐based genetic association test
title_full_unstemmed A generalized robust allele‐based genetic association test
title_short A generalized robust allele‐based genetic association test
title_sort generalized robust allele‐based genetic association test
topic Biometric Methodology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9544499/
https://www.ncbi.nlm.nih.gov/pubmed/33729547
http://dx.doi.org/10.1111/biom.13456
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