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Modeling the Dependence Structure in Genome Wide Association Studies of Binary Phenotypes in Family Data

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Abstract

Genome-wide association studies (GWASs) are a popular tool for detecting association between genetic variants or single nucleotide polymorphisms (SNPs) and complex traits. Family data introduce complexity due to the non-independence of the family members. Methods for non-independent data are well established, but when the GWAS contains distinct family types, explicit modeling of between-family-type differences in the dependence structure comes at the cost of significantly increased computational burden. The situation is exacerbated with binary traits. In this paper, we perform several simulation studies to compare multiple candidate methods to perform single SNP association analysis with binary traits. We consider generalized estimating equations (GEE), generalized linear mixed models (GLMMs), or generalized least square (GLS) approaches. We study the influence of different working correlation structures for GEE on the GWAS findings and also the performance of different analysis method(s) to conduct a GWAS with binary trait data in families. We discuss the merits of each approach with attention to their applicability in a GWAS. We also compare the performances of the methods on the alcoholism data from the Minnesota Center for Twin and Family Research (MCTFR) study.

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Acknowledgements

This research was supported by NIH Grant Nos. R01-DA033958 and R21-DA046188 (PI: Saonli Basu).

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Authors and Affiliations

  1. Division of Biostatistics, University of Minnesota, Minneapolis, MN, USA

    Souvik Seal, Jeffrey A. Boatman & Saonli Basu

  2. Department of Psychology, University of Minnesota, Minneapolis, MN, USA

    Matt McGue

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  1. Souvik Seal
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  2. Jeffrey A. Boatman
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  3. Matt McGue
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  4. Saonli Basu
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Correspondence to Souvik Seal.

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Conflict of interest

Souvik Seal, Jeffrey A. Boatman, Saonli Basu, and Matt McGue have no conflict of interests to declare.

Human and Animal Rights

As part of the Genes, Environment and Development Initiative (GEDI), the Minnesota Center for Twin and Family Research (MCTFR) undertook a genome-wide association study (GWAS). The procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national).

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Informed consent was obtained from all individual participants included in the study.

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Seal, S., Boatman, J.A., McGue, M. et al. Modeling the Dependence Structure in Genome Wide Association Studies of Binary Phenotypes in Family Data. Behav Genet 50, 423–439 (2020). https://doi.org/10.1007/s10519-020-10010-2

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  • DOI: https://doi.org/10.1007/s10519-020-10010-2

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