A Model-based approach to genetic association testing in Malaria studies
Date
2019
Authors
Akoth, Morine
Odhiambo, John
Omolo, Bernard
Journal Title
Journal ISSN
Volume Title
Publisher
Strathmore University
Abstract
In human genetics, heterozygote advantage (heterosis) has been detected in studies that focused
on specific genes, but not in genome-wide association studies (GWAS). For example, heterosis
is believed to confer resistance to certain strains of malaria in patients heterozygous for the
sickle-cell gene HbS. Yet the power of allele-based tests can be substantially diminished by
heterosis. Since GWAS (and haplotype-associations) also utilize allele-based tests, it is unclear
to what degree GWAS could underachieve because heterosis is ignored. In this study, we
propose a two-step approach to genetic association testing in malaria studies in a GWAS
setting that may enhance the power of the tests, by identifying the underlying genetic model
first before applying the association tests. We fit generalized linear models for the dominant,
recessive, additive and heterotic effects and perform tests of significance using the MAX and
the allelic tests, noting the minimum p-values across all the models and the proportion of tests
that a given genetic model was deemed the best, using simulated data. Case-control genotype
data on malaria from Kenya and the Gambia are used for validation. Results show that the
allelic test returned a number of false negatives under the heterosis model, suggesting reduced
power in testing genetic association. Thus, GWAS and haplotype associations should be
treated with caution, unless the underlying genetic model had been determined.
Description
Paper presented at the 5th Strathmore International Mathematics Conference (SIMC 2019), 12 - 16 August 2019, Strathmore University, Nairobi, Kenya