Haplotype heterogeneity and low linkage disequilibrium reduce reliable prediction of genotypes for the alpha (3.7I) form of alpha-thalassaemia using genome-wide microarray data

Ndila CM, Nyirongo V, Macharia AW, Jeffreys AE, Rowlands K, Hubbart C, Busby GBJ, Band G, Harding RM, Rockett KA, Williams TN, Malaria GENConsortium
Wellcome Open Res. 2020;5

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Background: The -alpha (3.7I)-thalassaemia deletion is very common throughout Africa because it protects against malaria. When undertaking studies to investigate human genetic adaptations to malaria or other diseases, it is important to account for any confounding effects of alpha-thalassaemia to rule out spurious associations. Methods: In this study, we have used direct alpha-thalassaemia genotyping to understand why GWAS data from a large malaria association study in Kilifi Kenya did not identify the alpha-thalassaemia signal. We then explored the potential use of a number of new approaches to using GWAS data for imputing alpha-thalassaemia as an alternative to direct genotyping by PCR. Results: We found very low linkage-disequilibrium of the directly typed data with the GWAS SNP markers around alpha-thalassaemia and across the haemoglobin-alpha ( HBA) gene region, which along with a complex haplotype structure, could explain the lack of an association signal from the GWAS SNP data. Some indirect typing methods gave results that were in broad agreement with those derived from direct genotyping and could identify an association signal, but none were sufficiently accurate to allow correct interpretation compared with direct typing, leading to confusing or erroneous results. Conclusions: We conclude that going forwards, direct typing methods such as PCR will still be required to account for alpha-thalassaemia in GWAS studies.