The impact of non-additive genetic associations on age-related complex diseases.
Caitlin E Carey,
Joanne B Cole,
Elizabeth G. Atkinson,
Duncan S Palmer,
Krishna G. Aragam,
Jose C. Florez,
Rosa Maria Badia,
Josep M Mercader,
Posted 14 May 2020
bioRxiv DOI: 10.1101/2020.05.12.084608
Posted 14 May 2020
Genome-wide association studies (GWAS) are not fully comprehensive as current strategies typically test only the additive model, exclude the X chromosome, and use only one reference panel for genotype imputation. We implemented an extensive GWAS strategy, GUIDANCE, which improves genotype imputation by using multiple reference panels, includes the analysis of the X chromosome and non-additive models to test for association. We applied this methodology to 62,281 subjects across 22 age-related diseases and identified 94 genome-wide associated loci, including 26 previously unreported. We observed that 27.6% of the 94 loci would be missed if we only used standard imputation strategies and only tested the additive model. Among the new findings, we identified three novel low-frequency recessive variants with odds ratios larger than 4, which would need at least a three-fold larger sample size to be detected under the additive model. This study highlights the benefits of applying innovative strategies to better uncover the genetic architecture of complex diseases. ### Competing Interest Statement The authors have declared no competing interest.
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