@article {Guindo-Mart{\'\i}nez2020.05.12.084608, author = {Marta Guindo-Mart{\'\i}nez and Ramon Amela and Silvia Bon{\`a}s-Guarch and Montserrat Puiggr{\`o}s and Cecilia Salvoro and Irene Miguel-Escalada and Caitlin E Carey and Joanne B. Cole and Sina R{\"u}eger and Elizabeth Atkinson and Aaron Leong and Friman Sanchez and Cristian Ramon-Cortes and Jorge Ejarque and Duncan S Palmer and Mitja Kurki and FinnGen Consortium and Krishna Aragam and Jose C Florez and Rosa M. Badia and Josep M. Mercader and David Torrents}, title = {The impact of non-additive genetic associations on age-related complex diseases}, elocation-id = {2020.05.12.084608}, year = {2020}, doi = {10.1101/2020.05.12.084608}, publisher = {Cold Spring Harbor Laboratory}, abstract = {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 StatementThe authors have declared no competing interest.}, URL = {https://www.biorxiv.org/content/early/2020/05/14/2020.05.12.084608}, eprint = {https://www.biorxiv.org/content/early/2020/05/14/2020.05.12.084608.full.pdf}, journal = {bioRxiv} }