A1 Refereed original research article in a scientific journal
The impact of non-additive genetic associations on age-related complex diseases
Authors: Guindo-Martinez Marta, Amela Ramon, Bonàs-Guarch Silvia, Puiggros Montserrat, Salvoro Cecilia, Miguel-Escalada Irene, Carey Caitlin E, Cole Joanne B, Rüeger Sina, Atkinson Elizabeth, Leong Aaron, Sanchez Friman, Ramon-Cortes Cristian, Ejarque Jorge, Palmer Duncan S, Kurki Mitja, Aragam Krishna, Florez Jose C, Badia Rosa M, Mercader Josep M, Torrents David; FinnGen
Publisher: NATURE RESEARCH
Publication year: 2021
Journal: Nature Communications
Journal name in source: NATURE COMMUNICATIONS
Journal acronym: NAT COMMUN
Article number: ARTN 2436
Volume: 12
Number of pages: 14
ISSN: 2041-1723
eISSN: 2041-1723
DOI: https://doi.org/10.1038/s41467-021-21952-4
Web address : https://www.nature.com/articles/s41467-021-21952-4
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 implement an extensive GWAS strategy, GUIDANCE, which improves genotype imputation by using multiple reference panels and includes the analysis of the X chromosome and non-additive models to test for association. We apply this methodology to 62,281 subjects across 22 age-related diseases and identify 94 genome-wide associated loci, including 26 previously unreported. Moreover, we observe that 27.7% of the 94 loci are missed if we use standard imputation strategies with a single reference panel, such as HRC, and only test the additive model. Among the new findings, we identify three novel low-frequency recessive variants with odds ratios larger than 4, which 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. Most genome-wide association studies assume an additive model, exclude the X chromosome, and use one reference panel. Here, the authors implement a strategy including non-additive models and find that the number of loci for age-related traits increases as compared to the additive model alone.
