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.

Download data

• Downloaded 784 times
• Download rankings, all-time:
  • Site-wide: 29,530
  • In genomics: 2,690
• Year to date:
  • Site-wide: 20,328
• Since beginning of last month:
  • Site-wide: 34,093

Altmetric data

Downloads over time

Distribution of downloads per paper, site-wide