The Impact of Non-additive Genetic Associations on Age-related Complex Diseases

Overview

Journal Nat Commun

Specialty Biology

Date 2021 Apr 24

PMID 33893285

Citations 48

Authors

Marta Guindo-Martinez

Ramon Amela

Silvia Bonas-Guarch

Montserrat Puiggros

Cecilia Salvoro

Irene Miguel-Escalada

Caitlin E Carey

Joanne B Cole

Sina Rueger

Elizabeth Atkinson

Aaron Leong

Friman Sanchez

Cristian Ramon-Cortes

Jorge Ejarque

Duncan S Palmer

Mitja Kurki

Krishna Aragam

Jose C Florez

Rosa M Badia

Josep M Mercader

David Torrents

Affiliations

Soon will be listed here.

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 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.

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