The impact of non-additive genetic associations on age-related complex diseases
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. ; This work has been sponsored by the grant SEV-2011-00067 and SEV2015-0493 of Severo Ochoa Program, awarded by the Spanish Government, by the grant TIN2015- 65316-P, awarded by the Spanish Ministry of Science and Innovation, and by the Generalitat de Catalunya (contract 2014-SGR-1051). This work was supported by an EFSD/Lilly research fellowship. Josep M. Mercader was supported by a Sara Borrell Fellowship from the Instituto Carlos III, Beatriu de Pinós fellowship from the Agency for Management of University and Research Grants (AGAUR) and by the American Diabetes Association Innovative and Clinical Translational Award 1-19-ICTS-068. Sílvia Bonàs was supported by FI-DGR Fellowship from FIDGR 2013 from Agència de Gestió d'Ajuts Universitaris i de Recerca (AGAUR, Generalitat de Catalunya), and a 'Juan de la Cierva' postdoctoral fellowship (MINECO;FJCI-2017-32090). Cecilia Salvoro received funding from the European Union's Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement H2020-MSCA-COFUND-2016- 754433. Cristian Ramon-Cortes pre-doctoral contract is financed by the Spanish Ministry of Science, Innovation, and Universities under contract BES-2016-076791. Elizabeth G. Atkinson was supported by the National Institutes of Mental Health (grants K01MH121659 and T32MH017119). Jose Florez was supported by NIH/NIDDK award K24 DK110550. This study made use of data generated by the UK10K Consortium, derived from samples from UK10K COHORT IMPUTATION (EGAS00001000713). A full list of the investigators who contributed to the generation of the data is available at www.UK10K.org. Funding for UK10K was provided by the Wellcome Trust under award WT091310. This study made use of data generated by the 'Genome of the Netherlands' project, which is funded by the Netherlands Organization for Scientific Research (grant no. 184021007). The data were made available as a Rainbow Project of BBMRI-NL. Samples were contributed by LifeLines (http://lifelines.nl/lifelines-research/general), the Leiden Longevity Study (http://www.healthy-ageing.nl; http://www.langleven.net), the Netherlands Twin Registry (NTR: http://www.tweelingenregister.org), the Rotterdam studies (http://www.erasmus-epidemiology.nl/rotterdamstudy) and the Genetic Research in Isolated Populations program (http://www.epib.nl/research/geneticepi/research. html#gip). The sequencing was carried out in collaboration with the Beijing Institute for Genomics (BGI). This study also made use of data generated by The Haplotype Reference Consortium (HRC) accessed through The European Genome-phenome Archive at the European Bioinformatics Institute with the accession numbers EGAD00001002729, after a form agreed by the Barcelona Supercomputing Center (BSC) with WTSI. This research has been conducted using also the UK Biobank Resource (application number 31063 and 27892). The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. The data used for the analyses described in this manuscript were obtained from the GTEx Portal on 07/16/2019. We acknowledge PRACE for awarding us access to both MareNostrum supercomputer from the Barcelona Supercomputing Center, based in Spain at Barcelona, and the SuperMUC supercomputer of the Leibniz Supercomputing Center (LRZ), based in Garching at Germany (proposals numbers 2016143358 and 2016163985). The technical support group from the Barcelona Supercomputing Center is gratefully acknowledged. Finally, we thank all the Computational Genomics group at the BSC for their helpful discussions and valuable comments on the manuscript. We also acknowledge Elias Rodriguez Fos for designing the GUIDANCE logo. ; Peer Reviewed ; Article signat per 22 autors/autores: Marta Guindo-Martínez 1,18; Ramon Amela 1,18; Silvia Bonàs-Guarch 1,2,3; Montserrat Puiggròs 1; Cecilia Salvoro 1; Irene Miguel-Escalada 1,2,3; Caitlin E. Carey 4,5; Joanne B. Cole 6,7,8,9; Sina Rüeger 10; Elizabeth Atkinson 4,5,11; Aaron Leong 8,12; Friman Sanchez 1; Cristian Ramon-Cortes 1; Jorge Ejarque 1; Duncan S. Palmer 4,5,17; Mitja Kurki 10; FinnGen Consortium*, Krishna Aragam 11,13,14; Jose C. Florez 6,7,15; Rosa M. Badia 1; Josep M. Mercader 1,6,7,15,19✉ & David Torrents 1,16,19✉ *A full list of members and their affiliations appears in the Supplementary Information 1 Barcelona Supercomputing Center (BSC), Barcelona, Spain. 2 Regulatory Genomics and Diabetes, Centre for Genomic Regulation, The Barcelona Institute of Science and Technology, Barcelona, Spain. 3 CIBER de Diabetes y Enfermedades Metabólicas Asociadas, Madrid, Spain. 4 Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA. 5 Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. 6 Programs in Metabolism and Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA. 7 Diabetes Unit and Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA. 8 Harvard Medical School, Boston, MA, USA. 9 Division of Endocrinology and Center for Basic and Translational Obesity Research, Boston Children's Hospital, Boston, MA, USA. 10 Institute for Molecular Medicine Finland, FIMM, HiLIFE, University of Helsinki, Helsinki, Finland. 11 Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA. 12 Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. 13 Cardiology Division, Massachusetts General Hospital, Boston, MA, USA. 14 Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA. 15 Department of Medicine, Harvard Medical School, Boston, MA, USA. 16 Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain. 17 Present address: GENOMICS plc, Oxford, UK. 18 These authors contributed equally: Marta Guindo-Martínez, Ramon Amela. 19 These authors jointly supervised this work: Josep M. Mercader, David Torrents. ; Postprint (published version)