Premium
Can OMICS data help us to understand the mechanisms of APOE?
Author(s) -
Sáez María Eugenia,
MorenoGrau Sonia,
Madrid Laura,
Ramirez Alfredo,
Ried Janina S.,
GonzálezPérez Antonio,
Ruiz Agustín
Publication year - 2020
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1002/alz.040276
Subject(s) - apolipoprotein e , biology , computational biology , genome wide association study , proteome , genotype , proteomics , transcriptome , omics , disease , bioinformatics , genetics , gene , medicine , gene expression , single nucleotide polymorphism
Background While being the most prominent genetic risk factor for Alzheimer’s disease (AD), the effects of APOE variants on the biology and development of AD are still poorly understood. The IMI ADAPTED consortium strives to illuminate the mechanisms underlying the effects of APOE following a holistic approach. In this presentation we describe how the integration of a systematic APOE‐stratified re‐analysis of publicly available GWAS, transcriptomics and proteomics for AD led to new insights in APOE mediated effects in AD. Method We re‐analysed AD relevant data including 39,186 human genomes, 2,338 transcriptomes, and 2,365 proteomes along with snRNAseq brain data from diverse AD cohorts. Data were obtained from diverse public repositories and AD research consortia (AddNeuroMed,ADGC,ADNI,AMP‐AD,CHARGE,GERAD,GR@ACE,Mount Sinai,NIA‐GENADA,MAYO,ROSMAP and TGEN). Genes showing differences between cases and controls stratified by APOE genotype were identified as well as those showing differences between the APOE genotype carriers. Results of the different OMICS were integrated using the robust rank aggregation (RRA) method to identify effects which are consistent across multiple layers of OMICS data followed by pathway analysis. Results The stratified GWAS analysis identified genome‐wide significant loci for AD in the APOE ε3 and APOE ε4 genotype strata. After integration with plasma and brain expression profiles, the pathway analysis found enrichment for several processes related to the immune system and glia function among other relevant pathways, of which those differing between APOE strata are of particular interest. Conclusion The systematic APOE genotype‐stratified analysis of human GWAS, transcriptomics, and proteomics data revealed promising candidate genes and pathways that help to elucidate the mechanisms by which APOE affects the AD risk. OMICS data in APOE relevant cell models will refine these findings. Disclosure: This project has received funding from the Innovative Medicines Initiative 2 JU under grant agreement No 115975. This Joint Undertaking receives support from the EU’s Horizon2020 research and innovation programme and EFPIA. This study was sponsored by AbbVie Deutschland GmbH & Co KG. AbbVie contributed to the study design, research, and interpretation of data, writing, reviewing, and approving the abstract. Some authors are currently employed by AbbVie and may own AbbVie stock.