TY - JOUR
T1 - Exome sequencing identifies rare damaging variants in the ATB8B4 and ABCA1 genes as novel risk factors for Alzheimer's disease
AU - Holstege, Henne
AU - Hulsman, Marc
AU - Charbonnier, Camille
AU - Grenier-Boley, Benjamin
AU - Quenez, Olivier
AU - Grozeva, Detelina
AU - van Rooij, Jeroen G. J.
AU - Sims, Rebecca
AU - Ahmad, Shahzad
AU - Amin, Najaf
AU - Norsworthy, Penny
AU - Dols-Icardo, Oriol
AU - Hummerich, Holger
AU - Kawalia, Amit
AU - Amouyel, Philippe
AU - Beecham, Gary W.
AU - Berr, Claudine
AU - Bis, Josh C.
AU - Boland, Anne
AU - Bossù, Paola
AU - Bouwman, Femke H.
AU - Bras, Jose
AU - Campion, Dominique
AU - Cochran, J. Nicholas
AU - Daniele, Antonio
AU - Dartigues, Jean-François
AU - Debette, Stéphanie
AU - Deleuze, Jean-François
AU - Denning, Nicola
AU - Destefano, Anita L.
AU - Farrer, Lindsay A.
AU - Fernandez, Victoria
AU - Fox, Nick C.
AU - Galimberti, Daniela
AU - Génin, Emmanuelle
AU - Gille, Hans
AU - Guen, Yann Le
AU - Guerreiro, Rita
AU - Haines, Jonathan L.
AU - Holmes, Clive
AU - Ikram, M. Arfan
AU - Ikram, Mohammed Kamran
AU - Jansen, Iris E.
AU - Kraaij, Robert
AU - Lathrop, Mark
AU - Lemstra, Afina W.
AU - Lleó, Alberto
AU - Luckcuck, Lauren
AU - Marshall, Rachel
AU - Martin, Eden R.
AU - Masullo, Carlo
AU - Mayeux, Richard
AU - Mecocci, Patrizia
AU - Meggy, Alun
AU - Mol, Merel O.
AU - Morgan, Kevin
AU - Myers, Richard M.
AU - Nacmias, Benedetta
AU - Naj, Adam C.
AU - Napolioni, Valerio
AU - Pastor, Pau
AU - Pericak-Vance, Margaret A.
AU - Raybould, Rachel
AU - Redon, Richard
AU - Reinders, Marcel Jt
AU - Richard, Anne-Claire
AU - Riedel-Heller, Steffi G.
AU - Rivadeneira, Fernando
AU - Rousseau, Stéphane
AU - Ryan, Natalie S.
AU - Saad, Salha
AU - Sanchez-Juan, Pascual
AU - Schellenberg, Gerard D.
AU - Scheltens, Philip
AU - Schott, Jonathan M.
AU - Seripa, Davide
AU - Sie, Daoud
AU - Sistermans, Erik
AU - Sorbi, Sandro
AU - van Spaendonk, Rosalina M. L.
AU - Spalletta, Gianfranco
AU - Tesi, Niccoló
AU - Tijms, Betty M.
AU - van der Lee, Sven J.
AU - Uitterlinden, André G.
AU - Visser, Pieter Jelle
AU - Wagner, Michael
AU - Wallon, David
AU - Wang, Li-San
AU - Zarea, Aline
AU - Clarimón, Jordi
AU - van Swieten, John C.
AU - Hardy, John
AU - Greicius, Michael D.
AU - Ramirez, Alfredo
AU - Mead, Simon
AU - Yokoyama, Jennifer S.
AU - van der Flier, Wiesje M.
AU - Cruchaga, Carlos
AU - van Duijn, Cornelia M.
AU - Williams, Julie
AU - Nicolas, Gaël
AU - Bellenguez, C. line
AU - Lambert, Jean-Charles
PY - 2021/12/1
Y1 - 2021/12/1
N2 - BACKGROUND: Damaging rare variants in the TREM2, SORL1 and ABCA7 genes have been associated with an increased risk of developing Alzheimer's Disease (AD) with odds ratios that were not observed since the identification of the main AD genetic risk factor, the APOE-ε4 allele. Here, we aimed to identify additional AD-associated genes by investigating the burden of rare damaging variants in the exomes of AD cases and controls. METHOD: On a single server, we analyzed in two stages, the data from 52,270 exome sequences from several independent datasets from Europe and the United States. After comprehensive QC, Stage-1 and Stage-2 datasets comprised in total 16,396 AD cases (5,672 EOAD) and 18,107 controls with European ancestry. All detected non-synonymous and loss-of-function rare variants were prioritized by REVEL and LOFTEE, and analyzed in a per-gene burden analysis. After a Stage-1 discovery analysis, we replicated findings in an independent dataset (Stage-2). We combined the Stage-1 and Stage-2 datasets and determined, for each gene, the features of the variants that drive the burden-associations. RESULTS: We confirmed the AD-association of rare damaging variants SORL1, TREM2, ABCA7, and newly identified a significant AD-association of rare damaging variants in the ATP8B4 and ABCA1 genes. In addition, we find a strong indication for the AD-association of ADAM10 and SRC genes (Stage-2 p<0.05). For most genes, we observed a larger effect size for LOF variants compared to missense variants (Figure-A). High-impact variants in these genes are mostly extremely rare and enriched in AD patients with early ages at onset (Figure-B). CONCLUSION: We identified, for the first time, the AD-association of rare damaging variants in two genes: (i) microglial ATP8B4 which is involved in phospholipid transport, and (ii) ABCA1 which plays a critical role in lipidation of apoE thereby supporting Aβ processing. Further, we found strong evidence for the AD-association of damaging variants in ADAM10 and SRC genes. ADAM10 is involved in the proteolytic processing of APP, while SRC is a Non-Receptor Tyrosine Kinase which binds PTK2B/Pyk2, a known AD risk factor. Together, our study provides further evidence for the role of Aβ and microglia in AD pathophysiology.
AB - BACKGROUND: Damaging rare variants in the TREM2, SORL1 and ABCA7 genes have been associated with an increased risk of developing Alzheimer's Disease (AD) with odds ratios that were not observed since the identification of the main AD genetic risk factor, the APOE-ε4 allele. Here, we aimed to identify additional AD-associated genes by investigating the burden of rare damaging variants in the exomes of AD cases and controls. METHOD: On a single server, we analyzed in two stages, the data from 52,270 exome sequences from several independent datasets from Europe and the United States. After comprehensive QC, Stage-1 and Stage-2 datasets comprised in total 16,396 AD cases (5,672 EOAD) and 18,107 controls with European ancestry. All detected non-synonymous and loss-of-function rare variants were prioritized by REVEL and LOFTEE, and analyzed in a per-gene burden analysis. After a Stage-1 discovery analysis, we replicated findings in an independent dataset (Stage-2). We combined the Stage-1 and Stage-2 datasets and determined, for each gene, the features of the variants that drive the burden-associations. RESULTS: We confirmed the AD-association of rare damaging variants SORL1, TREM2, ABCA7, and newly identified a significant AD-association of rare damaging variants in the ATP8B4 and ABCA1 genes. In addition, we find a strong indication for the AD-association of ADAM10 and SRC genes (Stage-2 p<0.05). For most genes, we observed a larger effect size for LOF variants compared to missense variants (Figure-A). High-impact variants in these genes are mostly extremely rare and enriched in AD patients with early ages at onset (Figure-B). CONCLUSION: We identified, for the first time, the AD-association of rare damaging variants in two genes: (i) microglial ATP8B4 which is involved in phospholipid transport, and (ii) ABCA1 which plays a critical role in lipidation of apoE thereby supporting Aβ processing. Further, we found strong evidence for the AD-association of damaging variants in ADAM10 and SRC genes. ADAM10 is involved in the proteolytic processing of APP, while SRC is a Non-Receptor Tyrosine Kinase which binds PTK2B/Pyk2, a known AD risk factor. Together, our study provides further evidence for the role of Aβ and microglia in AD pathophysiology.
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85123974120&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/35109061
U2 - 10.1002/alz.055982
DO - 10.1002/alz.055982
M3 - Article
C2 - 35109061
SN - 1552-5260
VL - 17
SP - e055982
JO - Alzheimers & Dementia
JF - Alzheimers & Dementia
ER -