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Contribution to Alzheimer's disease risk of rare variants in TREM2, SORL1, and ABCA7 in 1779 cases and 1273 controls

Céline Bellenguez Camille Charbonnier Benjamin Grenier-Boley Olivier Quenez Kilan Le Guennec Gaël Nicolas Ganesh Chauhan David Wallon Stéphane Rousseau Anne Claire Richard Anne Boland Guillaume Bourque Hans Markus Munter Robert Olaso Vincent Meyer Adeline Rollin-Sillaire Florence Pasquier Luc Letenneur Richard Redon Jean-François Dartigues Christophe Tzourio Thierry Frebourg Mark Lathrop Jean-François Deleuze Didier Hannequin Emmanuelle Genin Philippe Amouyel Stéphanie Debette Jean-Charles Lambert Dominique Campion Olivier Martinaud Aline Zarea Stéphanie Bombois Marie-Anne Mackowiak Vincent Deramecourt Agnès Michon Isabelle Le Ber Bruno Dubois Olivier Godefroy Frédérique Etcharry-Bouyx Valérie Chauviré Ludivine Chamard Eric Berger Eloi Magnin 1 Sophie Auriacombe François Tison Vincent de La Sayette Dominique Castan Elsa Dionet François Sellal Olivier Rouaud Christel Thauvin Olivier Moreaud Mathilde Sauvée Maïté Formaglio Hélène Mollion Isabelle Roullet-Solignac Alain Vighetto Bernard Croisile Mira Didic Olivier Félician Lejla Koric Mathieu Ceccaldi Audrey Gabelle Cecilia Marelli Pierre Labauge Thérèse Jonveaux Martine Vercelletto Claire Boutoleau-Bretonnière Giovanni Castelnovo Claire Paquet Julien Dumurgier Jacques Hugon Foucauld de Boisgueheneuc Serge Belliard Serge Bakchine Marie Sarazin Marie-Odile Barrellon Bernard Laurent Frédéric Blanc Jérémie Pariente Snejana Jurici 
Abstract : We performed whole-exome and whole-genome sequencing in 927 late-onset Alzheimer disease (LOAD) cases, 852 early-onset AD (EOAD) cases, and 1273 controls from France. We assessed the evidence for gene-based association of rare variants with AD in 6 genes for which an association with such variants was previously claimed. When aggregating protein-truncating and missense-predicted damaging variants, we found exome-wide significant association between EOAD risk and rare variants in SORL1, TREM2, and ABCA7. No exome-wide significant signal was obtained in the LOAD sample, and significance of the order of 10-6 was observed in the whole AD group for TREM2. Our study confirms previous gene-level results for TREM2, SORL1, and ABCA7 and provides a clearer insight into the classes of rare variants involved. Despite different effect sizes and varying cumulative minor allele frequencies, the rare protein-truncating and missense-predicted damaging variants in TREM2, SORL1, and ABCA7 contribute similarly to the heritability of EOAD and explain between 1.1% and 1.5% of EOAD heritability each, compared with 9.12% for APOE ε4.
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Submitted on : Monday, April 4, 2022 - 6:40:24 PM
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Céline Bellenguez, Camille Charbonnier, Benjamin Grenier-Boley, Olivier Quenez, Kilan Le Guennec, et al.. Contribution to Alzheimer's disease risk of rare variants in TREM2, SORL1, and ABCA7 in 1779 cases and 1273 controls. Neurobiology of Aging, Elsevier, 2017, 59, pp.220.e1-220.e9. ⟨10.1016/j.neurobiolaging.2017.07.001⟩. ⟨hal-03630186⟩

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