Contribution to Alzheimer's disease risk of rare variants in TREM2, SORL1, and ABCA7 in 1779 cases and 1273 controls. Bellenguez, C., Charbonnier, C., Grenier-Boley, B., Quenez, O., Le Guennec, K., Nicolas, G., Chauhan, G., Wallon, D., Rousseau, S., Richard, A. C., Boland, A., Bourque, G., Munter, H. M., Olaso, R., Meyer, V., Rollin-Sillaire, A., Pasquier, F., Letenneur, L., Redon, R., Dartigues, J., Tzourio, C., Frebourg, T., Lathrop, M., Deleuze, J., Hannequin, D., Genin, E., Amouyel, P., Debette, S., Lambert, J., Campion, D., & CNR MAJ collaborators Neurobiology of Aging, 59:220.e1–220.e9, November, 2017. doi abstract bibtex 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.
@article{bellenguez_contribution_2017,
title = {Contribution to {Alzheimer}'s disease risk of rare variants in {TREM2}, {SORL1}, and {ABCA7} in 1779 cases and 1273 controls},
volume = {59},
issn = {1558-1497},
doi = {10.1016/j.neurobiolaging.2017.07.001},
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.},
language = {eng},
journal = {Neurobiology of Aging},
author = {Bellenguez, Céline and Charbonnier, Camille and Grenier-Boley, Benjamin and Quenez, Olivier and Le Guennec, Kilan and Nicolas, Gaël and Chauhan, Ganesh and Wallon, David and Rousseau, Stéphane and Richard, Anne Claire and Boland, Anne and Bourque, Guillaume and Munter, Hans Markus and Olaso, Robert and Meyer, Vincent and Rollin-Sillaire, Adeline and Pasquier, Florence and Letenneur, Luc and Redon, Richard and Dartigues, Jean-François and Tzourio, Christophe and Frebourg, Thierry and Lathrop, Mark and Deleuze, Jean-François and Hannequin, Didier and Genin, Emmanuelle and Amouyel, Philippe and Debette, Stéphanie and Lambert, Jean-Charles and Campion, Dominique and {CNR MAJ collaborators}},
month = nov,
year = {2017},
pmid = {28789839},
keywords = {Aged, Alzheimer Disease, Humans, Female, Male, Middle Aged, Adult, Aged, 80 and over, Alzheimer's disease, Genetic Predisposition to Disease, Apolipoprotein E4, Genome-Wide Association Study, Membrane Glycoproteins, Receptors, Immunologic, ATP-Binding Cassette Transporters, Genetic Variation, Young Adult, Genetic Association Studies, ABCA7, LDL-Receptor Related Proteins, Membrane Transport Proteins, SORL1, TREM2, Whole Genome Sequencing},
pages = {220.e1--220.e9}
}
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M.","Olaso, R.","Meyer, V.","Rollin-Sillaire, A.","Pasquier, F.","Letenneur, L.","Redon, R.","Dartigues, J.","Tzourio, C.","Frebourg, T.","Lathrop, M.","Deleuze, J.","Hannequin, D.","Genin, E.","Amouyel, P.","Debette, S.","Lambert, J.","Campion, D.","CNR MAJ collaborators"],"bibdata":{"bibtype":"article","type":"article","title":"Contribution to Alzheimer's disease risk of rare variants in TREM2, SORL1, and ABCA7 in 1779 cases and 1273 controls","volume":"59","issn":"1558-1497","doi":"10.1016/j.neurobiolaging.2017.07.001","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.","language":"eng","journal":"Neurobiology of Aging","author":[{"propositions":[],"lastnames":["Bellenguez"],"firstnames":["Céline"],"suffixes":[]},{"propositions":[],"lastnames":["Charbonnier"],"firstnames":["Camille"],"suffixes":[]},{"propositions":[],"lastnames":["Grenier-Boley"],"firstnames":["Benjamin"],"suffixes":[]},{"propositions":[],"lastnames":["Quenez"],"firstnames":["Olivier"],"suffixes":[]},{"propositions":[],"lastnames":["Le","Guennec"],"firstnames":["Kilan"],"suffixes":[]},{"propositions":[],"lastnames":["Nicolas"],"firstnames":["Gaël"],"suffixes":[]},{"propositions":[],"lastnames":["Chauhan"],"firstnames":["Ganesh"],"suffixes":[]},{"propositions":[],"lastnames":["Wallon"],"firstnames":["David"],"suffixes":[]},{"propositions":[],"lastnames":["Rousseau"],"firstnames":["Stéphane"],"suffixes":[]},{"propositions":[],"lastnames":["Richard"],"firstnames":["Anne","Claire"],"suffixes":[]},{"propositions":[],"lastnames":["Boland"],"firstnames":["Anne"],"suffixes":[]},{"propositions":[],"lastnames":["Bourque"],"firstnames":["Guillaume"],"suffixes":[]},{"propositions":[],"lastnames":["Munter"],"firstnames":["Hans","Markus"],"suffixes":[]},{"propositions":[],"lastnames":["Olaso"],"firstnames":["Robert"],"suffixes":[]},{"propositions":[],"lastnames":["Meyer"],"firstnames":["Vincent"],"suffixes":[]},{"propositions":[],"lastnames":["Rollin-Sillaire"],"firstnames":["Adeline"],"suffixes":[]},{"propositions":[],"lastnames":["Pasquier"],"firstnames":["Florence"],"suffixes":[]},{"propositions":[],"lastnames":["Letenneur"],"firstnames":["Luc"],"suffixes":[]},{"propositions":[],"lastnames":["Redon"],"firstnames":["Richard"],"suffixes":[]},{"propositions":[],"lastnames":["Dartigues"],"firstnames":["Jean-François"],"suffixes":[]},{"propositions":[],"lastnames":["Tzourio"],"firstnames":["Christophe"],"suffixes":[]},{"propositions":[],"lastnames":["Frebourg"],"firstnames":["Thierry"],"suffixes":[]},{"propositions":[],"lastnames":["Lathrop"],"firstnames":["Mark"],"suffixes":[]},{"propositions":[],"lastnames":["Deleuze"],"firstnames":["Jean-François"],"suffixes":[]},{"propositions":[],"lastnames":["Hannequin"],"firstnames":["Didier"],"suffixes":[]},{"propositions":[],"lastnames":["Genin"],"firstnames":["Emmanuelle"],"suffixes":[]},{"propositions":[],"lastnames":["Amouyel"],"firstnames":["Philippe"],"suffixes":[]},{"propositions":[],"lastnames":["Debette"],"firstnames":["Stéphanie"],"suffixes":[]},{"propositions":[],"lastnames":["Lambert"],"firstnames":["Jean-Charles"],"suffixes":[]},{"propositions":[],"lastnames":["Campion"],"firstnames":["Dominique"],"suffixes":[]},{"firstnames":[],"propositions":[],"lastnames":["CNR MAJ collaborators"],"suffixes":[]}],"month":"November","year":"2017","pmid":"28789839","keywords":"Aged, Alzheimer Disease, Humans, Female, Male, Middle Aged, Adult, Aged, 80 and over, Alzheimer's disease, Genetic Predisposition to Disease, Apolipoprotein E4, Genome-Wide Association Study, Membrane Glycoproteins, Receptors, Immunologic, ATP-Binding Cassette Transporters, Genetic Variation, Young Adult, Genetic Association Studies, ABCA7, LDL-Receptor Related Proteins, Membrane Transport Proteins, SORL1, TREM2, Whole Genome Sequencing","pages":"220.e1–220.e9","bibtex":"@article{bellenguez_contribution_2017,\n\ttitle = {Contribution to {Alzheimer}'s disease risk of rare variants in {TREM2}, {SORL1}, and {ABCA7} in 1779 cases and 1273 controls},\n\tvolume = {59},\n\tissn = {1558-1497},\n\tdoi = {10.1016/j.neurobiolaging.2017.07.001},\n\tabstract = {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. 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