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Holstege, Henne; Hulsman, Marc; Charbonnier, Camille; Grenier-Boley, Benjamin; Quenez, Olivier; Grozeva, Detelina; van Rooij, Jeroen G. J.; Sims, Rebecca; Ahmad, Shahzad; Amin, Najaf; Norsworthy, Penny J.; Dols-Icardo, Oriol; Hummerich, Holger; Kawalia, Amit; Amouyel, Philippe; Beecham, Gary W.; Berr, Claudine; Bis, Joshua C.; Boland, Anne; Bossù, Paola; Bouwman, Femke; Bras, Jose; Campion, Dominique; Cochran, J. Nicholas; [...]

Exome sequencing identifies rare damaging variants in ATP8B4 and ABCA1 as risk factors for Alzheimer’s disease

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  • Medientyp: E-Artikel
  • Titel: Exome sequencing identifies rare damaging variants in ATP8B4 and ABCA1 as risk factors for Alzheimer’s disease
  • Beteiligte: Holstege, Henne; Hulsman, Marc; Charbonnier, Camille; Grenier-Boley, Benjamin; Quenez, Olivier; Grozeva, Detelina; van Rooij, Jeroen G. J.; Sims, Rebecca; Ahmad, Shahzad; Amin, Najaf; Norsworthy, Penny J.; Dols-Icardo, Oriol; Hummerich, Holger; Kawalia, Amit; Amouyel, Philippe; Beecham, Gary W.; Berr, Claudine; Bis, Joshua C.; Boland, Anne; Bossù, Paola; Bouwman, Femke; Bras, Jose; Campion, Dominique; Cochran, J. Nicholas; [...]
  • Erschienen: Springer Science and Business Media LLC, 2022
  • Erschienen in: Nature Genetics
  • Sprache: Englisch
  • DOI: 10.1038/s41588-022-01208-7
  • ISSN: 1061-4036; 1546-1718
  • Entstehung:
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  • Beschreibung: <jats:title>Abstract</jats:title><jats:p>Alzheimer’s disease (AD), the leading cause of dementia, has an estimated heritability of approximately 70%<jats:sup>1</jats:sup>. The genetic component of AD has been mainly assessed using genome-wide association studies, which do not capture the risk contributed by rare variants<jats:sup>2</jats:sup>. Here, we compared the gene-based burden of rare damaging variants in exome sequencing data from 32,558 individuals—16,036 AD cases and 16,522 controls. Next to variants in <jats:italic>TREM2</jats:italic>, <jats:italic>SORL1</jats:italic> and <jats:italic>ABCA7</jats:italic>, we observed a significant association of rare, predicted damaging variants in <jats:italic>ATP8B4</jats:italic> and <jats:italic>ABCA1</jats:italic> with AD risk, and a suggestive signal in <jats:italic>ADAM10</jats:italic>. Additionally, the rare-variant burden in <jats:italic>RIN3, CLU, ZCWPW1</jats:italic> and <jats:italic>ACE</jats:italic> highlighted these genes as potential drivers of respective AD-genome-wide association study loci. Variants associated with the strongest effect on AD risk, in particular loss-of-function variants, are enriched in early-onset AD cases. Our results provide additional evidence for a major role for amyloid-β precursor protein processing, amyloid-β aggregation, lipid metabolism and microglial function in AD.</jats:p>