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Whole exome sequencing study identifies novel rare and common Alzheimer’s-Associated variants involved in immune response and transcriptional regulation

2018; Springer Nature; Volume: 25; Issue: 8 Linguagem: Inglês

10.1038/s41380-018-0112-7

1476-5578

Joshua C. Bis, Xueqiu Jian, Brian W. Kunkle, Yuning Chen, Kara L. Hamilton‐Nelson, William S. Bush, William Salerno, Daniel Lancour, Yiyi Ma, Alan E. Renton, Edoardo Marcora, John Farrell, Yi Zhao, Liming Qu, Shahzad Ahmad, Najaf Amin, Philippe Amouyel, Gary W. Beecham, Jennifer E. Below, Dominique Campion, Laura Cantwell, Camille Charbonnier, Jaeyoon Chung, Paul K. Crane, Carlos Cruchaga, L. Adrienne Cupples, Jean‐François Dartigues, Stéphanie Debette, Jean‐François Deleuze, Lucinda A. Fulton, Stacey Gabriel, Emmanuelle Génin, Richard A. Gibbs, Alison Goate, Benjamin Grenier‐Boley, Namrata Gupta, Jonathan L. Haines, Aki S. Havulinna, Seppo Helisalmi, Mikko Hiltunen, Daniel P. Howrigan, M. Arfan Ikram, Jaakko Kaprio, Jan Konrad, Amanda Kuzma, Eric S. Lander, Mark Lathrop, Terho Lehtimäki, Honghuang Lin, Kari Mattila, Richard Mayeux, Donna M. Muzny, Waleed Nasser, Benjamin M. Neale, Kwangsik Nho, Gaël Nicolas, Devanshi Patel, Margaret A. Pericak‐Vance, Markus Perola, Bruce M. Psaty, Olivier Quenez, Farid Rajabli, Richard Redon, Christiane Reitz, Anne M. Remes, Veikko Salomaa, Chloé Sarnowski, Helena Schmidt, Michael A. Schmidt, Reinhold Schmidt, Hilkka Soininen, Timothy Thornton, Giuseppe Tosto, Christophe Tzourio, Sven J. van der Lee, Cornelia M. van Duijn, Otto Valladares, Badri N. Vardarajan, Li-San Wang, Weixin Wang, Ellen M. Wijsman, Richard K. Wilson, Daniela Witten, Kim C. Worley, Xiaoling Zhang, Céline Bellenguez, Jean‐Charles Lambert, Mitja I. Kurki, Aarno Palotie, Mark J. Daly, Eric Boerwinkle, Kathryn L. Lunetta, Anita L. DeStefano, Josée Dupuis, Eden R. Martin, Gerard D. Schellenberg, Sudha Seshadri, Adam C. Naj, Myriam Fornage, Lindsay A. Farrer,

Nuclear Receptors and Signaling

The Alzheimer's Disease Sequencing Project (ADSP) undertook whole exome sequencing in 5,740 late-onset Alzheimer disease (AD) cases and 5,096 cognitively normal controls primarily of European ancestry (EA), among whom 218 cases and 177 controls were Caribbean Hispanic (CH). An age-, sex- and APOE based risk score and family history were used to select cases most likely to harbor novel AD risk variants and controls least likely to develop AD by age 85 years. We tested ~1.5 million single nucleotide variants (SNVs) and 50,000 insertion-deletion polymorphisms (indels) for association to AD, using multiple models considering individual variants as well as gene-based tests aggregating rare, predicted functional, and loss of function variants. Sixteen single variants and 19 genes that met criteria for significant or suggestive associations after multiple-testing correction were evaluated for replication in four independent samples; three with whole exome sequencing (2,778 cases, 7,262 controls) and one with genome-wide genotyping imputed to the Haplotype Reference Consortium panel (9,343 cases, 11,527 controls). The top findings in the discovery sample were also followed-up in the ADSP whole-genome sequenced family-based dataset (197 members of 42 EA families and 501 members of 157 CH families). We identified novel and predicted functional genetic variants in genes previously associated with AD. We also detected associations in three novel genes: IGHG3 (p = 9.8 × 10