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

TitleWhole exome sequencing study identifies novel rare and common Alzheimer's-Associated variants involved in immune response and transcriptional regulation.
Publication TypeJournal Article
Year of Publication2018
AuthorsBis, JC, Jian, X, Kunkle, BW, Chen, Y, Hamilton-Nelson, KL, Bush, WS, Salerno, WJ, Lancour, D, Ma, Y, Renton, AE, Marcora, E, Farrell, JJ, Zhao, Y, Qu, L, Ahmad, S, Amin, N, Amouyel, P, Beecham, GW, Below, JE, Campion, D, Charbonnier, C, Chung, J, Crane, PK, Cruchaga, C, L Cupples, A, Dartigues, J-F, Debette, S, Deleuze, J-F, Fulton, L, Gabriel, SB, Genin, E, Gibbs, RA, Goate, A, Grenier-Boley, B, Gupta, N, Haines, JL, Havulinna, AS, Helisalmi, S, Hiltunen, M, Howrigan, DP, M Ikram, A, Kaprio, J, Konrad, J, Kuzma, A, Lander, ES, Lathrop, M, Lehtimäki, T, Lin, H, Mattila, K, Mayeux, R, Muzny, DM, Nasser, W, Neale, B, Nho, K, Nicolas, G, Patel, D, Pericak-Vance, MA, Perola, M, Psaty, BM, Quenez, O, Rajabli, F, Redon, R, Reitz, C, Remes, AM, Salomaa, V, Sarnowski, C, Schmidt, H, Schmidt, M, Schmidt, R, Soininen, H, Thornton, TA, Tosto, G, Tzourio, C, van der Lee, SJ, van Duijn, CM, Vardarajan, B, Wang, W, Wijsman, E, Wilson, RK, Witten, D, Worley, KC, Zhang, X, Bellenguez, C, Lambert, J-C, Kurki, MI, Palotie, A, Daly, M, Boerwinkle, E, Lunetta, KL, DeStefano, AL, Dupuis, J, Martin, ER, Schellenberg, GD, Seshadri, S, Naj, AC, Fornage, M, Farrer, LA
Corporate Authors
JournalMol Psychiatry
Date Published2018 Aug 14
ISSN1476-5578
Abstract

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), an immunoglobulin gene whose antibodies interact with β-amyloid, a long non-coding RNA AC099552.4 (p = 1.2 × 10), and a zinc-finger protein ZNF655 (gene-based p = 5.0 × 10). The latter two suggest an important role for transcriptional regulation in AD pathogenesis.

DOI10.1038/s41380-018-0112-7
Alternate JournalMol. Psychiatry
PubMed ID30108311
Grant ListR01 AG058501 / AG / NIA NIH HHS / United States
U01AG049508 / / U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging) /
U01 AG032984 / AG / NIA NIH HHS / United States
U01AG049506 / / U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging) /
P01 AG003991 / AG / NIA NIH HHS / United States
P50 AG005681 / AG / NIA NIH HHS / United States
P30 AG013846 / AG / NIA NIH HHS / United States
UF1AG047133 / / U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging) /
UF1 AG047133 / AG / NIA NIH HHS / United States
U01AG049507 / / U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging) /
U01 AG049508 / AG / NIA NIH HHS / United States
R01 AG048927 / AG / NIA NIH HHS / United States
U01AG049505 / / U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging) /
R01 AG025259 / AG / NIA NIH HHS / United States
RF1 AG057519 / AG / NIA NIH HHS / United States