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. 2018 Aug 14;10.1038/s41380-018-0112-7.
doi: 10.1038/s41380-018-0112-7. Online ahead of print.

Whole Exome Sequencing Study Identifies Novel Rare and Common Alzheimer's-Associated Variants Involved in Immune Response and Transcriptional Regulation

Joshua C Bis  1 Xueqiu Jian  2 Brian W Kunkle  3 Yuning Chen  4 Kara L Hamilton-Nelson  3 William S Bush  5 William J Salerno  6 Daniel Lancour  7 Yiyi Ma  7 Alan E Renton  8 Edoardo Marcora  8   9 John J Farrell  7 Yi Zhao  10 Liming Qu  10 Shahzad Ahmad  11 Najaf Amin  12 Philippe Amouyel  12   13   14 Gary W Beecham  3 Jennifer E Below  15 Dominique Campion  16   17 Laura Cantwell  10 Camille Charbonnier  16 Jaeyoon Chung  7 Paul K Crane  1 Carlos Cruchaga  18 L Adrienne Cupples  4   19 Jean-François Dartigues  20 Stéphanie Debette  20   21 Jean-François Deleuze  22 Lucinda Fulton  23 Stacey B Gabriel  24 Emmanuelle Genin  25 Richard A Gibbs  6 Alison Goate  8   9 Benjamin Grenier-Boley  12 Namrata Gupta  24 Jonathan L Haines  5 Aki S Havulinna  26   27 Seppo Helisalmi  28 Mikko Hiltunen  29 Daniel P Howrigan  30   31 M Arfan Ikram  11 Jaakko Kaprio  26 Jan Konrad  18 Amanda Kuzma  10 Eric S Lander  24 Mark Lathrop  32 Terho Lehtimäki  33 Honghuang Lin  34 Kari Mattila  33 Richard Mayeux  35 Donna M Muzny  6 Waleed Nasser  6 Benjamin Neale  30   31 Kwangsik Nho  36 Gaël Nicolas  16 Devanshi Patel  7 Margaret A Pericak-Vance  3 Markus Perola  26   27   37 Bruce M Psaty  1   38   39   40 Olivier Quenez  16 Farid Rajabli  3 Richard Redon  41 Christiane Reitz  35 Anne M Remes  28   42 Veikko Salomaa  27 Chloe Sarnowski  4 Helena Schmidt  43 Michael Schmidt  3 Reinhold Schmidt  43 Hilkka Soininen  28   44 Timothy A Thornton  45 Giuseppe Tosto  35 Christophe Tzourio  20 Sven J van der Lee  11 Cornelia M van Duijn  11 Otto Valladares  10 Badri Vardarajan  35 Li-San Wang  10 Weixin Wang  10 Ellen Wijsman  46   47 Richard K Wilson  23 Daniela Witten  45   47 Kim C Worley  6 Xiaoling Zhang  4   7 Alzheimer’s Disease Sequencing ProjectCeline Bellenguez  12 Jean-Charles Lambert  12 Mitja I Kurki  26   30   31 Aarno Palotie  26   30   31 Mark Daly  24   26   31 Eric Boerwinkle  6   48 Kathryn L Lunetta  4 Anita L Destefano  4   49 Josée Dupuis  4 Eden R Martin  3 Gerard D Schellenberg  10 Sudha Seshadri  19   49   50 Adam C Naj  10 Myriam Fornage  2   48 Lindsay A Farrer  51   52   53   54   55
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Free PMC article

Whole Exome Sequencing Study Identifies Novel Rare and Common Alzheimer's-Associated Variants Involved in Immune Response and Transcriptional Regulation

Joshua C Bis et al. Mol Psychiatry. .
Free PMC article

Erratum in

  • Correction: Whole exome sequencing study identifies novel rare and common Alzheimer's-Associated variants involved in immune response and transcriptional regulation.
    Bis 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, Cantwell L, Charbonnier C, Chung J, Crane PK, Cruchaga C, Cupples LA, Dartigues JF, Debette S, Deleuze JF, 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, Ikram MA, 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, Valladares O, Vardarajan B, Wang LS, Wang W, Wijsman E, Wilson RK, Witten D, Worley KC, Zhang X; Alzheimer’s Disease Sequencing Project, Bellenguez C, Lambert JC, 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. Bis JC, et al. Mol Psychiatry. 2019 Oct 21. doi: 10.1038/s41380-019-0529-7. Online ahead of print. Mol Psychiatry. 2019. PMID: 31636380

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 × 10-7), an immunoglobulin gene whose antibodies interact with β-amyloid, a long non-coding RNA AC099552.4 (p = 1.2 × 10-7), and a zinc-finger protein ZNF655 (gene-based p = 5.0 × 10-6). The latter two suggest an important role for transcriptional regulation in AD pathogenesis.

Conflict of interest statement

Conflict of interest

Celine Bellenguez received personal fees from Genoscrenn unrelated to current study. HS reports grants from Austrian Science Fond (FWF) and Österreichische Nationalbank Anniversary Fund during the conduct of the study. AMG received grants from NIA, Genentech, Pfizer, and Astra Zeneca as well as personal fees from Finnegan HC, Cognition Therapeutics, Dickstein Shapiro, Genentech, and Amgen, all unrelated to the current study. In addition, AMG has a patent (US20070258898) issued, and a patent with royalties paid by Taconic. J-FD received grants and personal fees from IPSEN and Novartis, and personal fees from Newron. MAP-V received personal fees from Athena Neurosciences unrelated to current study. The other authors declare no conflict of interest.

Figures

Fig. 1
Fig. 1
Manhattan plot showing genome-wide association results for individual common variants. The plot shows the p-values from the Discovery meta-analysis against their genomic position for association with AD. Only variants with a combined minor allele count of ≥ 10 were included; the minimum p-value from the three adjustment models for either the meta-analysis, European Ancestry (EA), or Caribbean Hispanic (CH) is plotted for each variant. Genes containing the variant are indicated above points that surpassed our significance threshold for follow-up. The dotted line indicates the threshold for follow-up, p < 6.1 × 10−6, corresponding to (1 / #variants) tested. The dashed line indicates the threshold for exome-wide significance, p < 3.1 × 10−7, corresponding to (0.05 / #variants tested)
Fig. 2
Fig. 2
Manhattan plots showing exome-wide association results for gene-based tests of rare functional variants. The plots show the gene-based p-values from the Discovery meta-analysis against their geno-mic position for association with AD. Each point represents a p-value from SKAT-O test aggregating rare variants (MAF < 5%), by gene, on the basis of predicted functional impact. Only genes with a cumulative minor allele count of ≥ 10 were included; the minimum p-value from the three adjustment models for either the meta-analysis, European Ancestry (EA), or Caribbean Hispanic (CH) is plotted for each variant. Genes are indicated above points that surpassed our significance threshold for follow-up in tests aggregating only (a) moderate or high impact variants, (b) high impact variants; (c) loss-of-function variants. In each plot, the dotted line indicates the threshold for follow-up: (a) p<5.5 × 10−5, (b) p<6.3 × 10−5, (c) p<2.8 × 10−4, each corresponding to 1 / # genes tested. The dashed line indicates the threshold for exome-wide significance: (a) p<2.7 × 10−6, (b) p<3.1 × 10−6, (c) p < 1.4 × 10−5, each corresponding to 0.05 / # genes tested
Fig. 3
Fig. 3
Distribution of high impact, LoF and high-confidence LoF variants grouped by predicted consequence

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References

    1. Escott-Price V, Bellenguez C, Wang LS, Choi SH, Harold D, Jones L, et al. Gene-wide analysis detects two new susceptibility genes for Alzheimer’s disease. PLoS One 2014;9:e94661. - PMC - PubMed
    1. Escott-Price V, Sims R, Bannister C, Harold D, Vronskaya M, Majounie E, et al. Common polygenic variation enhances risk prediction for Alzheimer’s disease. Brain 2015;138:3673–84. - PMC - PubMed
    1. Guerreiro R, Wojtas A, Bras J, Carrasquillo M, Rogaeva E, Majounie E, et al. TREM2 variants in Alzheimer’s disease. N Engl J Med 2013;368:117–27. - PMC - PubMed
    1. Harold D, Abraham R, Hollingworth P, Sims R, Gerrish A, Hamshere ML, et al. Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer’s disease. Nat Genet 2009;41:1088–93. - PMC - PubMed
    1. Hollingworth P, Harold D, Sims R, Gerrish A, Lambert JC, Carrasquillo MM, et al. Common variants at ABCA7, MS4A6A/ MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer’s disease. Nat Genet 2011;43:429–35. - PMC - PubMed

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