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| [PMID]: | 28738127 |
| [Au] Autor: | Kunkle BW; Vardarajan BN; Naj AC; Whitehead PL; Rolati S; Slifer S; Carney RM; Cuccaro ML; Vance JM; Gilbert JR; Wang LS; Farrer LA; Reitz C; Haines JL; Beecham GW; Martin ER; Schellenberg GD; Mayeux RP; Pericak-Vance MA |
| [Ad] Endereço: | John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, Florida. |
| [Ti] Título: | Early-Onset Alzheimer Disease and Candidate Risk Genes Involved in Endolysosomal Transport. |
| [So] Source: | JAMA Neurol;74(9):1113-1122, 2017 Sep 01. | | [Is] ISSN: | 2168-6157 |
| [Cp] País de publicação: | United States |
| [La] Idioma: | eng |
| [Ab] Resumo: | Importance: Mutations in APP, PSEN1, and PSEN2 lead to early-onset Alzheimer disease (EOAD) but account for only approximately 11% of EOAD overall, leaving most of the genetic risk for the most severe form of Alzheimer disease unexplained. This extreme phenotype likely harbors highly penetrant risk variants, making it primed for discovery of novel risk genes and pathways for AD. Objective: To search for rare variants contributing to the risk for EOAD. Design, Setting, and Participants: In this case-control study, whole-exome sequencing (WES) was performed in 51 non-Hispanic white (NHW) patients with EOAD (age at onset <65 years) and 19 Caribbean Hispanic families previously screened as negative for established APP, PSEN1, and PSEN2 causal variants. Participants were recruited from John P. Hussman Institute for Human Genomics, Case Western Reserve University, and Columbia University. Rare, deleterious, nonsynonymous, or loss-of-function variants were filtered to identify variants in known and suspected AD genes, variants in multiple unrelated NHW patients, variants present in 19 Hispanic EOAD WES families, and genes with variants in multiple unrelated NHW patients. These variants/genes were tested for association in an independent cohort of 1524 patients with EOAD, 7046 patients with late-onset AD (LOAD), and 7001 cognitively intact controls (age at examination, >65 years) from the Alzheimer's Disease Genetics Consortium. The study was conducted from January 21, 2013, to October 13, 2016. Main Outcomes and Measures: Alzheimer disease diagnosed according to standard National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer Disease and Related Disorders Association criteria. Association between Alzheimer disease and genetic variants and genes was measured using logistic regression and sequence kernel association test-optimal gene tests, respectively. Results: Of the 1524 NHW patients with EOAD, 765 (50.2%) were women and mean (SD) age was 60.0 (4.9) years; of the 7046 NHW patients with LOAD, 4171 (59.2%) were women and mean (SD) age was 77.4 (8.6) years; and of the 7001 NHW controls, 4215 (60.2%) were women and mean (SD) age was 77.4 (8.6) years. The gene PSD2, for which multiple unrelated NHW cases had rare missense variants, was significantly associated with EOAD (P = 2.05 × 10-6; Bonferroni-corrected P value [BP] = 1.3 × 10-3) and LOAD (P = 6.22 × 10-6; BP = 4.1 × 10-3). A missense variant in TCIRG1, present in a NHW patient and segregating in 3 cases of a Hispanic family, was more frequent in EOAD cases (odds ratio [OR], 2.13; 95% CI, 0.99-4.55; P = .06; BP = 0.413), and significantly associated with LOAD (OR, 2.23; 95% CI, 1.37-3.62; P = 7.2 × 10-4; BP = 5.0 × 10-3). A missense variant in the LOAD risk gene RIN3 showed suggestive evidence of association with EOAD after Bonferroni correction (OR, 4.56; 95% CI, 1.26-16.48; P = .02, BP = 0.091). In addition, a missense variant in RUFY1 identified in 2 NHW EOAD cases showed suggestive evidence of an association with EOAD as well (OR, 18.63; 95% CI, 1.62-213.45; P = .003; BP = 0.129). Conclusions and Relevance: The genes PSD2, TCIRG1, RIN3, and RUFY1 all may be involved in endolysosomal transport-a process known to be important to development of AD. Furthermore, this study identified shared risk genes between EOAD and LOAD similar to previously reported genes, such as SORL1, PSEN2, and TREM2. |
| [Mh] Termos MeSH primário: |
Doença de Alzheimer/genética
Transporte Biológico/genética
Proteínas de Transporte/genética
Fatores de Troca do Nucleotídeo Guanina/genética
Peptídeos e Proteínas de Sinalização Intracelular/genética
ATPases Vacuolares Próton-Translocadoras/genética
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| [Mh] Termos MeSH secundário: |
Idade de Início
Idoso
Idoso de 80 Anos ou mais
Região do Caribe
Estudos de Casos e Controles
Grupo com Ancestrais do Continente Europeu/genética
Exoma
Feminino
Hispano-Americanos/genética
Seres Humanos
Masculino
Meia-Idade
Fatores de Risco
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| [Pt] Tipo de publicação: | JOURNAL ARTICLE |
[Nm] Nome de substância:
| 0 (Carrier Proteins); 0 (Guanine Nucleotide Exchange Factors); 0 (Intracellular Signaling Peptides and Proteins); 0 (RIN3 protein, human); 0 (RUFY1 protein, human); 0 (TCIRG1 protein, human); EC 3.6.1.- (Vacuolar Proton-Translocating ATPases) |
| [Em] Mês de entrada: | 1710 |
| [Cu] Atualização por classe: | 171004 |
[Lr] Data última revisão:
| 171004 |
| [Sb] Subgrupo de revista: | AIM; IM |
| [Da] Data de entrada para processamento: | 170725 |
| [St] Status: | MEDLINE |
| [do] DOI: | 10.1001/jamaneurol.2017.1518 |
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