BRAIN and NERVE－神経研究の進歩71巻10号

2019年10月発行

特集 認知症と遺伝

アルツハイマー病の遺伝的背景—GWASから何がわかったか

著者： 尾崎浩一¹² 新飯田俊平¹

所属機関： ¹国立長寿医療研究センターメディカルゲノムセンター ²理化学研究所生命医科学研究センター

ページ範囲：P.1039 - P.1051

文献概要

認知症，特にアルツハイマー病の発症には遺伝素因が大きく関与していることが知られており，遺伝素因の解明を出発点とすることにより，エビデンスに基づいた精密医療が可能になると考えられる。近年，数万人を対象として，全ゲノムにわたる一塩基多型を用いた大規模ゲノムワイド関連解析などの体系的解析が進められ，真の疾患感受性遺伝子群の同定や疾患発症パスウェイの解明から病態が明らかになりつつある。

参考文献

1)Prince M, Bryce R, Albanese E, Wimo A, Ribeiro W, et al: The global prevalence of dementia: a systematic review and metaanalysis. Alzheimers Dement 9: 63-75. e2, 2013

2)Nicolas G, Charbonnier C, Campion D: From common to rare variants: the genetic component of Alzheimer disease. Hum Hered 81: 129-141, 2016

3)Gatz M, Reynolds CA, Fratiglioni L, Johansson B, Mortimer JA, et al: Role of genes and environments for explaining Alzheimer disease. Arch Gen Psychiatry 63: 168-174, 2006

4)Matsukura M, Ozaki K, Takahashi A, Onouchi Y, Morizono T, et al: Genome-wide association study of peripheral arterial disease in a Japanese population. PLOS ONE 10: e0139262, 2015［doi: 10.1371/journal.pone.0139262］

5)Ozaki K, Ohnishi Y, Iida A, Sekine A, Yamada R, et al: Functional SNPs in the lymphotoxin-alpha gene that are associated with susceptibility to myocardial infarction. Nat Genet 32: 650-654, 2002

6)Ozaki K, Inoue K, Sato H, Iida A, Ohnishi Y, et al: Functional variation in LGALS2 confers risk of myocardial infarction and regulates lymphotoxin-alpha secretion in vitro. Nature 429: 72-75, 2004

7)Ozaki K, Sato H, Iida A, Mizuno H, Nakamura T, et al: A functional SNP in PSMA6 confers risk of myocardial infarction in the Japanese population. Nat Genet 38: 921-925, 2006

8)Ozaki K, Sato H, Inoue K, Tsunoda T, Sakata Y, et al: SNPs in BRAP associated with risk of myocardial infarction in Asian populations. Nat Genet 41: 329-333, 2009

9)Ozaki K, Tanaka T: Molecular genetics of coronary artery disease. J Hum Genet 61: 71-77, 2016

10)International HapMap Consortium: The International HapMap Project. Nature 426: 789-796, 2003

11)The 1000 Genomes Project Consortium: A global reference for human genetic variation. Nature 526: 68-74, 2015

12)Cuyvers E, Sleegers K: Genetic variations underlying Alzheimer's disease: evidence from genome-wide association studies and beyond. Lancet Neurol 15: 857-868, 2016

13)Lambert JC, Ibrahim-Verbaas CA, Harold D, Naj AC, Sims R, et al: Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease. Nat Genet 45: 1452-1458, 2013

14)Jansen IE, Savage JE, Watanabe K, Bryois J, Williams DM, et al: Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer's disease risk. Nat Genet 51: 404-413, 2019

15)Kunkle BW, Grenier-Boley B, Sims R, Bis JC, Damotte V, et al: Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing. Nat Genet 51: 414-430, 2019

16)Martin AR, Kanai M, Kamatani Y, Okada Y, Neale BM, et Al: Clinical use of current polygenic risk scores may exacerbate health disparities. Nat Genet 51: 584-591, 2019

17)Miyashita A, Koike A, Jun G, Wang LS, Takahashi S, et al: SORL1 is genetically associated with late-onset Alzheimer's disease in Japanese, Koreans and Caucasians. PLOS ONE 8: e58618, 2013［doi: 10.1371/journal.pone.0058618］

18)Hirano A, Ohara T, Takahashi A, Aoki M, Fuyuno Y, et al: A genome-wide association study of late-onset Alzheimer's disease in a Japanese population. Psychiatr Genet 25: 139-146, 2015

19)Sims R, van der Lee SJ, Naj AC, Bellenguez C, Badarinarayan N, et al: Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease. Nat Genet 49: 1373-1384, 2017

20)Asanomi Y, Shigemizu D, Miyashita A, Mitsumori R, Mori T, et al: A rare functional variant of SHARPIN attenuates the inflammatory response and associates with increased risk of late-onset Alzheimer's disease. Mol Med 25: 20, 2019［doi: 10.1186/s10020-019-0090-5］

21)Abbott A: Is ‘friendly fire’ in the brain provoking Alzheimer's disease? Nature 556: 426-428, 2018