2021 Fiscal Year Final Research Report

Exploring rare variants associated with Alzheimer disease

Research Project

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Project/Area Number	19H03425
Research Category	Grant-in-Aid for Scientific Research (B)
Allocation Type	Single-year Grants
Section	一般
Review Section	Basic Section 48040:Medical biochemistry-related
Research Institution	International University of Health and Welfare
Principal Investigator	Tsuji Shoji 国際医療福祉大学, 医学部, 教授 (70150612)
Co-Investigator(Kenkyū-buntansha)	池内健新潟大学, 脳研究所, 教授 (20372469) 田中真生国際医療福祉大学, 医学部, 講師 (30774252) 石浦浩之東京大学, 医学部附属病院, 講師 (40632849)
Project Period (FY)	2019-04-01 – 2022-03-31
Keywords	association study / Alzheimer disease / rare variants
Outline of Final Research Achievements	To improve the power of association studies for relatively small sample size, we employed permutation testing to determine the p-value to be used for association studies. Employing exome sequence data obtained from 446 cases of sporadic Alzheimer disease (AD) and 446 aged controls with preserved cognitive function, we identified a candidate gene associated with AD. Since the candidate gene contains GC-rich regions, we optimized the methods for exon capture and library construction. We newly conducted exome sequence analysis of 262 cases of AD and 260 aged controls with preserved cognitive function. We confirmed that sequence data with high quality were obtained with the improved procedures. Although significant association of the candidate gene was not replicated, we found several candidate genes possibly associated with AD. The current study confirmed the utility of permutation testing for exome association studies.
Free Research Field	分子遺伝学
Academic Significance and Societal Importance of the Research Achievements	多因子疾患の発症に関わる遺伝子の探索は，ゲノムワイド関連解析 (genome-wide association study, GWAS)が行われる．関連解析では，個々の変異毎に，疾患群と対照群の間で検定を行うが，変異の数に対応した多重検定の補正が必要になり，有意水準としてのp値が極めて小さくなり，検出力を確保するために，巨大なサンプルサイズが必要となる．この課題を克服するために，permutationにより，有意水準としてのp値を定めることにより，検出力を高めることを検討し，この手法の有用性が高いことを見出し，多因子疾患の関連解析の新たな手法を提案した点に本研究の意義がある．