Whole‐genome sequencing study in Koreans identifies novel loci for Alzheimer's disease

초록

<jats:title>Abstract</jats:title><jats:sec><jats:title>INTRODUCTION</jats:title><jats:p>The genetic basis of Alzheimer's disease (AD) in Koreans is poorly understood.</jats:p></jats:sec><jats:sec><jats:title>METHODS</jats:title><jats:p>We performed an AD genome‐wide association study using whole‐genome sequence data from 3540 Koreans (1583 AD cases, 1957 controls) and single‐nucleotide polymorphism array data from 2978 Japanese (1336 AD cases, 1642 controls). Significant findings were evaluated by pathway enrichment and differential gene expression analysis in brain tissue from controls and AD cases with and without dementia prior to death.</jats:p></jats:sec><jats:sec><jats:title>RESULTS</jats:title><jats:p>We identified genome‐wide significant associations with <jats:italic>APOE</jats:italic> in the total sample and <jats:italic>ROCK2</jats:italic> (rs76484417, <jats:italic>p </jats:italic>= 2.71×10<jats:sup>−8</jats:sup>) among <jats:italic>APOE ε</jats:italic>4 non‐carriers. A study‐wide significant association was found with aggregated rare variants in <jats:italic>MICALL1</jats:italic> (MICAL like 1) (<jats:italic>p </jats:italic>= 9.04×10<jats:sup>−7</jats:sup>). Several novel AD‐associated genes, including <jats:italic>ROCK2</jats:italic> and <jats:italic>MICALL1</jats:italic>, were differentially expressed in AD cases compared to controls (<jats:italic>p</jats:italic> < 3.33×10<jats:sup>−3</jats:sup>). <jats:italic>ROCK2</jats:italic> was also differentially expressed between AD cases with and without dementia (<jats:italic>p </jats:italic>= 1.34×10<jats:sup>−4</jats:sup>).</jats:p></jats:sec><jats:sec><jats:title>DISCUSSION</jats:title><jats:p>Our results provide insight into genetic mechanisms leading to AD and cognitive resilience in East Asians.</jats:p></jats:sec><jats:sec><jats:title>Highlights</jats:title><jats:p><jats:list list-type="bullet"> <jats:list-item><jats:p>Novel genome‐wide significant associations for AD identified with <jats:italic>ROCK2</jats:italic> and <jats:italic>MICALL1</jats:italic>.</jats:p></jats:list-item> <jats:list-item><jats:p><jats:italic>ROCK2</jats:italic> and <jats:italic>MICALL1</jats:italic> are differentially expressed between AD cases and controls in the brain.</jats:p></jats:list-item> <jats:list-item><jats:p>This is the largest whole‐genome‐sequence study of AD in an East Asian population.</jats:p></jats:list-item> </jats:list></jats:p></jats:sec>

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