GWAS of multiple neuropathology endophenotypes identifies new risk loci and provides insights into the genetic risk of dementia

IF 31.7 1区 生物学 Q1 GENETICS & HEREDITY Nature genetics Pub Date : 2024-10-08 DOI:10.1038/s41588-024-01939-9
Lincoln M. P. Shade, Yuriko Katsumata, Erin L. Abner, Khine Zin Aung, Steven A. Claas, Qi Qiao, Bernardo Aguzzoli Heberle, J. Anthony Brandon, Madeline L. Page, Timothy J. Hohman, Shubhabrata Mukherjee, Richard P. Mayeux, Lindsay A. Farrer, Gerard D. Schellenberg, Jonathan L. Haines, Walter A. Kukull, Kwangsik Nho, Andrew J. Saykin, David A. Bennett, Julie A. Schneider, The National Alzheimer’s Coordinating Center, Mark T. W. Ebbert, Peter T. Nelson, David W. Fardo
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Abstract

Genome-wide association studies (GWAS) have identified >80 Alzheimer’s disease and related dementias (ADRD)-associated genetic loci. However, the clinical outcomes used in most previous studies belie the complex nature of underlying neuropathologies. Here we performed GWAS on 11 ADRD-related neuropathology endophenotypes with participants drawn from the following three sources: the National Alzheimer’s Coordinating Center, the Religious Orders Study and Rush Memory and Aging Project, and the Adult Changes in Thought study (n = 7,804 total autopsied participants). We identified eight independent significantly associated loci, of which four were new (COL4A1, PIK3R5, LZTS1 and APOC2). Separately testing known ADRD loci, 19 loci were significantly associated with at least one neuropathology after false-discovery rate adjustment. Genetic colocalization analyses identified pleiotropic effects and quantitative trait loci. Methylation in the cerebral cortex at two sites near APOC2 was associated with cerebral amyloid angiopathy. Studies that include neuropathology endophenotypes are an important step in understanding the mechanisms underlying genetic ADRD risk. Genome-wide analyses identify common variants associated with 11 distinct neuropathology endophenotypes, providing insights into the mechanisms underlying the genetic risk of Alzheimer’s disease and related dementias.

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多种神经病理学内表型的 GWAS 发现了新的风险基因位点,有助于深入了解痴呆症的遗传风险
全基因组关联研究(GWAS)发现了 80 个阿尔茨海默病及相关痴呆症(ADRD)的相关基因位点。然而,以往大多数研究采用的临床结果掩盖了潜在神经病理学的复杂性。在此,我们对 11 种与 ADRD 相关的神经病理学内表型进行了 GWAS 分析,参与者来自以下三个来源:国家阿尔茨海默氏症协调中心、宗教习俗研究和拉什记忆与衰老项目,以及成人思维变化研究(n = 7804 名尸检参与者)。我们发现了八个独立的明显相关基因位点,其中四个是新的基因位点(COL4A1、PIK3R5、LZTS1 和 APOC2)。在对已知的 ADRD 基因位点进行单独检测后,19 个基因位点与至少一种神经病理学有明显相关性。遗传共定位分析确定了多效应和数量性状位点。APOC2附近大脑皮层两个位点的甲基化与脑淀粉样血管病相关。包含神经病理学内表型的研究是了解遗传性 ADRD 风险机制的重要一步。
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来源期刊
Nature genetics
Nature genetics 生物-遗传学
CiteScore
43.00
自引率
2.60%
发文量
241
审稿时长
3 months
期刊介绍: Nature Genetics publishes the very highest quality research in genetics. It encompasses genetic and functional genomic studies on human and plant traits and on other model organisms. Current emphasis is on the genetic basis for common and complex diseases and on the functional mechanism, architecture and evolution of gene networks, studied by experimental perturbation. Integrative genetic topics comprise, but are not limited to: -Genes in the pathology of human disease -Molecular analysis of simple and complex genetic traits -Cancer genetics -Agricultural genomics -Developmental genetics -Regulatory variation in gene expression -Strategies and technologies for extracting function from genomic data -Pharmacological genomics -Genome evolution
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