Genetic correlation analysis of Alzheimer's disease and stroke implicates PHLPP1 as a shared locus in individuals of African ancestry.
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Ray Nicholas R, Kurup Jiji, Kumar Ajneesh, Rajabli Farid, Wang Liyong, Xu Wanying, Jin Fulai, Yilmaz Elanur, Kizil Caghan, Bertholim-Nasciben Luciana, Moura Sofia, Ramirez Aura M, Baiyewu Olusegun, Griswold Anthony J, Coker Motunrayo, Scott Kyle M, Akinwande Kazeem, Adams Larry D, Diala Samuel, Whitehead Patrice G, McCauley Jacob L, Ogunronbi Mayowa, Hamilton-Nelson Kara L, Damasceno Albertino, Zaman Andrew F, Blanton Susan H, Akpalu Albert, Cuccaro Michael L, Wahab Kolawole, McInerney Katalina F, Nuytemans Karen, Obiako Reginald, Mena Pedro R, Okubadejo Njideka, Martinez Izri M, Zewde Yared Z, Gugssa Seid A, Sarfo Fred S, Kalaria Raj, Ndetei David M, Williams Scott M, Caban-Holt Allison, ADGC, AfDC, Tosto Giuseppe, Haines Jonathan L, Akinyemi Rufus O, Ogunniyi Adesola, Byrd Goldie S, Bush William S, Kunkle Brian W, Vance Jeffery M, Pericak-Vance Margaret A, Reitz Christiane
Аннотация
METHODS: Local genetic correlation analysis was conducted with LAVA (Local Analysis of [co]Variant Annotation) using the results from genome-wide association studies on AD and stroke in individuals of African ancestry. Enhanced Hi-C Capture Analysis (eHiCA) examined chromatin interactions using induced pluripotent stem cell (iPSC) -derived cells from AD brain autopsy samples.
RESULTS: LAVA identified a region shared between AD and stroke on chromosome 18q21.33(rg = 0.77, p = 2.41×10-6). eHiCA demonstrated that the AD and stroke loci interact with regulatory elements in PHLPP1. Variants at PHLPP1 were also associated with AD in an independent set of individuals of African ancestry (p = 4.56 × 10-5).
DISCUSSION: This study identified a region on top of PHLPP1 as a locus associated with both AD and stroke. PHLPP1 inhibits protein kinase B, which contributes to both AD and stroke pathophysiology.