A meta-analysis of genome-wide association studies identifies new genetic loci associated with all-cause and vascular dementia
Author:
Fongang BernardORCID, Sargurupremraj Muralidharan, Jian Xueqiu, Mishra Aniket, Damotte Vincent, Bis Joshua C, Kang-Hsien Fan, Li Gloria, Yang Jingyun, Hilal Saima, Knol M.J., Concas Maria Pina, Giorgia Girotto, Riaz Moeen, Guðjónsson Alexander, Lacaze Paul, Naj Adam C, van der Lee Sven J., Goss Monica, Ngouongo Yannick W., Skrobot Olivia, Guðnason Vilmundur, Launer Lenore, Lopez Oscar, Haan Mary, Bosnes Ingunn, Dufouil Carole, Ganguli Mary, Cheung Ching-Lung, Bennett David A, Chen Christopher, Ilyas Kamboh M., Satizabal Claudia, Ikram Arfan M., Debette Stephanie, Fornage Myriam, Qiong Yang, Schellenberg Gerard D., Winsvold Bendik, Kehoe Patrick G., Ruiz Agustin, Lambert Jean-Charles, Weinstein Galit, Seshadri Sudha,
Abstract
ABSTRACTDementia is multifactorial with Alzheimer (AD) and vascular (VaD) pathologies making the largest contributions. Genome-wide association studies (GWAS) have identified over 70 genetic risk loci for AD but the genomic determinants of other dementias, including VaD remain understudied. We hypothesize that common forms of dementia will share genetic risk factors and conducted the largest GWAS to date of “all-cause dementia” (ACD) and examined the genetic overlap with VaD. Our dataset includes 809,299 individuals from European, African, Asian, and Hispanic ancestries with 46,902 and 8,702 cases of ACD and VaD, respectively. We replicated known AD loci at genome-wide significance for both ACD and VaD and conducted bioinformatic analyses to prioritize genes that are likely functionally relevant, and shared with closely related traits and risk factors. For ACD, novel loci identified were associated with energy transport (SEMA4D), neuronal excitability (ANO3), amyloid deposition in the brain (RBFOX1), and MRI markers of small vessel disease (HBEGF). Novel VaD loci were associated with hypertension, diabetes, and neuron maintenance (SPRY2, FOXA2, AJAP1, andPSMA3). Our study identified genetic risks underlying all-cause dementia, demonstrating overlap with neurodegenerative processes, vascular risk factors (Type-II diabetes, blood pressure, lipid) and cerebral small vessel disease. These novel insights could lead to new prevention and treatment strategies for all dementias.
Publisher
Cold Spring Harbor Laboratory
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