期刊
MOLECULAR PSYCHIATRY
卷 18, 期 4, 页码 461-470出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/mp.2012.14
关键词
Alzheimer; amyloid; FRMD4A; GWAS; plasma
资金
- National Foundation for Alzheimer's disease and related disorders
- Institut Pasteur de Lille
- Centre National de Genotypage
- Inserm
- FRC (fondation sur la recherche sur le cerveau)
- Rotary
- Fondation pour la Recherche Medicale
- Caisse Nationale Maladie des Travailleurs Salaries
- Direction Generale de la Sante
- MGEN
- Institut de la Longevite
- Agence Francaise de Securite Sanitaire des Produits de Sante
- Aquitaine Regional Council
- Bourgogne Regional Council
- Fondation de France
- joint French Ministry of Research/INSERM 'Cohortes et collections de donnees biologiques' programme
- Eisai
- Belgian Science Policy Office [P6/43]
- Foundation for Alzheimer Research (SAO-FRMA)
- Flemish Government
- Research Foundation Flanders (FWO)
- University of Antwerp
- Antwerp Medical Research Foundation
- Neurosearch, Belgium
- Italian Ministry of Health: Progetto Strategico
- Ministry of Health [PS39]
- Fondazione Monzino
- Ministerio de Educacion y Ciencia
- Ministerio de Sanidad y Consumo (Instituto de Salud Carlos III)
- Fundacion Ramon Areces
- Fundacion Canaria de Investigacion en Salud (FUNCIS)
- German National Genome Research Network (NGFN) [01GS08125]
- Deutsche Forschungsgemeinschaft (DFG) [INST 256/317-1 FUGG]
- US National Institutes of Health [AG028555, AG08724, AG 04563, AG10175, AG08861]
- Swedish Brain Power network
- Marianne and Marcus Wallenberg Foundation
- Swedish Research Council [521-2010-3134]
- King Gustaf V and Queen Victoria's Foundation of Freemasons
- Regional Agreement on Medical Training and Clinical Research
- Stockholm County Council
- Karolinska Institutet
- MRC [G0902227, MR/K013041/1] Funding Source: UKRI
- Alzheimers Research UK [ARUK-PG2014-1] Funding Source: researchfish
- Medical Research Council [G0801418B, G0902227, MR/K013041/1] Funding Source: researchfish
Recently, several genome-wide association studies (GWASs) have led to the discovery of nine new loci of genetic susceptibility in Alzheimer's disease (AD). However, the landscape of the AD genetic susceptibility is far away to be complete and in addition to single-SNP (single-nucleotide polymorphism) analyses as performed in conventional GWAS, complementary strategies need to be applied to overcome limitations inherent to this type of approaches. We performed a genome-wide haplotype association (GWHA) study in the EADI1 study (n = 2025 AD cases and 5328 controls) by applying a sliding-windows approach. After exclusion of loci already known to be involved in AD (APOE, BIN1 and CR1), 91 regions with suggestive haplotype effects were identified. In a second step, we attempted to replicate the best suggestive haplotype associations in the GERAD1 consortium (2820 AD cases and 6356 controls) and observed that 9 of them showed nominal association. In a third step, we tested relevant haplotype associations in a combined analysis of five additional case-control studies (5093 AD cases and 4061 controls). We consistently replicated the association of a haplotype within FRMD4A on Chr.10p13 in all the data set analyzed (OR: 1.68; 95% CI: (1.43-1.96); P=1.1 x 10(-10)). We finally searched for association between SNPs within the FRMD4A locus and A beta plasma concentrations in three independent non-demented populations (n = 2579). We reported that polymorphisms were associated with plasma A beta 42/A beta 40 ratio (best signal, P=5.4 x 10(-7)). In conclusion, combining both GWHA study and a conservative three-stage replication approach, we characterised FRMD4A as a new genetic risk factor of AD. Molecular Psychiatry (2013) 18, 461-470; doi:10.1038/mp.2012.14; published online 20 March 2012
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