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Springer Nature [academic journals on nature.com], Molecular Psychiatry, 4(18), p. 521-521, 2012

DOI: 10.1038/mp.2012.75

Springer Nature [academic journals on nature.com], Molecular Psychiatry, 4(18), p. 461-470, 2012

DOI: 10.1038/mp.2012.14

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Genome-wide haplotype association study identifies the FRMD4A gene as a risk locus for Alzheimer's disease

Journal article published in 2012 by France [2] Institut Pasteur de Lille, France [3] Université Lille-Nord de France, Philippe Amouyel Genome wide haplotype association study identifies the Frmd4a gene as a. risk locus for Alzheimer’s disease, M. Del Zompo, Jean-Charles Lambert, Benjamin Grenier-Boley, Denise Harold, Diana Zelenika, Vincent Chouraki ORCID, Yoichiro Kamatani, Kristel Sleegers, M. Arfan Ikram ORCID, Mikko Hiltunen, Christiane Reitz, Lambert Jc and other authors.
This paper is made freely available by the publisher.
This paper is made freely available by the publisher.

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Abstract

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 Abeta plasma concentrations in three independent non-demented populations (n=2579). We reported that polymorphisms were associated with plasma Abeta42/Abeta40 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 advance online publication, 20 March 2012; doi:10.1038/mp.2012.14.