Lambert J.-C.,French Institute of Health and Medical Research |
Lambert J.-C.,Institute Pasteur Of Lille |
Lambert J.-C.,University of Lille Nord de France |
Grenier-Boley B.,French Institute of Health and Medical Research |
And 88 more authors.
Molecular Psychiatry | Year: 2013
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 × 10 -10). We finally searched for association between SNPs within the FRMD4A locus and Aβ plasma concentrations in three independent non-demented populations (n=2579). We reported that polymorphisms were associated with plasma Aβ42/Aβ40 ratio (best signal, P=5.4 × 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. © 2013 Macmillan Publishers Limited.
PubMed | Institute Genomique, Karolinska Institutet, University of Cagliari, Fondation Jean Dausset CEPH and 75 more.
Type: Journal Article | Journal: PloS one | Year: 2014
Alzheimers disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimers Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimers cases and 48,466 controls.In addition to earlier reported genes, we detected genome-wide significant loci on chromosomes 8 (TP53INP1, p=1.410-6) and 14 (IGHV1-67 p=7.910-8) which indexed novel susceptibility loci.The additional genes identified in this study, have an array of functions previously implicated in Alzheimers disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimers disease.
PubMed | University of Rome Tor Vergata, Molecular Neurology Unit, University of Chieti Pescara, Clinical and Behavioral Neurology and Baylor College of Medicine
Type: Journal Article | Journal: Brain and behavior | Year: 2015
Deep brain gray matter (GM) structures are involved in several neurodegenerative disorders and are affected by aging. In this study, we investigated the potential relationship between levels of brain-derived neurotrophic factor (BDNF), a putative biomarker of age- and clinically relevant brain dysfunctions, and the presence of structural modifications that were evaluated by magnetic resonance imaging in six deep GM structures.Volume changes and diffusion tensor imaging (DTI) scalars were studied in the thalamus, putamen, hippocampus, caudate nucleus, amygdala and pallidum of a cohort of 120 healthy subjects. The cohort included young (18-39years old), adult (40-59 years old) and elderly (60-76 years old) subjects.No correlations were seen in the young and adult cohorts. In the elderly group, we observed reduced BDNF levels that correlated with increased DTI-based mean diffusivity occurring in the left hippocampus along with decreased normalized volume in the left amygdala.These findings suggest that, in elderly subjects, BDNF may exert regional and lateralized effects that allow the integrity of two strategic deep GM areas such as the hippocampus and the amygdala.