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Évry, France

Furney S.J.,Kings College London | Simmons A.,Kings College London | Breen G.,Kings College London | Pedroso I.,Kings College London | And 17 more authors.
Molecular Psychiatry | Year: 2011

Alzheimer's disease (AD) is a progressive neurodegenerative disorder with considerable evidence suggesting an initiation of disease in the entorhinal cortex and hippocampus and spreading thereafter to the rest of the brain. In this study, we combine genetics and imaging data obtained from the Alzheimer's Disease Neuroimaging Initiative and the AddNeuroMed study. To identify genetic susceptibility loci for AD, we conducted a genome-wide study of atrophy in regions associated with neurodegeneration in this condition. We identified one single-nucleotide polymorphism (SNP) with a disease-specific effect associated with entorhinal cortical volume in an intron of the ZNF292 gene (rs1925690; P-value=2.6 × 10 -8; corrected P-value for equivalent number of independent quantitative traits=7.7 × 10 -8) and an intergenic SNP, flanking the ARPP-21 gene, with an overall effect on entorhinal cortical thickness (rs11129640; P-value=5.6 × 10 -8; corrected P-value=1.7 × 10 -7). Gene-wide scoring also highlighted PICALM as the most significant gene associated with entorhinal cortical thickness (P-value=6.7 × 10 -6). © 2011 Macmillan Publishers Limited All rights reserved.

Priebe L.,University of Bonn | Degenhardt F.A.,University of Bonn | Herms S.,University of Bonn | Haenisch B.,University of Bonn | And 20 more authors.
Molecular Psychiatry | Year: 2012

We used genome-wide single nucleotide polymorphism (SNP) data to search for the presence of copy number variants (CNVs) in 882 patients with bipolar disorder (BD) and 872 population-based controls. A total of 291 (33%) patients had an early age-at-onset ≤21 years (AO≤21years). We systematically filtered for CNVs that cover at least 30 consecutive SNPs and which directly affect at least one RefSeq gene. We tested whether (a) the genome-wide burden of these filtered CNVs differed between patients and controls and whether (b) the frequency of specific CNVs differed between patients and controls. Genome-wide burden analyses revealed that the frequency and size of CNVs did not differ substantially between the total samples of BD patients and controls. However, separate analysis of patients with AO≤21years and AO>21years showed that the frequency of microduplications was significantly higher (P=0.0004) and the average size of singleton microdeletions was significantly larger (P=0.0056) in patients with AO≤21years compared with controls. A search for specific BD-associated CNVs identified two common CNVs: (a) a 160 kb microduplication on 10q11 was overrepresented in AO≤21years patients (9.62%) compared with controls (3.67%, P=0.0005) and (b) a 248 kb microduplication on 6q27 was overrepresented in the AO≤21years subgroup (5.84%) compared with controls (2.52%, P=0.0039). These data suggest that CNVs have an influence on the development of early-onset, but not later-onset BD. Our study provides further support for previous hypotheses of an etiological difference between early-onset and later-onset BD. © 2012 Macmillan Publishers Limited All rights reserved.

Michel S.,Hannover Medical School | Liang L.,University of Michigan | Depner M.,Ludwig Maximilians University of Munich | Klopp N.,Helmholtz Center Munich | And 18 more authors.
PLoS ONE | Year: 2010

The first genome wide association study (GWAS) for childhood asthma identified a novel major susceptibility locus on chromosome 17q21 harboring the ORMDL3 gene, but the role of previous asthma candidate genes was not specifically analyzed in this GWAS. We systematically identified 89 SNPs in 14 candidate genes previously associated with asthma in.3 independent study populations. We re-genotyped 39 SNPs in these genes not covered by GWAS performed in 703 asthmatics and 658 reference children. Genotyping data were compared to imputation data derived from Illumina HumanHap300 chip genotyping. Results were combined to analyze 566 SNPs covering all 14 candidate gene loci. Genotyped polymorphisms in ADAM33, GSTP1 and VDR showed effects with p-values,0.0035 (corrected for multiple testing). Combining genotyping and imputation, polymorphisms in DPP10, EDN1, IL12B, IL13, IL4, IL4R and TNF showed associations at a significance level between p=0.05 and p =0.0035. These data indicate that (a) GWAS coverage is insufficient for many asthma candidate genes, (b) imputation based on these data is reliable but incomplete, and (c) SNPs in three previously identified asthma candidate genes replicate in our GWAS population with significance after correction for multiple testing in 14 genes. © 2010 Michel et al.

Cipriani V.,University College London | Leung H.,University of Cambridge | Leung H.,Chinese University of Hong Kong | Plagnol V.,University College London | And 36 more authors.
Human Molecular Genetics | Year: 2012

Age-related macular degeneration (AMD) is a leading cause of visual loss in Western populations. Susceptibility is influenced by age, environmental and genetic factors. Known genetic risk loci do not account for all the heritability. We therefore carried out a genome-wide association study of AMD in the UK population with 893 cases of advanced AMD and 2199 controls. This showed an association with the well-established AMD risk loci ARMS2 (age-related maculopathy susceptibility 2)-HTRA1 (HtrA serine peptidase 1) (P =2.7 × 10-72), CFH (complement factor H) (P =2.3 × 10-47), C2 (complement component 2)-CFB (complement factor B) (P =5.2 × 10-9), C3 (complement component 3) (P =2.2 × 10-3) and CFI (P =3.6 × 10-3) and with more recently reported risk loci at VEGFA (P =1.2 × 10-3) and LIPC (hepatic lipase) (P =0.04). Using a replication sample of 1411 advanced AMD cases and 1431 examined controls, we confirmed a novel association between AMD and single-nucleotide polymorphisms on chromosome 6p21.3 at TNXB (tenascin XB)-FKBPL (FK506 binding protein like) [rs12153855/rs9391734; discovery P =4.3 × 10-7, replication P =3.0 × 10-4, combined P =1.3 × 10-9, odds ratio (OR) = 1.4, 95% confidence interval (CI) = 1.3-1.6] and the neighbouring gene NOTCH4 (Notch 4) (rs2071277; discovery P =3.2 × 10-8, replication P =3.8 × 10-5, combined P =2.0 × 10-11, OR = 1.3, 95% CI = 1.2-1.4). These associations remained significant in conditional analyses which included the adjacent C2-CFB locus. TNXB, FKBPL and NOTCH4 are all plausible AMD susceptibility genes, but further research will be needed to identify the causal variants and determine whether any of these genes are involved in the pathogenesis of AMD. © The Author 2012. Published by Oxford University Press.

Chapuis J.,University of Lille Nord de France | Hansmannel F.,University of Lille Nord de France | Mounier A.,University of Lille Nord de France | Van Cauwenberghe C.,Neurodegenerative Brain Diseases Group | And 54 more authors.
Molecular Psychiatry | Year: 2013

Genome-wide association studies (GWAS) have identified a region upstream the BIN1 gene as the most important genetic susceptibility locus in Alzheimer's disease (AD) after APOE. We report that BIN1 transcript levels were increased in AD brains and identified a novel 3 bp insertion allele ∼28 kb upstream of BIN1, which increased (i) transcriptional activity in vitro, (ii) BIN1 expression levels in human brain and (iii) AD risk in three independent case-control cohorts (Meta-analysed Odds ratio of 1.20 (1.14-1.26) (P=3.8 × 10 -11)). Interestingly, decreased expression of the Drosophila BIN1 ortholog Amph suppressed Tau-mediated neurotoxicity in three different assays. Accordingly, Tau and BIN1 colocalized and interacted in human neuroblastoma cells and in mouse brain. Finally, the 3 bp insertion was associated with Tau but not Amyloid loads in AD brains. We propose that BIN1 mediates AD risk by modulating Tau pathology. © 2013 Macmillan Publishers Limited.

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