Long runs of homozygosity are associated with Alzheimer's disease

Altres ajuts: The Genome Research at Fundació ACE project (GR@ACE) is supported by Fundación bancaria "La Caixa," Grifols SA and Fundació ACE. L.M.R. is supported by Consejería de Salud de la Junta de Andalucía (Grant PI-0001/2017).Long runs of homozygosity (ROH) are contiguous stretches of homozygous genotypes, which are a footprint of inbreeding and recessive inheritance. The presence of recessive loci is suggested for Alzheimer's disease (AD); however, their search has been poorly assessed to date. To investigate homozygosity in AD, here we performed a fine-scale ROH analysis using 10 independent cohorts of European ancestry (11,919 AD cases and 9181 controls.) We detected an increase of homozygosity in AD cases compared to controls [ β (CI 95%) = 0.070 (0.037-0.104); P = 3.91 × 10 −5 ; β (CI95%) = 0.043 (0.009-0.076); P = 0.013]. ROHs increasing the risk of AD (OR > 1) were significantly overrepresented compared to ROHs increasing protection (p < 2.20 × 10 −16). A significant ROH association with AD risk was detected upstream the HS3ST1 locus (chr4:11,189,482‒11,305,456), (β (CI 95%) = 1.09 (0.48 ‒ 1.48), p value = 9.03 × 10 −4), previously related to AD. Next, to search for recessive candidate variants in ROHs, we constructed a homozygosity map of inbred AD cases extracted from an outbred population and explored ROH regions in whole-exome sequencing data (N = 1449). We detected a candidate marker, rs117458494, mapped in the SPON1 locus, which has been previously associated with amyloid metabolism. Here, we provide a research framework to look for recessive variants in AD using outbred populations. Our results showed that AD cases have enriched homozygosity, suggesting that recessive effects may explain a proportion of AD heritability

Effects of oxidative stress on HSV-1 protein expression.

<p>The accumulation of viral proteins ICP4, VP16 and gC was analysed by immunoblotting in SK-N-MC cells simultaneously treated with X-XOD and infected with HSV-1 at a moi of 1 and 10 for 18 h (<b>A</b>) or at a moi of 0.1 for 42 h (<b>B</b>). The blots shown are representative of three independent experiments. A tubulin blot was performed as a loading control. In all blots, the ratio of viral proteins to tubulin is shown below the blots.</p

Effects of oxidative stress on HSV-1 entry.

<p><b>A)</b> Immunofluorescence analysis of HSV-1-infected SK-N-MC cells at a moi of 10 in the presence and absence of X-XOD. The immunoreactivity of ICP4 protein is shown at 3 and 5 hours post-infection (h.p.i.). Nuclei are stained with DAPI. Scale bar: 20 µm. <b>B)</b> Quantification of infected cells by ICP4 staining. The graph shows the percentage of ICP4-positive cells. At least 400 nuclei were counted for each condition. <b>C)</b> Analysis of ICP4 levels by Western blotting in SK-N-MC cells infected with HSV-1 at a moi of 1 and 10 for 3 h and 5 h, in the presence and absence of X-XOD.</p

Oxidative stress does not affect the autophagosomal localization of Aβ in HSV-1-infected cells.

<p>Confocal images obtained with anti-Aβ and anti-LC3 antibodies showing endogenous LC3 and Aβ patterns in HSV-1-infected SK-APP cells at a moi of 10 for 18 h in the presence and absence of oxidative stress (X-XOD). Colocalization is shown by yellow fluorescence signals in the merged panels. Scale bar: 10 µm.</p

Oxidative stress reduces HSV-1 replication and increases cell viability of infected cells.

<p><b>A)</b> Quantification of viral DNA by real-time quantitative PCR in SK-N-MC cells simultaneously treated with X-XOD and infected with HSV-1 at a moi of 1 and 10 for 18 h or at a moi of 0.1 for 42 h. <b>B)</b> Intracellular (intra) and extracellular (extra) viral titres were determined by plaque assays in SK-N-MC cells infected under the same conditions as in (<b>A</b>). In (<b>A</b>) and (<b>B</b>), the data represent the mean ± SEM of five experiments performed in triplicate and are expressed as a percentage with respect to untreated cells (- X-XOD) (*p<0.05; **p<0.01; ***p<0.001). <b>C)</b> The cell viability of mock and HSV-1-infected SK-N-MC cells exposed to X-XOD was monitored using the MTT reduction assay. Cells were infected with HSV-1 at a moi of 1 and 10 for 18 h or at a moi of 0.1 for 42 h. Values are expressed relative to the optical density of untreated mock-infected cells. The data shown represent the mean ± SEM for four independent experiments performed in triplicate (*p<0.05; **p<0.01).</p

The CALHM1 P86L polymorphism is a genetic modifier of age at onset in Alzheimer's disease: A meta-analysis study

The only established genetic determinant of non-Mendelian forms of Alzheimer’s disease (AD) is the ε4 allele of the apolipoprotein E gene (APOE). Recently, it has been reported that the P86L polymorphism of the calcium homeostasis modulator 1 gene (CALHM1) is associated with the risk of developing AD. In order to independently assess this association, we performed a meta-analysis of 7,873 AD cases and 13,274 controls of Caucasian origin (from a total of 24 centres in Belgium, Finland, France, Italy, Spain, Sweden, the UK and the USA). Our results indicate that the CALHM1 P86L polymorphism is likely not a genetic determinant of AD but may modulate age at onset by interacting with the effect of the ε4 allele of the APOE gene

The CALHM1 P86L Polymorphism is a Genetic Modifier of Age at Onset in Alzheimer's Disease: a Meta-Analysis Study

The only established genetic determinant of non-Mendelian forms of Alzheimer's disease (AD) is the ε4 allele of the apolipoprotein E gene (APOE). Recently, it has been reported that the P86L polymorphism of the calcium homeostasis modulator 1 gene (CALHM1) is associated with the risk of developing AD. In order to independently assess this association, we performed a meta-analysis of 7,873 AD cases and 13,274 controls of Caucasian origin (from a total of 24 centers in Belgium, Finland, France, Italy, Spain, Sweden, the UK, and the USA). Our results indicate that the CALHM1 P86L polymorphism is likely not a genetic determinant of AD but may modulate age of onset by interacting with the effect of the ε4 allele of the APOE gene. © 2010 IOS Press and the authors. All rights reserved