ATP5H/KCTD2 locus is associated with Alzheimer's disease risk.

To identify loci associated with Alzheimer disease, we conducted a three-stage analysis using existing genome-wide association studies (GWAS) and genotyping in a new sample. In Stage I, all suggestive single-nucleotide polymorphisms (at P<0.001) in a previously reported GWAS of seven independent studies (8082 Alzheimer's disease (AD) cases; 12 040 controls) were selected, and in Stage II these were examined in an in silico analysis within the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium GWAS (1367 cases and 12904 controls). Six novel signals reaching P<5 × 10(-6) were genotyped in an independent Stage III sample (the Fundació ACE data set) of 2200 sporadic AD patients and 2301 controls. We identified a novel association with AD in the adenosine triphosphate (ATP) synthase, H+ transporting, mitochondrial F0 (ATP5H)/Potassium channel tetramerization domain-containing protein 2 (KCTD2) locus, which reached genome-wide significance in the combined discovery and genotyping sample (rs11870474, odds ratio (OR)=1.58, P=2.6 × 10(-7) in discovery and OR=1.43, P=0.004 in Fundació ACE data set; combined OR=1.53, P=4.7 × 10(-9)). This ATP5H/KCTD2 locus has an important function in mitochondrial energy production and neuronal hyperpolarization during cellular stress conditions, such as hypoxia or glucose deprivation.

Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease.

Eleven susceptibility loci for late-onset Alzheimer's disease (LOAD) were identified by previous studies; however, a large portion of the genetic risk for this disease remains unexplained. We conducted a large, two-stage meta-analysis of genome-wide association studies (GWAS) in individuals of European ancestry. In stage 1, we used genotyped and imputed data (7,055,881 SNPs) to perform meta-analysis on 4 previously published GWAS data sets consisting of 17,008 Alzheimer's disease cases and 37,154 controls. In stage 2, 11,632 SNPs were genotyped and tested for association in an independent set of 8,572 Alzheimer's disease cases and 11,312 controls. In addition to the APOE locus (encoding apolipoprotein E), 19 loci reached genome-wide significance (P < 5 × 10(-8)) in the combined stage 1 and stage 2 analysis, of which 11 are newly associated with Alzheimer's disease.

Absence of allelic imbalance involving EMSY, CAPN5, and PAK1 genes in papillary thyroid carcinoma.

Papillary thyroid cancer (PTC) accounts for 80% of all thyroid malignancies, and genetic alterations associated to its etiology remain largely unknown. Chromosomal band 11q13 seems to be one of the most frequently amplified regions in human cancer, providing several candidate genes that need detailed characterization. The aim of our study was to investigate the existence of allelic imbalance at EMSY, CAPN5, and PAK1, as candidate genes within 11q13.5-q14 region using a single nucleotide polymorphism-based analysis. We selected a panel of 9 polymorphisms that were analyzed in 41 thyroid carcinoma samples, their contralateral non-pathological tissue and 178 controls from the general population. We did not detect allelic imbalance at these loci in our series. However, we observed a difference in the EMSY-haplotype distribution among PTC patients when compared to controls (odds ratio=2.00; p=0.02). We conclude that 11q13.5-q14 is not imbalanced in PTC, but there is evidence suggesting that EMSY might be of relevance in PTC etiology.

Metilación y expresión del gen FMR1 / Methylation and expression for the FMR1 gene

Objetivo. En este artículo se hace una breve revisión sobre la metilación del ADN, las enzimas y proteínas involucradas en la formación del complejo represor y la importancia de la metilación del gen FMR1 en el síndrome X frágil. Desarrollo. El estado de metilación de regiones de control en el genoma desempeña un papel fundamental en la regulación de la expresión genética. En genes susceptibles, los que contienen una isla CpG en el promotor, la metilación de la citosina favorece un estado represivo de la cromatina que previene la unión de los factores de transcripción. Las enzimas ADN metiltransferasas transfieren un grupo metilo de la S-adenosilmetionina al carbono 5 de la citosina en las secuencias CG. Se ha descrito un grupo de proteínas que reconocen a las citosinas metiladas y reclutan al correpresor y las desacetilasas de las histonas. La pérdida del grupo acetilo de las histonas produce la compactación de la cromatina. El síndrome X frágil se debe, en la mayoría de los casos, a la expansión por encima de un umbral de las repeticiones CGG del primer exón del gen FMR1. Por causas no bien conocidas estas expansiones se acompañan de la metilación del promotor y como consecuencia del silencio del gen. Conclusiones. La metilación del ADN etiqueta a los genes de forma que la misma secuencia de bases puede tener repercusiones fenotípicas diferentes. La metilación aberrante de los genes es causa de diversas patologías como el síndrome X frágil. El conocimiento de los mecanismos de represión de la expresión genética por metilación y el estudio de agentes que haga reversible el proceso son importantes para el tratamiento de dichas enfermedades (AU)

[Methylation and expression of the FMR1 gene]. / Metilación y expresión del gen FMR1.

OBJECTIVE: In this paper we present a brief review on DNA methylation, the enzymes and proteins involved in the repression complex and the importance of methylation of FMR1 gene in fragile X syndrome. DEVELOPMENT: Methylation status of control region in the genome plays a critical role in the regulation of gene expression. In susceptible genes containing CpG island in the promoter, cytosine methylation favors a repressive chromatin structure that prevents the binding of transcriptional activators to the promoter. The enzyme DNA methyltransferase transfers a methyl group from the S-adenosylmethionine to the 5 carbon of cytosine in the CG sequences. Several proteins have been described that recognize the methyl cytosine and recruit the co-repressor and the histones deacetylases. The lost of the acetyl groups produces the compacting of the chromatin. Fragile X syndrome is due, in the majority of the cases, to the expansion above a threshold of the CGG repeats in the first exon of FMR1 gene. These expansions are concomitant with the methylation of the promoter and the silencing of FMR1. CONCLUSIONS: DNA methylation is a tag that enables different phenotypic expression from an identical nucleotide sequence. Aberrant methylation is the cause of different pathologies including fragile X syndrome. The comprehension of the mechanisms by which methylation induces the silencing of the genes and the study of agents that could revert this process are important for the treatment of these diseases.