Genomic convergence to identify candidate genes for Alzheimer Disease on chromosome 10

Abstract

A broad region of chromosome 10 (chr10) has engendered continued interest in the etiology of late-onset Alzheimer Disease (LOAD) from both linkage and candidate gene studies. However, there is a very extensive heterogeneity on chr10. We converged linkage analysis and gene expression data using the concept of genomic convergence that suggests that genes showing positive results across multiple different data types are more likely to be involved in AD. We identified and examined 28 genes on chr10 for association with AD in a Caucasian case-control dataset of 506 cases and 558 controls with substantial clinical information. The cases were all LOAD (minimum age at onset ≥ 60 years). Both single marker and haplotypic associations were tested in the overall dataset and 8 subsets defined by age, gender, ApoE and clinical status. PTPLA showed allelic, genotypic and haplotypic association in the overall dataset. SORCS1 was significant in the overall data sets (p=0.0025) and most significant in the female subset (allelic association p=0.00002, a 3-locus haplotype had p=0.0005). Odds Ratio of SORCS1 in the female subset was 1.7 (p<0.0001). SORCS1 is an interesting candidate gene involved in the Aβ pathway. Therefore, genetic variations in PTPLA and SORCS1 may be associated and have modest effect to the risk of AD by affecting Aβ pathway. The replication of the effect of these genes in different study populations and search for susceptible variants and functional studies of these genes are necessary to get a better understanding of the roles of the genes in Alzheimer disease.

Gene-gene and gene-sex epistatic interactions of <i>DNMT1</i>, <i>DNMT3A</i> and <i>DNMT3B</i> in autoimmune thyroid disease

“…The MDR method has been shown to have good power in relatively case-control studies [38,39]. So far, MDR and its extensions have identified many interacting genetic variants underlying various complex human diseases, such as Alzheimer disease [40], asthma [41], Type II diabetes [42] and so on. These findings may account for some of the ''missing heritability'' for complex diseases.…”

Towards Alzheimer's root cause: ECSIT as an integrating hub between oxidative stress, inflammation and mitochondrial dysfunction

“…Albeit the molecular mechanisms by which ECSIT mediates the cross-talk remain uncertain, we suggest that a fine balance between ubiquitination, alternative splicing and degradation could be responsible for different levels of temporal/spatial intervention. somal region contains susceptibility loci involved in the etiology of SAD or FAD with unknown genetic cause [40,41]. However, besides the APOE-e4 gene, very few associations could be established with specific genes [42].…”

The human genome is composed of viral DNA: Viral homologues of the protein products cause Alzheimer&apos;s disease and others via autoimmune mechanisms.

“…In relation to Alzheimer's disease, the areas of viral insertion within the human genome (rhinovirus, HSV1, cytomegalovirus, HIV-1) correspond to genetic linkage hotspots in Alzheimer's disease (157 genes in the linkage hotspot on chromosome 10 alone) 48 and to over 120 Alzheimer's disease susceptibility genes. These genes included all the major players (APP and beta-amyloid, Presenilins 1 and 2, BACE1, clusterin, complement receptor 1 , PICALM, glycogen synthase kinase-3 beta and tau) This viral/human overlap is effectively a viral linkage map for Alzheimer's disease and others where the HSV-1 virus has been implicated.…”