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Aug 7, 2009

Researchers Identify New Alzheimer’s Risk Gene

  • Having certain alleles of TOMM40 increases one’s susceptibility to Alzheimer’s disease (AD) when other risk factors are present, according to a consortium of investigators. Additionally, their research revealed a number of genes or chromosomal areas with at least one SNP that could be considered a potential new candidate loci to explore in the etiology of sporadic AD.

    “The TOMM40 gene influences the ease with which molecules can get in and out of mitochondria,” explains Steven G. Potkin, M.D., lead author of the study and UCI psychiatry and human behavior professor. “With aging, the number and function of mitochondria decrease, accompanied by a parallel increased risk of developing Alzheimer’s.” TOMM40 also processes materials that form amyloid plaque, Dr. Potkins adds.

    The results appear August 7 in PLoS One in a paper titled, “Hippocampal Atrophy as a Quantitative Trait in a Genome-Wide Association Study Identifying Novel Susceptibility Genes for Alzheimer’s Disease.”

    Prior research from Duke University scientists found that patients with TOMM40 developed Alzheimer’s an average of seven years earlier than those without the gene. The current work involved a genome-wide association study on 381 participants. Samples were genotyped using the Illumina Human610-Quad BeadChip. The scientists report that 516,645 unique SNPs were included in the analysis following quality control measures.

    Two analyses were completed: a standard case-control analysis and a novel approach using hippocampal atrophy measured on MRI as an objectively defined, quantitative phenotype. A general linear model was applied to identify SNPs for which there was an interaction between the genotype and diagnosis on the quantitative trait.

    The case-control analysis validated APOE and identified TOMM40 (translocase of outer mitochondrial membrane 40). TOMM40 risk alleles were approximately twice as frequent in AD subjects as controls.

    The quantitative trait analysis resulted in 21 genes or chromosomal areas, which require further validation, the scientists assert. These candidates included EFNA5, CAND1, MAGI2, ARSB, and PRUNE2, which are involved in the regulation of protein degradation, apoptosis, neuronal loss, and neurodevelopment.

     



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