Mapping and Functional Characterization of Novel Alzheimer's Disease (AD) Risk Genes and Alleles

Identification of functional variants within candidate AD susceptibility genes, which can reliably be replicated in multiple independent series, can ultimately be utilized to detect at-risk populations. Furthermore, discovery of such variants will shed light on the details of the underlying pathophysiology of this common, complex disease and could potentially provide therapeutic targets.

In our laboratory, candidate AD genes identified from linkage and association studies are assessed thoroughly to identify functional susceptibility alleles as follows:

  1. Using bioinformatics as well as de novo variant discovery through sequencing, we identify putative functional genetic variants in candidate genes.
  2. These genetic variants are genotyped using high-throughput technologies in late-onset AD (LOAD) case-control series, longitudinal cohorts of elderly controls as well as multi-generational LOAD families.
  3. Statistical genetics methods are used to assess for replicable association with LOAD risk in multiple series.
  4. Effects of genetic variants on biological phenotypes (e.g., brain pathology, neuroimaging variables) and gene expression levels are tested.
  5. Effects of overexpression or knock-down of the candidate genes on known AD pathways, such as amyloid production, are assessed in-vitro.

Our current research focuses on the analysis of a number of candidate AD genes, including leucine-rich repeat transmembrane protein 3 (LRRTM3) and alpha-T catenin (VR22) genes on chromosome 10. AD is characterized by the invariable deposition of senile plaques predominantly composed of the amyloid ß peptide (Aß) and intracellular accumulation of neurofibrillary tangles made of hyperphosphorylated microtubule-associated protein, tau. Earlier studies on early-onset familial AD have led to the identification of autosomal dominant mutations in the amyloid precursor protein, and the presenilin genes, all of which affect the processing of Aß and most of which lead to elevated Aß levels which can be detected in plasma.

Our previous work aimed at the analysis of plasma Aß levels in late-onset AD (LOAD) families led to the realization that plasma Aß is a highly heritable trait substantially affected by genetic components. Using Aß as a quantitative biomarker, we mapped a locus on chromosome 10 in LOAD families, which was also mapped independently by others using AD as a risk trait. Subsequent to the identification of this novel AD risk locus on chromosome 10, which likely acts via affecting Aß, we analyzed a number of candidate genes on chromosome 10, including alpha-T catenin (VR22).

VR22 is located at the chromosome 10 linkage locus and is a binding partner of ß-catenin, which itself binds presenilin. VR22 is a large gene that harbors another entire gene in its intron, LRRTM3, which is a neuronally expressed gene that is transcribed in the opposite direction to VR22 and that has functional implications in Aß production and synaptogenesis. VR22 and LRRTM3 are therefore both excellent positional and functional candidate LOAD genes.

Our studies on VR22 led to the identification of variants within this gene, which strongly associate with Aß42 levels and account for most, if not all, of our Aß42 linkage signal on chromosome 10. These variants also appear to confer risk of AD in LOAD case-control series. We also analyzed LRRTM3 as an AD risk susceptibility gene. This analysis already led to the discovery of LRRTM3 variants with replicable association with AD. Importantly, the LRRTM3 variants act independently of those within VR22.

Our current work on the VR22/LRRTM3 genes include:

  1. Next-generation targeted sequencing of key individuals from the LOAD families that show strong association with VR22 variants to identify all genetic variation in these genes
  2. Testing the effects of these variants on AD risk in LOAD case-control series
  3. Evaluating the effects of overexpression and knock-down of LRRTM3 and VR22 on Aß metabolism.

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