Mapping 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 be ultimately 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 genes identified from linkage and association studies are assessed thoroughly to identify functional susceptibility alleles as follows: a) Public databases are mined using bioinformatics for putative disease susceptibility variants. b) These genetic variants are genotyped using high-throughput technologies in late-onset AD (LOAD) series. c) Statistical genetics methods are used to assess for replicable association with LOAD risk in multiple series. d) Effects of genetic variants on biological phenotypes (e.g., brain pathology, neuroimaging variables) and gene expression levels are tested.
Our present 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 alpha-catenin, which itself binds presenilin. This makes VR22 an excellent positional and functional candidate gene. The 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.
LRRTM3 is a neuronally expressed gene, which resides within an intron of VR22 on chromosome 10. We have already identified variants within VR22 which strongly associate with Aß42 and account for most, if not all, of our linkage signal on chromosome 10, as previously mentioned. These VR22 variants are intronic and unlikely to be functional themselves. Thus, in addition to detailed screening of VR22 for functional variants, we are also analyzing 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. Further studies on the VR22/LRRTM3 gene complex is likely to lead to a better understanding of their role in AD and may possibly shed light on a novel pathway which may influence this common, complex disease.