Of all the regions that have been detected in genome scans for late onset Alzheimer's disease (LOAD) only a few have consistently provided positive findings, suggesting that they likely harbor a LOAD susceptibility gene. One such region is close to the centromere on chromosome 10. We recently reported a strong linkage finding in this region in our subset of the NIMH genetics initiative pedigrees, accompanied by a parent of origin effect. We have now investigated an additional independent subset of pedigrees, those collected by the University of Alabama, and replicated the parental origin effect in the region. In the combined maternal pedigree set after fine mapping the multipoint LOD score is 3.53 reaching the conservative threshold for genome-wide significance. Our 1-LOD interval is 15 cM wide with our current density of 1.4 cM per marker (information content =0.7).
Our first aim i s to perform an association analysis comparing cases from our families with controls that are cognitively healthy and have no family history of Alzheimer's disease. We will genotype 242 cases and 242 controls for 3,000 SNPs selected from those genotyped for the HapMap project and found to be non-redundant (not in perfect LD) in Caucasians and including 50 genomic control markers for correction of population substructure. We expect this aim to narrow down the finding to a few disease associate regions. Those will be followed up with a family based association analysis in an independent sample in order to be confirmed or rejected.
In aim 2 we will further analyze the confirmed or convincing associated region(s) by genotyping more known variation within them and variation detected through nucleotide sequencing in expressed, conserved and known functional areas. We will also genotype additional SNPs in areas where the coverage in aim 1 was inadequate due to low linkage disequilibrium. Finally in aim 3 we will analyze the confirmed and convincing region(s) to detect expression in the brain of sequences known or predicted to be transcribed and we will examine the presence of expression variation between cases and controls and between positively and negatively associated alleles/haplotypes.
| Wang, R; Halper-Stromberg, E; Szymanski-Pierce, M et al. (2014) Genetic determinants of neuroglobin transcription. Neurogenetics 15:65-75 |
| Avramopoulos, Dimitrios; Szymanski, Megan; Wang, Ruihua et al. (2011) Gene expression reveals overlap between normal aging and Alzheimer's disease genes. Neurobiol Aging 32:2319.e27-34 |
| Szymanski, M; Wang, R; Bassett, S S et al. (2011) Alzheimer's risk variants in the clusterin gene are associated with alternative splicing. Transl Psychiatry 1:e18 |
| Szymanski, M; Wang, R; Bassett, S S et al. (2011) Alzheimer's risk variants in the clusterin gene are associated with alternative splicing. Transl Psychiatry 1: |
| Avramopoulos, Dimitrios (2010) Genetics of psychiatric disorders methods: molecular approaches. Psychiatr Clin North Am 33:1-13 |
| Avramopoulos, Dimitrios (2010) Genetics of psychiatric disorders methods: molecular approaches. Clin Lab Med 30:815-27 |
| Fallin, Margaret Daniele; Szymanski, Megan; Wang, Ruihua et al. (2010) Fine mapping of the chromosome 10q11-q21 linkage region in Alzheimer's disease cases and controls. Neurogenetics 11:335-48 |
| Szymanski, Megan; Wang, Ruihua; Fallin, M Danielle et al. (2010) Neuroglobin and Alzheimer's dementia: genetic association and gene expression changes. Neurobiol Aging 31:1835-42 |
| Avramopoulos, Dimitrios (2009) Genetics of Alzheimer's disease: recent advances. Genome Med 1:34 |
| Gherman, Adrian; Wang, Ruihua; Avramopoulos, Dimitrios (2009) Orientation, distance, regulation and function of neighbouring genes. Hum Genomics 3:143-56 |
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