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. 2010 Jul;11(3):335-48.
doi: 10.1007/s10048-010-0234-9. Epub 2010 Feb 25.

Fine mapping of the chromosome 10q11-q21 linkage region in Alzheimer's disease cases and controls

Margaret Daniele Fallin  1 , Megan Szymanski, Ruihua Wang, Adrian Gherman, Susan S Bassett, Dimitrios Avramopoulos
Affiliations

Fine mapping of the chromosome 10q11-q21 linkage region in Alzheimer's disease cases and controls

Margaret Daniele Fallin et al. Neurogenetics. 2010 Jul.

Abstract

We have previously reported strong linkage on chromosome 10q in pedigrees transmitting Alzheimer's disease through the mother, overlapping with many significant linkage reports including the largest reported study. Here, we report the most comprehensive fine mapping of this region to date. In a sample of 638 late-onset Alzheimer's disease (LOAD) cases and controls including 104 maternal LOAD cases, we genotyped 3,884 single nucleotide polymorphisms (SNPs) covering 15.2 Mb. We then used imputations and publicly available data to generate an extended dataset including 4,329 SNPs for 1,209 AD cases and 839 controls in the same region. Further, we screened eight genes in this region for rare alleles in 283 individuals by nucleotide sequencing, and we tested for possible monoallelic expression as it might underlie our maternal parent of origin linkage. We excluded the possibility of multiple rare coding risk variants for these genes and monoallelic expression when we could test for it. One SNP, rs10824310 in the PRKG1 gene, showed study-wide significant association without a parent of origin effect, but the effect size estimate is not of sufficient magnitude to explain the linkage, and no association is observed in an independent genome-wide association studies (GWAS) report. Further, no causative variants were identified though sequencing. Analysis of cases with maternal disease origin pointed to a few regions of interest that included the genes PRKG1 and PCDH15 and an intergenic interval of 200 Kb. It is likely that non-transcribed rare variants or other mechanisms involving these genomic regions underlie the observed linkage and parent of origin effect. Acquiring additional support and clarifying the mechanisms of such involvement is important for AD and other complex disorder genetics research.

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Figures

Fig. 1
Fig. 1
Runs of homozygosity (ROH) within our region of interest. The fraction of individuals carrying an ROH greater than 300 Kb is plotted against the mid-point location of the ROH. Maternal cases, all cases, and controls are plotted separately
Fig. 2
Fig. 2
p values for single nucleotide polymorphism associations across the linkage region among all cases and controls (blue) and when restricted to maternal cases versus controls (red)
Fig. 3
Fig. 3
Regions with enrichment for nominally significant single nucleotide polymorphisms. Full case-control comparisons in blue, maternal case-control comparisons in red. Genes and conservation information from University of California, Santa Cruz shown at bottom of each panel
Fig. 4
Fig. 4
p values for single nucleotide polymorphism associations across the linkage region in the extended dataset. The shaded areas are the same as in Fig. 2
See this image and copyright information in PMC

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