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

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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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Acknowledgements

This work was supported by National Institute on Aging (NIA) grants to DA and SSB (RO1AG022099 and RO1AG021804) and an award from the Neurosciences Education and Research Foundation to DA. We thank the Harvard Brain Tissue Resource Center (MH/NS077550) and the Johns Hopkins Brain resource center for providing us with the postmortem brain tissue used for these studies. Genotyping was in part subsidized by the Broad Institute Center for Genotyping and Analysis, which is supported by grant U54 RR020278-01 from the National Center for Research Resources. Samples from the NCRAD, which receives government support under a cooperative agreement grant (U24 AG21886) awarded by the NIA, were used in this study. We also thank Kelly Benke, Katherine Miller, and Delphine Fradin for help with data cleaning and descriptive analysis scripts. We thank contributors, including the Alzheimer's Disease Centers who collected samples used in this study, as well as patients and their families, whose help and participation made this work possible.

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Authors and Affiliations

  1. Department of Epidemiology, Johns Hopkins University, Bloomberg School of Public Health, Baltimore, MD, 21205, USA

    Margaret Daniele Fallin

  2. McKusick Nathans Institute of Genetic Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD, 21205, USA

    Megan Szymanski, Adrian Gherman & Dimitrios Avramopoulos

  3. Department of Psychiatry, School of Medicine, Johns Hopkins University, Broadway Research Building Room 509, 733 N. Broadway, Baltimore, MD, 21205, USA

    Ruihua Wang, Susan S. Bassett & Dimitrios Avramopoulos

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  1. Margaret Daniele Fallin
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  2. Megan Szymanski
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  3. Ruihua Wang
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  4. Adrian Gherman
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  5. Susan S. Bassett
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  6. Dimitrios Avramopoulos
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Correspondence to Dimitrios Avramopoulos.

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The experiments reported in this manuscript comply with the current laws of the country in which they were performed (USA).

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Supplementary Table 1

Power to detect association at \( \alpha = 1 \times {10^{ - {4}}} \) (DOC 31.5 kb)

Supplementary Table 2

Genotyped single nucleotide polymorphisms quality filters (DOC 28 kb)

Supplementary Table 3

Genotype counts and percentage for rs5984894 in PCDH11X. Allelic and genotype tests for association with Alzheimer's disease were not significant in the females, males, or overall (the total N of individuals with genotypes is 615). Tests for interaction with single nucleotide polymorphisms in PCDH15 (see Methods) were also not significant. (DOC 28.5 kb)

Supplementary Table 4

Top 1% of associated single nucleotide polymorphisms for maternal case–control comparison (DOC 188 kb)

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Fallin, M.D., Szymanski, M., Wang, R. et al. Fine mapping of the chromosome 10q11-q21 linkage region in Alzheimer's disease cases and controls. Neurogenetics 11, 335–348 (2010). https://doi.org/10.1007/s10048-010-0234-9

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