TY - JOUR
T1 - Fine mapping of the chromosome 10q11-q21 linkage region in Alzheimer's disease cases and controls
AU - Fallin, Margaret Daniele
AU - Szymanski, Megan
AU - Wang, Ruihua
AU - Gherman, Adrian
AU - Bassett, Susan S.
AU - Avramopoulos, Dimitrios
N1 - Funding Information:
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.
PY - 2010/7
Y1 - 2010/7
N2 - 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 lateonset 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 studywide 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 nontranscribed 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.
AB - 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 lateonset 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 studywide 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 nontranscribed 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.
KW - Alzheimer's disease
KW - Genetic association
KW - Genetic linkage
KW - Human chromosome 10
KW - Imprinting
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U2 - 10.1007/s10048-010-0234-9
DO - 10.1007/s10048-010-0234-9
M3 - Article
C2 - 20182759
AN - SCOPUS:77954660138
SN - 1364-6745
VL - 11
SP - 335
EP - 348
JO - Neurogenetics
JF - Neurogenetics
IS - 3
ER -