Fine mapping of the chromosome 10q11-q21 linkage region in Alzheimer's disease cases and controls.
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.
Fallin
Margaret Daniele
MD
Department of Epidemiology, Johns Hopkins University, Bloomberg School of Public Health, Baltimore, MD 21205, USA.
Szymanski
Megan
M
Wang
Ruihua
R
Gherman
Adrian
A
Bassett
Susan S
SS
Avramopoulos
Dimitrios
D
D000368:Aged; D000544:Alzheimer Disease / Q000235:genetics*; D000070585:Cadherin Related Proteins; D015820:Cadherins / Q000235:genetics; D002874:Chromosome Mapping; D002879:Chromosomes, Human, Pair 10 / Q000235:genetics*; D005260:Female; D008040:Genetic Linkage; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide
C498835:CDHR15, human; D000070585:Cadherin Related Proteins; D015820:Cadherins