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From the Departments of Neurology (Drs. Hiltunen, Helisalmi, Koivisto, Lehtovirta, and Soininen, M. Pirskanen) and Clinical Genetics (Drs. Hiltunen, Mannermaa, and Helisalmi, M. Pirskanen), University Hospital and University of Kuopio, and Department of Obstetrics and Gynaecology, Oulu University Hospital (Dr. Ryynänen), Finland; and CRC Genetic Epidemiology Group (Dr. Easton, D. Thompson), Strangeways Research Laboratory, University of Cambridge, UK.
Address correspondence and reprint requests to Dr. M. Hiltunen, Department of Clinical Genetics, Kuopio University Hospital, P.O. Box 1777, FIN-70211 Kuopio, Finland; e-mail: mikko.hiltunen{at}kuh.fi
Background:— AD is a complex neurodegenerative disorder comprising several disease-associated chromosome loci. To find novel susceptibility genes for late-onset AD, a population-based genome-wide search using linkage disequilibrium (LD) mapping approach has been performed.
Method:— Forty-seven patients with late-onset AD and 51 age-matched control subjects were carefully chosen from the same geographic area in eastern Finland, where the population is descended mainly from a small group of original founders. These subjects were initially genotyped with 366 polymorphic microsatellite markers, and a follow-up analysis was performed with additional microsatellite markers for those chromosome loci found to be associated with AD.
Results:— Initial genome-wide screening revealed 21 chromosomal loci significantly associated with AD in addition to the 13q12 locus described previously. Subsequent comparison of single-allele frequencies of the microsatellite markers in the AD and control groups indicated the presence both of possible risk alleles (odds ratio [OR] > 1) and of possible protective alleles (OR < 1). Screening of the LD regions with additional microsatellite markers revealed seven chromosomal loci where more than one microsatellite marker was associated with AD (1p36.12, 2p22.2, 3q28, 4p13, 10p13, 18q12.1, and 19p13.3) in addition to the 13q12 locus.
Conclusions:— These genome-wide LD screening data suggest that several AD-associated chromosomal loci exist, which may encompass novel susceptibility genes for late-onset AD. Therefore, extensive screening of the genes located in the vicinity of these LD regions is necessary to elucidate their role in AD.
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