APOE and other loci affect age-at-onset in Alzheimer's disease families with PS2 mutation.
Several kindreds of Volga German (VG) ancestry have a single PS2 mutation that causes an autosomal dominant form of Alzheimer's disease (AD). These families show a wide range in age-at-onset, which suggests the existence of modifying factors other than the PS2 mutation. To examine evidence for a genetic basis of variation in onset age, we performed a Bayesian oligogenic segregation and linkage analysis on nine VG families confirmed to have at least one affected PS2 carrier. This analysis simultaneously estimated the effects of APOE and PS2 and the number and effects of additional loci affecting AD age-at-onset. In addition, a family effect accounted for shared environmental effects. This analysis approach has the advantage of full use of the complete pedigree structure, as well as use of information on unsampled individuals with phenotypic data. These analyses provide evidence that APOE plays a small, but significant, role in modifying the age-at-onset in these VG families. The effects estimated for the APOE epsilon3 and epsilon4 genotypes were consistent with those estimated in previous analysis of late-onset AD families, with evidence for a dose-dependent relationship between number of epsilon4 alleles and age-at-onset. We estimated an approximately 83% posterior probability of at least one modifier locus in addition to APOE, and that the fraction of the variance in age-at-onset attributable to PS2, APOE, other loci, and family effects is approximately 70, approximately 2, approximately 6.5, and approximately 8.5%, respectively. These results provide evidence that APOE and other loci modify onset in AD caused by PS2 mutation.
Wijsman
Ellen M
EM
Department of Medicine, Division of Medical Genetics, University of Washington, Box 357720, Seattle, WA 98195-7720, USA. Wijsman@u.washington.edu
Daw
E Warwick
EW
Yu
Xuesong
X
Steinbart
Ellen J
EJ
Nochlin
David
D
Bird
Thomas D
TD
Schellenberg
Gerard D
GD
D000328:Adult; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics*; D000704:Analysis of Variance; D001057:Apolipoproteins E / Q000235:genetics*; D001499:Bayes Theorem; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics; D005192:Family Health; D005260:Female; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D018895:Microsatellite Repeats; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D053766:Presenilin-2; D040641:Quantitative Trait Loci / Q000235:genetics
D001057:Apolipoproteins E; D008565:Membrane Proteins; C508861:PSEN2 protein, human; D053766:Presenilin-2