Association between presenilin‐1 polymorphism and maternal meiosis II errors in Down syndrome

Several lines of evidence suggest a shared genetic susceptibility to Down syndrome (DS) and Alzheimer disease (AD). Rare forms of autosomal‐dominant AD are caused by mutations in the APP and presenilin genes (PS‐1 and PS‐2). The presenilin proteins have been localized to the nuclear membrane, kinetochores, and centrosomes, suggesting a function in chromosome segregation. A genetic association between a polymorphism in intron 8 of the PS‐1 gene and AD has been described in some series, and an increased risk of AD has been reported in mothers of DS probands. We therefore studied 168 probands with free trisomy 21 of known parental and meiotic origin and their parents from a population‐based material, by analyzing the intron 8 polymorphism in the PS‐1 gene. An increased frequency of allele 1 in mothers with a meiosis II error (70.8%) was found compared with mothers with a meiosis I error (52.7%, P < 0.01), with an excess of the 11 genotype in the meiosis II mothers. The frequency of allele 1 in mothers carrying apolipoprotein E (APOE) ϵ4 allele (68.0%) was higher than in mothers without ϵ4 (52.2%, P < 0.01). We hypothesize that the PS‐1 intronic polymorphism might be involved in chromosomal nondisjunction through an influence on the expression level of PS‐1 or due to linkage disequilibrium with biologically relevant polymorphisms in or outside the PS‐1 gene. Am. J. Med. Genet. 93:366–372, 2000. © 2000 Wiley‐Liss, Inc.