An inherited variable poly-T repeat genotype in TOMM40 in Alzheimer disease

Abstract

I coauthored a recently published research article describing a variable length, poly-T polymorphism in the TOMM40 gene, adjacent to apolipoprotein E (APOE) on chromosome 19, that accounts for the age at onset distribution for a complex disease, late-onset Alzheimer disease. These new data explain the mean age at disease onset for patients with the APOE4/4 genotype and differentiate 2 forms of TOMM40 poly-T polymorphisms linked to APOE, with each form associated with a different age at disease onset distribution. When linked to APOE3 (encoding the epsilon3 isoform of APOE), the longer TOMM40 poly-T repeats (19-39 nucleotides) at the rs10524523 (hereafter, 523) locus are associated with earlier age at onset and the shorter TOMM40 523 alleles (11-16 nucleotides) are associated with later age at onset. The data suggest that the poly-T alleles are codominant, with the age at onset phenotype determined by the 2 inherited 523 alleles, but with variable expressivity. Additional data will further refine the relationship between the length of the poly-T alleles and age at disease onset and determine if the relationship is linear.

Figure 1

Cartoon of the 10 Kb region of TOMM40 included in the phylogenetic analysis. Shown are exons 6–10 (E6–E10) of TOMM40 and intervening introns. Vertical lines indicate SNPs, and small boxes indicate poly-T variants.

Figure 2

Phylogenetic tree constructed for the region of interest in TOMM40. Figure 2 (left panel) illustrates the first major branch point in this tree, at rs8106922 (922). The ovals capture subsequent branch points (mutation events). Frequencies of APOE genotypes in clades A and B are indicated. The dotted line highlights the separation between the two major clades. The boxes in figure 2 (right panel) indicate the clades that are differentiated by length of the poly-T allele (523). APOE3 can be linked to long or short 523 poly-T alleles (black boxes). APOE4 is connected to long poly-T alleles (red boxes).

Figure 3

Frequency distributions of lengths of the poly-T tracts at rs10524523. The data is from two independent LOAD case/control populations (left and right). The frequency of each 523 length allele connected to either APOE3 (top panels) or APOE4 (bottom panels) is shown. Two rare instances of APOE4 linked to a short 523 allele are boxed (bottom right panel).

Figure 4

The average age of LOAD onset for APOE3/4 patients carrying different APOE3-523 length alleles. All APOE4 alleles are connected to long 523 alleles; the subjects in this cohort differ by the length of the 523 allele connected to APOE3. The average age of disease onset was significantly younger for individuals carrying APOE3-long 523 (`Long', ~70 years) than for patients carrying APOE3-short 523 (`Short', ~78 years). This data is from a cohort of 34 Caucasian APOE3/4 LOAD patients for whom age of disease onset was accurately documented.