TOMM40 poly-T repeat lengths, age of onset and psychosis risk in Alzheimer disease

Abstract

Apolipoprotein E (APOE) ε4 alleles increase the risk for late-onset Alzheimer disease (LOAD) and decrease the age of onset. Recently, sequencing the APOE region in a small sample of LOAD subjects identified a variable length poly-T repeat sequence in the nearby gene, TOMM40, which may affect age of onset. We genotyped the TOMM40 poly-T repeat using a novel statistical approach to refine the identification of allele length in 892 LOAD subjects and evaluated its effects on age of onset. Because psychosis in LOAD is a heritable phenotype which has shown conflicting associations with APOE genotype, we also evaluated the association of poly-T repeat length with psychosis. Poly-T repeat lengths had a trimodal distribution which differed between APOE genotype groups. After accounting for APOE ε4 there was no association of poly-T repeat length with age of onset. Neither APOE ε4 nor poly-T repeat length was associated with psychosis. Our findings do not support the association of poly-T repeat length with age of onset in LOAD. The clinical implications of this repeat length polymorphism remain to be elucidated.

Figure 1. Count of PCR fragment sizes (intensity) versus size of fragment (top) and probability mass per integer bin versus size of fragments (bottom) for well-separated (left) and coalesced (right) distributions

Distributions of the measured intensity scores from the GeneMapper readout (top panels) and probability of an allele being a particular integer length of repeats (bottom panels). Note the dots in the bottom panels are separated by 1 unit, corresponding to 1 T, and represent the maximum intensity falling into bins of length 1 defined implicitly by the location of the dots.

Figure 2. Count of PCR fragment sizes (intensity) versus size of fragment

GeneMapper readout for a sample that was measured five times (2A) and close-ups of the sample’s first allele readouts (2B). Each read is slightly different due to measurement error, but the error is very small. This is further illustrated in 2B, where the dashed line occurs at the location of maximum intensity for the smaller allele and the first measurement. Note that the differences in readout are very small across all the measurements.

Figure 3. Estimated number of poly-T repeats in the full sample

The most common allele calls in these samples occur at lengths 17, 31, and 37.

Figure 4. Frequency and relative frequency of repeat lengths by APOE allele combinations

The frequency distributions (left panels) show the absolute counts of poly-T repeats per bin for each APOE genotype, and the relative frequency distributions (right panels) show the proportions (the counts of alleles divided by the total count of alleles, within each APOE genotype).