Ordered-subsets linkage analysis detects novel Alzheimer disease loci on chromosomes 2q34 and 15q22

Abstract

Alzheimer disease (AD) is a complex disorder characterized by a wide range, within and between families, of ages at onset of symptoms. Consideration of age at onset as a covariate in genetic-linkage studies may reduce genetic heterogeneity and increase statistical power. Ordered-subsets analysis includes continuous covariates in linkage analysis by rank ordering families by a covariate and summing LOD scores to find a subset giving a significantly increased LOD score relative to the overall sample. We have analyzed data from 336 markers in 437 multiplex (>/=2 sampled individuals with AD) families included in a recent genomic screen for AD loci. To identify genetic heterogeneity by age at onset, families were ordered by increasing and decreasing mean and minimum ages at onset. Chromosomewide significance of increases in the LOD score in subsets relative to the overall sample was assessed by permutation. A statistically significant increase in the nonparametric multipoint LOD score was observed on chromosome 2q34, with a peak LOD score of 3.2 at D2S2944 (P=.008) in 31 families with a minimum age at onset between 50 and 60 years. The LOD score in the chromosome 9p region previously linked to AD increased to 4.6 at D9S741 (P=.01) in 334 families with minimum age at onset between 60 and 75 years. LOD scores were also significantly increased on chromosome 15q22: a peak LOD score of 2.8 (P=.0004) was detected at D15S1507 (60 cM) in 38 families with minimum age at onset >/=79 years, and a peak LOD score of 3.1 (P=.0006) was obtained at D15S153 (62 cM) in 43 families with mean age at onset >80 years. Thirty-one families were contained in both 15q22 subsets, indicating that these results are likely detecting the same locus. There is little overlap in these subsets, underscoring the utility of age at onset as a marker of genetic heterogeneity. These results indicate that linkage to chromosome 9p is strongest in late-onset AD and that regions on chromosome 2q34 and 15q22 are linked to early-onset AD and very-late-onset AD, respectively.

Figure 1

Nonparametric LOD score plot for chromosome 2. LOD scores for the overall sample (n=437 [solid line]) and the subset with minimum age at onset with a range of 50–60 years (n=31 [dashed line]) are presented. The 1-LOD–unit down SI (192–239 cM) is marked by the bold horizontal line.

Figure 2

Nonparametric LOD score plot for chromosome 9. LOD scores for the overall sample (n=437 [solid line]) and the subset with minimum age at onset with a range of 60–75 years (n=32 [dashed line]) are presented. The 1-LOD–unit down SI (33–48 cM) is marked by the bold horizontal line.

Figure 3

Nonparametric LOD score plot for chromosome 15. LOD scores for the overall sample (n=437 [solid line]), the subset with minimum age at onset >79 years (n=38 [dashed line]), and the subset with mean age at onset >80 years (n=43 [dotted line]) are presented. The 1-LOD–unit down SIs for the minimum–age-at-onset curve (51–72 cM) and the mean age at onset curve (56–70 cM) are marked by the bold horizontal lines.