Fine mapping of 10q and 18q for familial Alzheimer's disease in Caribbean Hispanics

Abstract

Familial Alzheimer's disease (AD [MIM 104300]) has been a focus of intense investigation, primarily in Caucasian families from Europe and North America families. Although the late-onset form of familial AD, beginning after age 65 years, has been linked to regions on chromosomes 10q and 12p, the specific genetic variants have not yet been consistently identified. Using a unique cohort of families of Caribbean Hispanics ancestry, we screened the genome using 340 markers on 490 family members from 96 families with predominantly late-onset AD. We observed the strongest support for linkage on 18q (LOD=3.14). However, 17 additional markers (chromosomes 1-6, 8, 10, 12, and 14) exceeded a two-point LOD score of 1.0 under the affecteds-only autosomal dominant model or affected sibpair model. As we previously reported the fine-mapping effort on 12p showing modest evidence of linkage, we focused our fine-mapping efforts on two other candidate regions in the current report, namely 10q and 18q. We added 31 family members and eight additional Caribbean Hispanic families to fine map 10q and 18q. With additional microsatellite markers, the evidence for linkage for 18q strengthened near 112 cM, where the two-point LOD score for D18S541 was 3.37 and the highest NPL score in that region was 3.65 (P=0.000177). This narrow region contains a small number of genes expressed in the brain. However, at 10q (134-138 cM), the NPL score decreased from 3.15 (P=0.000486) to 2.1 (P=0.0218), but two broad peaks remained overlapping with previously reported peaks. Our results provide modest support for linkage on 10q and 12p in this cohort of Caribbean Hispanic families with familial Alzheimer's disease, and strong evidence for a new locus on 18q.

Figure 1

The multipoint nonparametric analysis for 18q from the second-stage fine mapping using all families. The heavy solid line represents the linkage analysis using all families; the light solid line the Apolipoprotein E ε4-positive conditional linkage analysis; and the dotted line the Apolipoprotein E ε4-negative conditional linkage analysis. Map distances are based on the Marshfield genetic map. (Marshfield Medical Research Foundation, Center for Medical Genetics, http://research.marshfieldclinic.org/genetics/).

Figure 2

The multipoint nonparametric analysis for 10q from the second-stage fine mapping using all families. The locations and markers of reported suggestive linkage findings by other groups on 10q are shown below. To estimate confidence intervals, we subtracted one from the highest reported LOD Score. The number next to each bar or dot indicates the reference (1. Bertram et al., 2000; 2. Ertekin-Taner et al., 2002; 3. Myer et al., 2000; 4. Kehoe et al., 1999; 5. Blacker et al., 2003; 6. Myer et al., 2002; 7. Farrer et al., 2003; 8. Li et al., 2003; 9. Ertekin-Taner et al., 2003). Map distances are based on the Marshfield genetics map (Marshfield Medical Research Foundation, Center for Medical Genetics, http://research.marshfieldclinic.org/genetics/).