Expanded Genomewide Scan Implicates a Novel Locus at 3q28 Among Caribbean Hispanics With Familial Alzheimer Disease

Lee, Joseph H.; Cheng, Rong; Santana, Vincent; Williamson, Jennifer; Lantigua, Rafael; Medrano, Martin; Arriaga, Alex; Stern, Yaakov; Tycko, Benjamin; Rogaeva, Ekaterina; Wakutani, Yosuke; Kawarai, Toshitaka; St George–Hyslop, Peter; Mayeux, Richard

Objectives: To identify novel candidate regions for late-onset Alzheimer disease (LOAD) and to confirm linkage in previously identified chromosomal regions.

Design: Family-based linkage analysis.

Setting: Probands with familial LOAD identified in clinics in the Dominican Republic, Puerto Rico, and the United States.

Patients: We conducted a genome scan in 1161 members primarily clinically diagnosed as having LOAD; these members were from 209 families of Caribbean Hispanic ancestry.

Main Outcome Measures: We analyzed 376 microsatellite markers with an average intermarker distance of 9.3 centimorgan. We conducted linkage analysis using possible and probable LOAD, and we performed affecteds-only 2-point linkage analyses assuming either an autosomal dominant or a recessive model. Subsequently, we conducted a multipoint affected sibling pair linkage analysis.

Results: Two-point parametric linkage analysis identified a locus at 3q28 with a genomewide empirical P value of .03 (logarithm of odds [LOD], 3.09) in a dominant model for probable and possible LOAD. Other regions suggestive of linkage included 2p25.3 (LOD, 1.77), 7p21.1 (LOD, 1.82), and 9q32 (LOD, 1.94). Under a recessive model, we also identified loci at 5p15.33 (LOD, 1.86), 12q24.21 (LOD, 2.43), 14q22.3 (LOD, 2.53), and 14q23.1 (LOD, 2.16) as suggestive for linkage. Restricted to probable LOAD, many of these loci continued to meet criteria suggestive for linkage, as did loci at 2p25.3 (LOD, 2.72), 3q28 (LOD, 2.28), 6p21.31 (LOD, 2.19), and 7p21.1 (LOD, 2.05). APOE conditional analysis indicated that the observed linkage at 3q28 was independent of the APOE ε4 allele. Multipoint nonparametric affected sibling pair linkage analysis provided confirmation of suggestive linkage for most, but not all, loci.

Conclusions: Seven loci with LOD scores greater than 2.0 were identified among multiple affected Caribbean Hispanic families with LOAD. The highest LOD score was found at chromosome 3q28. At least 2 other independent studies have observed support for significant linkage at chromosome 3q28, highlighting this region as a locus for further genetic exploration.

The ε4 variant of the apolipoprotein E (APOE) gene remains the only known genetic risk factor associated with late-onset Alzheimer disease (LOAD).1 Daw et al2 predicted that there may be as many as 4 additional genetic variants that influence the age at onset of LOAD. Several genomewide genetic linkage surveys also suggest additional LOAD loci.3-16 Despite these efforts, to our knowledge, no single gene has been found to show consistent associations in multiple data sets. Nevertheless, broadly overlapping loci conferring modest susceptibility to LOAD have been reported in families from North America or Europe on chromosomes 12p11 to 12q13,13,16,17 10q21 to 10q25,4,6,18 and 9p21 to 9p22.12,14,19,20 Within these regions, analyses have implicated several candidate genes, but most lack confirmation in independent studies or their replication has been inconsistent. The susceptibility locus for complex traits is often difficult to replicate because the number of families included in the follow-up study is too few.21 Nevertheless, replication of linkage or association remains the critical step in the validation of genetic studies.

In a previous genomewide study of Caribbean Hispanic families,10 confirmatory evidence for linkage to chromosome 12p22 and 10q,10 and evidence for a novel locus on 18q,10 were reported. In the present report, we describe the second phase of this study, with the results of a follow-up genome scan that included additional families of the same ethnic origin.



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February 11, 2022