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

Abstract

To identify novel candidate regions for lateonset 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.

A Genomewide Screen for Late-Onset Alzheimer Disease in a Genetically Isolated Dutch Population

“…A recent linkage-based genome scan of Caribbean Hispanic families revealed a new locus on chromosome 3q28, with a 2-point LOD score of 3.09 at marker D3S2418. 35 However, this region is ∼50 cM downstream of the region we identified in our study. The linked region on chromosome 3q22-24 contains various possible candidate genes, including the TF gene, the gene encoding for butyrylcholinesterase (BCHE [MIM 177400]), the neprilysin gene (MME [MIM 120520]), and the somatostatin gene (SST [MIM 182450]).…”

A Genomewide Screen for Late-Onset Alzheimer Disease in a Genetically Isolated Dutch Population

“…A recent linkage-based genome scan of Caribbean Hispanic families revealed a new locus on chromosome 3q28, with a 2-point LOD score of 3.09 at marker D3S2418. 35 However, this region is ∼50 cM downstream of the region we identified in our study. The linked region on chromosome 3q22-24 contains various possible candidate genes, including the TF gene, the gene encoding for butyrylcholinesterase (BCHE [MIM 177400]), the neprilysin gene (MME [MIM 120520]), and the somatostatin gene (SST [MIM 182450]).…”

Somatostatin genetic variants modify the risk for Alzheimer's disease among Finnish patients

“…At least three independent studies have observed support for significant linkage with late-onset AD at chromosome 3q28 [9,11,12] including our paper with the microsatellite marker D3S2436 [11]. The somatostatin gene is located ~500 kb away from D3S2436 marker and thus it can be considered as a positional candidate gene for AD.…”

Linkage analysis of multiplex Caribbean Hispanic families loaded for unexplained early‐onset cases identifies novel Alzheimer's disease loci

“…Four loci (13q33.1, 16p12.1, 18p11.23, and 20p12.1) had significant linkage signals under both models. In addition, two previously reported regions on chromosomes 3q13.3 and 3q23 [38] yielded HLOD scores suggestive of linkage in the affecteds-only model (HLOD 3.5 and 3.3, respectively). Although the APOE region on chromosome 19q13.2 did not reach the threshold of HLOD ≥ 3.6, there was evidence of suggestive linkage within a 5 cM range in the age-dependent penetrance model (HLOD = 2.4).…”

A Genomewide Screen for Late-Onset Alzheimer Disease in a Genetically Isolated Dutch Population

“…A recent linkage-based genome scan of Caribbean Hispanic families revealed a new locus on chromosome 3q28, with a 2-point LOD score of 3.09 at marker D3S2418. 35 However, this region is ∼50 cM downstream of the region we identified in our study. The linked region on chromosome 3q22-24 contains various possible candidate genes, including the TF gene, the gene encoding for butyrylcholinesterase (BCHE [MIM 177400]), the neprilysin gene (MME [MIM 120520]), and the somatostatin gene (SST [MIM 182450]).…”

Somatostatin genetic variants modify the risk for Alzheimer's disease among Finnish patients

“…At least three independent studies have observed support for significant linkage with late-onset AD at chromosome 3q28 [9,11,12] including our paper with the microsatellite marker D3S2436 [11]. The somatostatin gene is located ~500 kb away from D3S2436 marker and thus it can be considered as a positional candidate gene for AD.…”

Linkage analysis of multiplex Caribbean Hispanic families loaded for unexplained early‐onset cases identifies novel Alzheimer's disease loci

“…Four loci (13q33.1, 16p12.1, 18p11.23, and 20p12.1) had significant linkage signals under both models. In addition, two previously reported regions on chromosomes 3q13.3 and 3q23 [38] yielded HLOD scores suggestive of linkage in the affecteds-only model (HLOD 3.5 and 3.3, respectively). Although the APOE region on chromosome 19q13.2 did not reach the threshold of HLOD ≥ 3.6, there was evidence of suggestive linkage within a 5 cM range in the age-dependent penetrance model (HLOD = 2.4).…”

A Genomewide Screen for Late-Onset Alzheimer Disease in a Genetically Isolated Dutch Population

“…A recent linkage-based genome scan of Caribbean Hispanic families revealed a new locus on chromosome 3q28, with a 2-point LOD score of 3.09 at marker D3S2418. 35 However, this region is ∼50 cM downstream of the region we identified in our study. The linked region on chromosome 3q22-24 contains various possible candidate genes, including the TF gene, the gene encoding for butyrylcholinesterase (BCHE [MIM 177400]), the neprilysin gene (MME [MIM 120520]), and the somatostatin gene (SST [MIM 182450]).…”

Somatostatin genetic variants modify the risk for Alzheimer's disease among Finnish patients

“…At least three independent studies have observed support for significant linkage with late-onset AD at chromosome 3q28 [9,11,12] including our paper with the microsatellite marker D3S2436 [11]. The somatostatin gene is located ~500 kb away from D3S2436 marker and thus it can be considered as a positional candidate gene for AD.…”

Linkage analysis of multiplex Caribbean Hispanic families loaded for unexplained early‐onset cases identifies novel Alzheimer's disease loci

“…Four loci (13q33.1, 16p12.1, 18p11.23, and 20p12.1) had significant linkage signals under both models. In addition, two previously reported regions on chromosomes 3q13.3 and 3q23 [38] yielded HLOD scores suggestive of linkage in the affecteds-only model (HLOD 3.5 and 3.3, respectively). Although the APOE region on chromosome 19q13.2 did not reach the threshold of HLOD ≥ 3.6, there was evidence of suggestive linkage within a 5 cM range in the age-dependent penetrance model (HLOD = 2.4).…”