A Founder Mutation in Presenilin 1 Causing Early-Onset Alzheimer Disease in Unrelated Caribbean Hispanic Families

Athan, E; Williamson, Jennifer; Ciappa, Alejandra; Santana, Vincent; Romas, Stavra N.; Lee, Joseph H.; Rondon, Haydee Z.; Lantigua, Rafael; Medrano, Martin; Torres, Mayobanex; Arawaka, Shigeki; Rogaeva, Ekaterina; Song, You‐Qiang; Sato, Christine; Kawarai, Toshitaka; Fafel, Kimberley C.; Boss, Michael A.; Seltzer, William; Stern, Yaakov; George‐Hyslop, Peter St; Tycko, Benjamin; Mayeux, Richard

doi:10.1001/jama.286.18.2257

Cited by 96 publications

(80 citation statements)

References 42 publications

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“…APOE genotyping was carried out as previously described with slight modifications [29,30]. Genotyping for the PSEN1 Gly206Ala mutation, which we previously described as a founder mutation in this population, was performed as in Athan et al [31].…”

Section: Genotypingmentioning

confidence: 99%

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Age-at-onset linkage analysis in Caribbean Hispanics with familial late-onset Alzheimer’s disease

et al. 2007

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The aim of the study was to identify chromosomal regions containing putative genetic variants influencing age-at-onset in familial late-onset Alzheimer's disease. Data from a genome-wide scan that included genotyping of APOE was analyzed in 1,161 individuals from 209 families of Caribbean Hispanic ancestry with a mean age-at-onset of 73.3 years multiply affected by late-onset Alzheimer's disease. Two-point and multipoint analyses were conducted using variance component methods from 376 microsatellite markers with an average inter-marker distance of 9.3 cM. Family-based test of association were also conducted for the same set of markers. Age-at-onset of symptoms among affected individuals was used as the quantitative trait. Our results showed that the presence of APOE-ε4 lowered the age-at-onset by three years. Using linkage analysis strategy, the highest LOD scores were obtained using a conservative definition of LOAD at 5q15 (LOD 3.1) 17q25.1 (LOD=2.94) and 14q32.12 (LOD=2.36) and 7q36.3 (LOD=2.29) in covariate adjusted models that included APOE-ε4. Both linkage and family-based association identified 17p13 as a candidate region. In addition, family-based association analysis showed markers at 12q13 (p=0.00002), 13q (p=0.00043) and 14q23 (p=0.00046) to be significantly associated with age at onset. The current study supports the hypothesis that there are additional genetic loci that could influence age-at-onset of late onset

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Section: Genotypingmentioning

confidence: 99%

“…Because the marker at 14q32 yielded a significant LOD and is proximal to PSEN, we screened one affected person from each family for a PSEN1 mutation, Gly206Ala, specific to Caribbean Hispanics [31]. From the screen, we identified six individuals with this mutation who had an average age-at-onset of 57 years.…”

Section: Linkage Analysismentioning

confidence: 99%

Age-at-onset linkage analysis in Caribbean Hispanics with familial late-onset Alzheimer’s disease

et al. 2007

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“…Previously, we have shown that the study population is relatively homogeneous. 15 Overall, 237 individuals met the criteria for probable AD, 157 were unaffected. The study included families with affected sibpairs as well as families with multiple individuals with AD who were distantly related (eg, avunculars, cousins).…”

Section: Subjects and Familiesmentioning

confidence: 99%

“…12,13 To investigate the genetics of AD in this population, we initiated a linkage study. Our initial results included a strong association between APOE-e4 and late-onset familial AD, 14 a founder mutation in presenilin 1 (PSEN1 [MIM 104311]) among families with early-onset AD, 15 and modest evidence for linkage to chromosome 12p for late-onset AD in this population. 16 In this report, we describe the results of fine mapping on chromosomes 10q and 18q based on the results of the first genome scan for familial AD using families of Caribbean Hispanic descent.…”

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confidence: 99%

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

et al. 2004

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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 lateonset 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 lateonset AD. We observed the strongest support for linkage on 18q (LOD ¼ 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 ¼ 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 ¼ 0.000486) to 2.1 (P ¼ 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.

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“…AD can be subdivided into sporadic type and familial type. The familial AD (FAD) is mostly early-onset, accounting for less than 5% of all AD cases, with Presenilin-1(PSEN1) and Presenilin-2 (PSEN2) as its genes, of which PSEN1 stands at the top [1][2][3][4]. Though, DLB is found mostly sporadic, without any confirmed genetic risk factor.…”

Section: Introductionmentioning

confidence: 99%

Presenilin 1 Mutation (A431V) Causing Features of Dementia with Lewy Bodies in a Chinese Family of Alzheimer’s Disease

Qiao¹,

Peng²,

Jin³

et al. 2017

J Alzheimers Dis Parkinsonism

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A Founder Mutation in Presenilin 1 Causing Early-Onset Alzheimer Disease in Unrelated Caribbean Hispanic Families

Abstract: The Gly206Ala mutation was found in 8 of 19 unrelated Caribbean Hispanic families with early-onset familial AD. This genetic change may be a prevalent cause of early-onset familial AD in the Caribbean Hispanic population.

Cited by 96 publications

References 42 publications

Age-at-onset linkage analysis in Caribbean Hispanics with familial late-onset Alzheimer’s disease

Age-at-onset linkage analysis in Caribbean Hispanics with familial late-onset Alzheimer’s disease

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

Presenilin 1 Mutation (A431V) Causing Features of Dementia with Lewy Bodies in a Chinese Family of Alzheimer’s Disease

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