Identification of Novel Loci for Alzheimer Disease and Replication of CLU, PICALM, and BIN1 in Caribbean Hispanic Individuals

Lee, Joseph H.; Cheng, Rong; Barral, Sandra; Reitz, Christiane; Medrano, Martin; Lantigua, Rafael; Jiménez‐Velázquez, Ivonne Z.; Rogaeva, Ekaterina; George-Hyslop, Peter St; Mayeux, Richard

doi:10.1001/archneurol.2010.292

Cited by 162 publications

(134 citation statements)

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“…All selected probands came from families with three or more affected individuals recruited in the Dominican Republic and New York. Recruitment for this family study began in 1998, and was restricted to Caribbean Hispanics,27, 28 predominately from the Dominican Republic. As a part of the ADSP, a set of 67 CH families and 47 Caucasian families were selected for whole genome sequencing from approximately 1400 families reviewed.…”

Section: Methodsmentioning

confidence: 99%

Whole genome sequencing of Caribbean Hispanic families with late‐onset Alzheimer's disease

Vardarajan

Barral

Jaworski

et al. 2018

Ann Clin Transl Neurol

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ObjectiveTo identify rare causal variants underlying known loci that segregate with late‐onset Alzheimer's disease (LOAD) in multiplex families.MethodsWe analyzed whole genome sequences (WGS) from 351 members of 67 Caribbean Hispanic (CH) families from Dominican Republic and New York multiply affected by LOAD. Members of 67 CH and additional 47 Caucasian families underwent WGS as a part of the Alzheimer's Disease Sequencing Project (ADSP). All members of 67 CH families, an additional 48 CH families and an independent CH case‐control cohort were subsequently genotyped for validation. Patients met criteria for LOAD, and controls were determined to be dementia free. We investigated rare variants segregating within families and gene‐based associations with disease within LOAD GWAS loci.ResultsA variant in AKAP9, p.R434W, segregated significantly with LOAD in two large families (OR = 5.77, 95% CI: 1.07–30.9, P = 0.041). In addition, missense mutations in MYRF and ASRGL1 under previously reported linkage peaks at 7q14.3 and 11q12.3 segregated completely in one family and in follow‐up genotyping both were nominally significant (P < 0.05). We also identified rare variants in a number of genes associated with LOAD in prior genome wide association studies, including CR1 (P = 0.049), BIN1 (P = 0.0098) and SLC24A4 (P = 0.040).Conclusions and RelevanceRare variants in multiple genes influence the risk of LOAD disease in multiplex families. These results suggest that rare variants may underlie loci identified in genome wide association studies.

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Section: Methodsmentioning

confidence: 99%

Whole genome sequencing of Caribbean Hispanic families with late‐onset Alzheimer's disease

Vardarajan

Barral

Jaworski

et al. 2018

Ann Clin Transl Neurol

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“…In 2012, Lee et al [40] conducted a GWAS among Caribbean Hispanic individuals and successfully replicated the association of AD with CLU, PICALM, and BIN1, and other 5 SNPs. Gaj et al [41] pooled DNA samples from female-only patient groups from Poland and identified rs7856774 at 9q21.33 as a novel LOAD candidate risk variant, independent of the effect of APOE.…”

Section: Finding Genetic Risk Factors In Diverse Ethnic Groupsmentioning

confidence: 99%

An Overview of Genome-Wide Association Studies in Alzheimer’s Disease

Shen

Jia

2016

Neurosci. Bull.

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Genome-wide association studies (GWASs) have revealed a plethora of putative susceptibility genes for Alzheimer's disease (AD). With the sole exception of the APOE gene, these AD susceptibility genes have not been unequivocally validated in independent studies. No single novel functional risk genetic variant has been identified. In this review, we evaluate recent GWASs of AD, and discuss their significance, limitations, and challenges in the investigation of the genetic spectrum of AD.

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“…Moreover, numerous case-control GWASs have been subsequently published, unambiguously verifying the association between various PICALM loci and LOAD risk in the Caucasian population [39][40][41][42][43][44] (Table 1). However, inconformity of the replication results occurred when the initial SNP (rs3851179) was investigated in Asian population ( Table 2).…”

Section: Genetics Of Picalm Gene In Admentioning

confidence: 99%

The Role of PICALM in Alzheimer’s Disease

Tan

2014

Mol Neurobiol

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Alzheimer's disease (AD) is a highly heritable disease (with heritability up to 76%) with a complex genetic profile of susceptibility, among which large genome-wide association studies (GWASs) pointed to the phosphatidylinositol-binding clathrin assembly protein (PICALM) gene as a susceptibility locus for late-onset Alzheimer's disease (LOAD) incidence. Here, we summarize the known functions of PICALM and discuss its genetic polymorphisms and their potential physiological effects associated with LOAD. Compelling data indicated that PICALM affects AD risk primarily by modulating production, transportation, and clearance of β-amyloid (Aβ) peptide, but other Aβ-independent pathways are discussed, including tauopathy, synaptic dysfunction, disorganized lipid metabolism, immune disorder, and disrupted iron homeostasis. Finally, given the potential involvement of PICALM in facilitating AD occurrence in multiple ways, it might be possible that targeting PICALM might provide promising and novel avenues for AD therapy.

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Identification of Novel Loci for Alzheimer Disease and Replication of CLU, PICALM, and BIN1 in Caribbean Hispanic Individuals

Cited by 162 publications

References 38 publications

Whole genome sequencing of Caribbean Hispanic families with late‐onset Alzheimer's disease

Whole genome sequencing of Caribbean Hispanic families with late‐onset Alzheimer's disease

An Overview of Genome-Wide Association Studies in Alzheimer’s Disease

The Role of PICALM in Alzheimer’s Disease

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