F‐box/
            <scp>LRR</scp>
            ‐repeat protein 7 is genetically associated with Alzheimer's disease

Tosto, Giuseppe; Fu, Hongjun; Vardarajan, Badri N.; Lee, Joseph H.; Cheng, Rong; Reyes‐Dumeyer, Dolly; Lantigua, Rafael; Medrano, Martin; Jiménez‐Velázquez, Ivonne Z.; Elkind, Mitchell S.V.; Wright, Clinton B.; Sacco, Ralph L.; Pericak‐Vance, Margaret A.; Farrer, Lindsay A.; Rogaeva, Ekaterina; George‐Hyslop, Peter St; Reitz, Christiane; Mayeux, Richard

doi:10.1002/acn3.223

Cited by 63 publications

(48 citation statements)

References 42 publications

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“…While the exact role of FBXL7 is still unknown, F-box proteins, of which FBXL7 is a member, are thought to be involved in cell growth, survival, and cell death [38]. This study along with a report by Lee et al also confirmed several risk loci as nominally significant in non-Hispanic Whites: CLU , PICALM , BIN1 , CD33 , FERMT2 , CELF1 , SLC24A4-RIN3 , and ABCA7 [15••, 33]. Further, in a GWAS of African Americans, ABCA7 was found to be genome-wide significant, and CR1 , BIN1 , EPHA1 , and CD33 [37••, 39] were replicated as well.…”

Section: Gwasmentioning

confidence: 54%

“…In a study of persons of Caribbean Hispanic descent, a novel locus on chromosome 5, FBXL7 , met genome-wide significance [15••]. While the exact role of FBXL7 is still unknown, F-box proteins, of which FBXL7 is a member, are thought to be involved in cell growth, survival, and cell death [38].…”

Section: Gwasmentioning

confidence: 99%

“…In 1993, genetic analysis identified APOE as a major genetic risk factor for LOAD [10]. The ε4 allele of APOE has the largest genetic effect, and has been replicated extensively across different forms of the disease (sporadic and familial LOAD [10, 11••], APP/presenilin mutation carriers [12], and across ethnic groups [13••, 14, 15••]). It has an attributable risk of approximately 25% [16], with ε 4 homozygotes showing an odds ratio up to 20 when compared to that of ε 3 homozygotes [17]; furthermore, one allele of ε 4 reduces the disease onset up to 5 years, and two copies up to 10 years.…”

Section: Introductionmentioning

confidence: 99%

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Genetics of Alzheimer’s Disease: the Importance of Polygenic and Epistatic Components

Raghavan

Tosto

2017

Curr Neurol Neurosci Rep

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Purpose of Review We aimed to summarize the recent advances in genetic findings of Alzheimer’s disease (AD), focusing on traditional single-marker and gene approaches and non-traditional ones, i.e., polygenic and epistatic components. Recent Findings Genetic studies have progressed over the last few decades from linkage to genome-wide association studies (GWAS), and most recently studies utilizing high-throughput sequencing. So far, GWASs have identified several common variants characterized by small effect sizes (besides APOE-ε4). Sequencing has facilitated the study of rare variants with larger effects. Nevertheless, missing heritability for AD remains extensive; a possible explanation might lie in the existence of polygenic and epistatic components. Summary We review findings achieved by single-marker approaches, but also polygenic and epistatic associations. The latter two are critical, yet-underexplored mechanisms. Genes involved in complex diseases are likely regulated by mechanisms and pathways involving many other genes, an aspect potentially missed by traditional approaches.

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Section: Gwasmentioning

confidence: 54%

Section: Gwasmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Genetics of Alzheimer’s Disease: the Importance of Polygenic and Epistatic Components

Raghavan

Tosto

2017

Curr Neurol Neurosci Rep

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“…; 2,451 cases and 2,063 controls) [41] . Second, the re-analysis of IGAP data after stratification on the APOE genotype unraveled a locus located near the MAPT gene which encodes the Tau protein [42] , which still remains to be replicated in independent studies.…”

Section: Results From Gwasmentioning

confidence: 99%

From Common to Rare Variants: The Genetic Component of Alzheimer Disease

Nicolas

Charbonnier²,

Campion³

2016

Hum Hered

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Alzheimer disease (AD) is a remarkable example of genetic heterogeneity. Extremely rare variants in the APP, PSEN1, or PSEN2 genes, or duplications of the APP gene cause autosomal dominant forms, generally with complete penetrance by the age of 65 years. Nonautosomal dominant forms are considered as a complex disorder with a high genetic component, whatever the age of onset. Although genetically heterogeneous, AD is defined by the same neuropathological criteria in all configurations. According to the amyloid cascade hypothesis, the Aβ peptide, which aggregates in AD brains, is a key player. APP, PSEN1, or PSEN2 gene mutations increase the production of more aggregation-prone forms of the Aβ peptide, triggering the pathological process. Several risk factors identified in association studies hit genes involved in Aβ production/secretion, aggregation, clearance, or toxicity. Among them, the APOE ε4 allele is a rare example of a common allele with a large effect size, the ORs ranging from 4 to 11-14 for heterozygous and homozygous carriers, respectively. In addition, genome-wide association studies have identified more than two dozen loci with a weak but significant association, the OR of the at-risk allele ranging from 1.08 to 1.30. Recently, the use of massive parallel sequencing has enabled the analysis of rare variants in a genome-wide manner. Two rare variants have been nominally associated with AD risk or protection (TREM2 p.R47H, MAF approximately 0.002, OR approximately 4 and APP p.A673T, MAF approximately 0.0005, OR approximately 0.2). Association analyses at the gene level identified rare loss-of-function and missense, predicted damaging, variants (MAF <0.01) in the SORL1 and ABCA7 genes associated with a moderate relative risk (OR approximately 5 and approximately 2.8, respectively). Although the latter analyses revealed association signals with moderately rare variants by collapsing them, the power to detect genes hit by extremely rare variants is still limited. An alternative approach is to consider the de novo paradigm, stating that de novo variants may contribute to AD genetics in sporadic patients. Here, we critically review AD genetics reports with a special focus on rare variants.

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“…The study has been described in detail elsewhere. 16 Collection of data for the WHICAP has been ongoing since 1992; these data were used as a replication sample for the present study. The WHICAP was approved by the institutional review board of Columbia University, New York City, and all participants provided written informed consent.…”

Section: Methodsmentioning

confidence: 99%