Meta-analysis of the Association Between Variants in SORL1 and Alzheimer Disease

Reitz, Christiane; Cheng, Rong; Rogaeva, Ekaterina; Lee, Joseph H.; Tokuhiro, Shinya; Zou, Fanggeng; Bettens, Karolien; Sleegers, Kristel; Tan, Eng King; Kimura, Ryo; Shibata, Nobuto; Arai, Heii; Kamboh, M. Ilyas; Prince, Jonathan A.; Maier, Wolfgang; Riemenschneider, Matthias; Owen, Michael John; Harold, Denise; Hollingworth, Paul; Cellini, Elena; Sorbi, Sandro; Nacmias, Benedetta; Takeda, Masatoshi; Pericak‐Vance, Margaret A.; Haines, Jonathan L.; Younkin, Steven G.; Williams, Julie; Broeckhoven, Christine Van; Farrer, Lindsay A.; George-Hyslop, P. H. St.; Mayeux, Richard

doi:10.1001/archneurol.2010.346

Cited by 153 publications

(132 citation statements)

References 37 publications

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“…5 SORL1 has already been the subject of numerous association studies focused on frequent polymorphisms (for a complete overview, see Alzgene, www.alzgene.org), yielding mixed results, although a recent meta-analysis, including more than 12 000 cases and 17 000 controls, concluded that multiple SORL1 alleles in distinct linkage disequilibrium blocks are associated with AD risk. 6 We also determined the allele frequency of each variant in a cohort of 1500 control individuals matched for ethnic origin. This work confirmed that all variants were indeed private variants not found in controls.…”

Section: Resultsmentioning

confidence: 99%

High frequency of potentially pathogenic SORL1 mutations in autosomal dominant early-onset Alzheimer disease

Pottier

Hannequin²,

Coutant³

et al. 2012

Mol Psychiatry

261

229

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Performing exome sequencing in 14 autosomal dominant early-onset Alzheimer disease (ADEOAD) index cases without mutation on known genes (amyloid precursor protein (APP), presenilin1 (PSEN1) and presenilin2 (PSEN2)), we found that in five patients, the SORL1 gene harbored unknown nonsense (n = 1) or missense (n = 4) mutations. These mutations were not retrieved in 1500 controls of same ethnic origin. In a replication sample, including 15 ADEOAD cases, 2 unknown non-synonymous mutations (1 missense, 1 nonsense) were retrieved, thus yielding to a total of 7/29 unknown mutations in the combined sample. Using in silico predictions, we conclude that these seven private mutations are likely to have a pathogenic effect. SORL1 encodes the Sortilin-related receptor LR11/SorLA, a protein involved in the control of amyloid beta peptide production. Our results suggest that besides the involvement of the APP and PSEN genes, further genetic heterogeneity, involving another gene of the same pathway is present in ADEOAD.

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Section: Resultsmentioning

confidence: 99%

High frequency of potentially pathogenic SORL1 mutations in autosomal dominant early-onset Alzheimer disease

Pottier

Hannequin²,

Coutant³

et al. 2012

Mol Psychiatry

261

229

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“…Nevertheless, there is strong support for the involvement of SORLA in sporadic AD, which stems from population-based studies that document association of genetic variants of SORL1 (the gene encoding SORLA) with sporadic AD in several ethnicities (Rogaeva et al, 2007;Bettens et al, 2008;Cuenco et al, 2008;Lee et al, 2008;Webster et al, 2008). Cumulative meta-analyses encompassing in excess of 30,000 individuals (Reitz et al, 2011) and genomewide association studies Naj et al, 2011) confirm the association of single nucleotide polymorphisms (SNPs) in SORL1 with AD.…”

Section: Sorla a Neuronal Trafficking Receptor Implicated In Admentioning

confidence: 99%

Sorting receptor SORLA – a trafficking path to avoid Alzheimer disease

Willnow

Andersen

2013

Journal of Cell Science

102

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SummaryExcessive proteolytic breakdown of the amyloid precursor protein (APP) to neurotoxic amyloid b peptides (Ab) by secretases in the brain is a molecular cause of Alzheimer disease (AD). According to current concepts, the complex route whereby APP moves between the secretory compartment, the cell surface and endosomes to encounter the various secretases determines its processing fate. However, the molecular mechanisms that control the intracellular trafficking of APP in neurons and their contribution to AD remain poorly understood. Here, we describe the functional elucidation of a new sorting receptor SORLA that emerges as a central regulator of trafficking and processing of APP. SORLA interacts with distinct sets of cytosolic adaptors for anterograde and retrograde movement of APP between the trans-Golgi network and early endosomes, thereby restricting delivery of the precursor to endocytic compartments that favor amyloidogenic breakdown. Defects in SORLA and its interacting adaptors result in transport defects and enhanced amyloidogenic processing of APP, and represent important risk factors for AD in patients. As discussed here, these findings uncovered a unique regulatory pathway for the control of neuronal protein transport, and provide clues as to why defects in this pathway cause neurodegenerative disease.

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“…One half of the genetic variance is attributable to mutations in APP, PSEN1, PSEN2, and the APOE e4-allele, and they have been shown to cause the overproduction or reduced clearance of Ab (Rogaeva et al 2006). More recently, it was demonstrated that single nucleotide polymorphisms (SNP) in SORL1 are significantly associated with late-onset AD in several independent cohorts (Rogaeva et al 2007;Reitz et al 2011). In addition,…”

mentioning

confidence: 99%

Genome-Wide Survey of Large Rare Copy Number Variants in Alzheimer’s Disease Among Caribbean Hispanics

Ghani

Pinto

Lee

et al. 2012

G3 Genes|Genomes|Genetics

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Recently genome-wide association studies have identified significant association between Alzheimer's disease (AD) and variations in CLU, PICALM, BIN1, CR1, MS4A4/MS4A6E, CD2AP, CD33, EPHA1, and ABCA7. However, the pathogenic variants in these loci have not yet been found. We conducted a genome-wide scan for large copy number variation (CNV) in a dataset of Caribbean Hispanic origin (554 controls and 559 AD cases that were previously investigated in a SNP-based genome-wide association study using Illumina HumanHap 650Y platform). We ran four CNV calling algorithms to obtain high-confidence calls for large CNVs (.100 kb) that were detected by at least two algorithms. Global burden analyses did not reveal significant differences between cases and controls in CNV rate, distribution of deletions or duplications, total or average CNV size; or number of genes affected by CNVs. However, we observed a nominal association between AD and a 470 kb duplication on chromosome 15q11.2 (P = 0.037). This duplication, encompassing up to five genes (TUBGCP5, CYFIP1, NIPA2, NIPA1, and WHAMML1) was present in 10 cases (2.6%) and 3 controls (0.8%). The dosage increase of CYFIP1 and NIPA1 genes was further confirmed by quantitative PCR. The current study did not detect CNVs that affect novel AD loci identified by recent genome-wide association studies. However, because the array technology used in our study has limitations in detecting small CNVs, future studies must carefully assess novel AD genes for the presence of disease-related CNVs. Alzheimer's disease (AD) is the most common form of dementia, affecting 30% of individuals over 80 years of age (Mayeux 2003). The hallmark of AD brain pathology is characterized by the accumulation of a neurotoxic proteolytic derivative of the amyloid precursor protein (APP; Ab peptides) and the formation of intraneuronal tau-associated neurofibrillary tangles. The majority of AD cases are sporadic (95%), with onset after 65 years of age. One half of the genetic variance is attributable to mutations in APP, PSEN1, PSEN2, and the APOE e4-allele, and they have been shown to cause the overproduction or reduced clearance of Ab (Rogaeva et al. 2006). More recently, it was demonstrated that single nucleotide polymorphisms (SNP) in SORL1 are significantly associated with late-onset AD in several independent cohorts (Rogaeva et al. 2007;Reitz et al. 2011). In addition,

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Meta-analysis of the Association Between Variants in SORL1 and Alzheimer Disease

Cited by 153 publications

References 37 publications

High frequency of potentially pathogenic SORL1 mutations in autosomal dominant early-onset Alzheimer disease

High frequency of potentially pathogenic SORL1 mutations in autosomal dominant early-onset Alzheimer disease

Sorting receptor SORLA – a trafficking path to avoid Alzheimer disease

Genome-Wide Survey of Large Rare Copy Number Variants in Alzheimer’s Disease Among Caribbean Hispanics

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