<i>SORL1</i>
            mutations in early- and late-onset Alzheimer disease

Cuccaro, Michael L.; Carney, Regina M.; Zhang, Yalun; Böhm, Christopher; Kunkle, Brian W.; Vardarajan, Badri N.; Whitehead, Patrice L.; Cukier, Holly N.; Mayeux, Richard; George-Hyslop, Peter St; Pericak‐Vance, Margaret A.

doi:10.1212/nxg.0000000000000116

Cited by 70 publications

(73 citation statements)

References 44 publications

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“…This is the first investigation to establish a genome‐wide statistically significant association between ultra‐rare variants in SORL1 and AD in a large, unbiased whole‐exome study of unrelated early‐ and late‐onset cases and controls. SORL1 has previously been implicated in both familial and sporadic, early‐ and late‐onset Alzheimer's disease …”

Section: Discussionmentioning

confidence: 99%

Whole‐exome sequencing in 20,197 persons for rare variants in Alzheimer's disease

Raghavan

Brickman

Andrews

et al. 2018

Ann Clin Transl Neurol

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120

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ObjectiveThe genetic bases of Alzheimer's disease remain uncertain. An international effort to fully articulate genetic risks and protective factors is underway with the hope of identifying potential therapeutic targets and preventive strategies. The goal here was to identify and characterize the frequency and impact of rare and ultra‐rare variants in Alzheimer's disease, using whole‐exome sequencing in 20,197 individuals.MethodsWe used a gene‐based collapsing analysis of loss‐of‐function ultra‐rare variants in a case–control study design with data from the Washington Heights‐Inwood Columbia Aging Project, the Alzheimer's Disease Sequencing Project and unrelated individuals from the Institute of Genomic Medicine at Columbia University.ResultsWe identified 19 cases carrying extremely rare SORL1 loss‐of‐function variants among a collection of 6,965 cases and a single loss‐of‐function variant among 13,252 controls (P = 2.17 × 10−8; OR: 36.2 [95% CI: 5.8–1493.0]). Age‐at‐onset was 7 years earlier for patients with SORL1 qualifying variant compared with noncarriers. No other gene attained a study‐wide level of statistical significance, but multiple top‐ranked genes, including GRID2IP,WDR76 and GRN, were among candidates for follow‐up studies.InterpretationThis study implicates ultra‐rare, loss‐of‐function variants in SORL1 as a significant genetic risk factor for Alzheimer's disease and provides a comprehensive dataset comparing the burden of rare variation in nearly all human genes in Alzheimer's disease cases and controls. This is the first investigation to establish a genome‐wide statistically significant association between multiple extremely rare loss‐of‐function variants in SORL1 and Alzheimer's disease in a large whole‐exome study of unrelated cases and controls.

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Section: Discussionmentioning

confidence: 99%

Whole‐exome sequencing in 20,197 persons for rare variants in Alzheimer's disease

Raghavan

Brickman

Andrews

et al. 2018

Ann Clin Transl Neurol

Self Cite

120

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“…SORL1 , was initially identified as a risk-factor in a case-control association-study [23], but has more recently been implicated in familial early-onset as well as late-onset AD [8, 16, 20, 21, 25, 26]. …”

Section: Discussionmentioning

confidence: 99%

Identification and description of three families with familial Alzheimer disease that segregate variants in the SORL1 gene

Thonberg

Chiang

Lilius

et al. 2017

acta neuropathol commun

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Alzheimer disease (AD) is a progressive neurodegenerative disorder and the most common form of dementia. The majority of AD cases are sporadic, while up to 5% are families with an early onset AD (EOAD). Mutations in one of the three genes: amyloid beta precursor protein (APP), presenilin 1 (PSEN1) or presenilin 2 (PSEN2) can be disease causing. However, most EOAD families do not carry mutations in any of these three genes, and candidate genes, such as the sortilin-related receptor 1 (SORL1), have been suggested to be potentially causative. To identify AD causative variants, we performed whole-exome sequencing on five individuals from a family with EOAD and a missense variant, p.Arg1303Cys (c.3907C > T) was identified in SORL1 which segregated with disease and was further characterized with immunohistochemistry on two post mortem autopsy cases from the same family. In a targeted re-sequencing effort on independent index patients from 35 EOAD-families, a second SORL1 variant, c.3050-2A > G, was found which segregated with the disease in 3 affected and was absent in one unaffected family member. The c.3050-2A > G variant is located two nucleotides upstream of exon 22 and was shown to cause exon 22 skipping, resulting in a deletion of amino acids Gly1017- Glu1074 of SORL1. Furthermore, a third SORL1 variant, c.5195G > C, recently identified in a Swedish case control cohort included in the European Early-Onset Dementia (EU EOD) consortium study, was detected in two affected siblings in a third family with familial EOAD. The finding of three SORL1-variants that segregate with disease in three separate families with EOAD supports the involvement of SORL1 in AD pathology. The cause of these rare monogenic forms of EOAD has proven difficult to find and the use of exome and genome sequencing may be a successful route to target them.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-017-0441-9) contains supplementary material, which is available to authorized users.

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“…Previous studies have revealed significant association between rs668387 and AD susceptibility [31][32][33][34][35]. Further, a meta-analysis by Wang et al [36] based on 35 studies suggested that SNP (rs668387, rs641120) has a decreased risk on AD susceptibility.…”

Section: Discussionmentioning

confidence: 99%

Association between SORL1 polymorphisms and the risk of Alzheimer’s disease

Cong

Kong

Wang

et al. 2018

J. Integr. Neurosci.

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A meta-analysis was performed to identify empirical data assessing the effects of a single nucleotide polymorphisms of sortilinrelated receptor on Alzheimer's disease based on 14 studies involving 37941 cases and 49727 control studies. Analysis showed, (i) Increased risk between the single nucleotide polymorphisms (rs641120, rs1010159) and Alzheimer's disease susceptibility in Asian populations, (ii) Single nucleotide polymorphism rs689021 was associated with decreased risk in Caucasians, and (iii) Single nucleotide polymorphism rs641120 was detected as a decreased risk in both populations. Given these data, crucial evidence is provided to demonstrate that a significant relationship exists between SORL1 polymorphisms and susceptibility to Alzheimer's disease.

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SORL1 mutations in early- and late-onset Alzheimer disease

Cited by 70 publications

References 44 publications

Whole‐exome sequencing in 20,197 persons for rare variants in Alzheimer's disease

Whole‐exome sequencing in 20,197 persons for rare variants in Alzheimer's disease

Identification and description of three families with familial Alzheimer disease that segregate variants in the SORL1 gene

Association between SORL1 polymorphisms and the risk of Alzheimer’s disease

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