SORL1 variants across Alzheimer’s disease European American cohorts

Fernández, María Victoria; Black, Kathleen; Carrell, David; Saef, Ben; Budde, John; Deming, Yuetiva; Howells, Bill; Del‐Aguila, Jorge L.; Ma, Sheng-mei; Bi, Catherine; Norton, Joanne; Chasse, Rachel; Morris, John C.; Goate, Alison M.; Cruchaga, Carlos

doi:10.1038/ejhg.2016.122

Cited by 21 publications

(15 citation statements)

References 18 publications

(22 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…APOE ε4 is the most common genetic risk factor, increasing the risk in 3-to 8-fold [19]. In addition, recent whole genome and whole exome analysis have identified rare coding variants in TREM2 [9,32], PLD3 [20], ABCA7 [22,63] and SORL1 [26,56] that are associated with AD and confer risk comparable to that of carrying one APOE ε4 allele. Besides age at onset, the clinical presentations of LOAD and ADAD are remarkably similar with an amnestic and cognitive impairment phenotype [57,66].…”

mentioning

confidence: 99%

Genetic variants associated with Alzheimer's disease confer different cerebral cortex cell-type population structure

Li¹,

Del‐Aguila²,

Dube³

et al. 2018

Preprint

Self Cite

View full text Add to dashboard Cite

Alzheimer's disease (AD) is characterized by neuronal loss and astrocytosis in the cerebral cortex. However, the effects of brain cellular composition are often ignored in high-throughput molecular studies. We developed and optimized a cell-type specific expression reference panel and employed digital deconvolution methods to determine brain cellular distribution in three independent transcriptomic studies. We found that neuronal and astrocyte proportions differ between healthy and diseased brains and also among AD cases that carry specific genetic risk variants. Brain carriers of pathogenic mutations in APP, PSEN1 or PSEN2 presented lower neurons and higher astrocytes proportions compared to sporadic AD. Similarly, the APOE ε4 allele also showed decreased neurons and increased astrocytes compared to AD non-carriers. On the contrary, carriers of variants in TREM2 risk showed a lower degree of neuronal loss than matched AD cases in multiple independent studies. These findings suggest that genetic risk factors associated with AD etiology have a specific imprinting in the cellular composition of AD brains. Our digital deconvolution reference panel provides an enhanced understanding of the fundamental molecular mechanisms underlying neurodegeneration, enabling the analysis of large bulk RNA-seq studies for cell composition, and suggests that correcting for the cellular structure when performing transcriptomic analysis will lead to novel insights of AD. KeywordsDigital deconvolution, Alzheimer's disease, cellular composition, bulk RNA-seq, autosomal dominant AD, TREM2.. CC-BY-NC-ND 4.0 International license It is made available under a (which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint . http://dx.doi.org/10.1101/266296 doi: bioRxiv preprint first posted online Feb. 15, 2018; 3 IntroductionAlzheimer's Disease (AD) is a neurodegenerative disorder characterized clinically by gradual and progressive memory loss and pathologically by the presence of senile plaques (Aβ deposits) and neurofibrillary tangles (NFTs, Tau deposits) in the brain [41]. AD has a substantial but heterogeneous genetic component. Mutations in the amyloid-beta precursor protein (APP) and Presenilin genes (PSEN1 and PSEN2) [21, 59] cause autosomal dominant AD (ADAD) which is typically associated with early-onset (<65 years). In contrast, the most common manifestation of AD presents late-onset (LOAD) and accounts for the majority of the cases (90-95%). Despite appearing sporadic in nature, a complex genetic architecture underlies LOAD risk. APOE ε4 is the most common genetic risk factor, increasing the risk in 3-to 8-fold [19]. In addition, recent whole genome and whole exome analysis have identified rare coding variants in TREM2 [9,32], PLD3 [20], ABCA7 [22,63] and SORL1 [26,56] that are associated with AD and confer risk comparable to that of carrying one APOE ε4 allele. Besides age at onset, the clinical presentations of LOAD a...

show abstract

mentioning

confidence: 99%

Genetic variants associated with Alzheimer's disease confer different cerebral cortex cell-type population structure

Li¹,

Del‐Aguila²,

Dube³

et al. 2018

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…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.

View full text Add to dashboard Cite

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.

show abstract

“…The additive effect that additional variants with lower frequency (MAF <5%) associated with AD (i.e. TREM2 [44,45], PLD3 [46], SORL1 [47,48] or ABCA7 [29,49]) still remains to be analyzed in these cohorts.…”

Section: Discussionmentioning

confidence: 99%

Polygenic Risk Score of Sporadic late Onset Alzheimer Disease Reveals a Shared Architecture with the Familial and Early Onset Forms

Aguila¹,

Saef²,

Black³

et al. 2017

Preprint

Self Cite

View full text Add to dashboard Cite

Objective: To determine whether the genetic architecture of sporadic late--onset Alzheimer's Disease (sLOAD) has an effect on familial late--onset AD (fLOAD), sporadic early--onset (sEOAD) and autosomal dominant early--onset (eADAD).Methods: Polygenic risk scores (PRS) were constructed using previously identified 21 genome--wide significant loci for LOAD risk.Results: We found that there is an overlap in the genetic architecture among sEOAD, fLOAD, and sLOAD. sEOAD showed the highest odds for the PRS (OR=2.27; p=1.29×10 --7 ), followed by fLOAD (OR=1.75; p=1.12×10 --7 ) and sLOAD (OR=1.40; p=1.21×10 --3 ). PRS is associated with cerebrospinal fluid ptau 181 --Aβ 42 on eADAD.Conclusion: Our analysis confirms that the genetic factors identified for sLOAD also modulate risk in fLOAD and sEOAD cohorts. Furthermore, our results suggest that the burden of these risk variants is associated with familial clustering and earlier--onset of AD. Although these variants are not associated with risk in the eADAD, they may be modulating age at onset.peer-reviewed)

show abstract

SORL1 variants across Alzheimer’s disease European American cohorts

Cited by 21 publications

References 18 publications

Genetic variants associated with Alzheimer's disease confer different cerebral cortex cell-type population structure

Genetic variants associated with Alzheimer's disease confer different cerebral cortex cell-type population structure

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

Polygenic Risk Score of Sporadic late Onset Alzheimer Disease Reveals a Shared Architecture with the Familial and Early Onset Forms

Contact Info

Product

Resources

About