Apolipoprotein E region molecular signatures of Alzheimer's disease

Kulminski, Alexander M.; Huang, Jian; Wang, Jiayi; He, Liyun; Loika, Yury; Culminskaya, Irina

doi:10.1111/acel.12779

Cited by 36 publications

(35 citation statements)

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“…Therefore, it should be noted that despite a major impact of the APOE genotypes on the associations of other SNPs inside the chromosome 19q13 region with AD, this result would not automatically imply that the APOE SNPs (i.e., rs429358 and rs7412) are the only contributors to AD pathogenesis because APOE -adjusted models highlighted the statistical correlations rather than biological (i.e., genetic) linkage. Further analyses such as those examining the role of haplotypes and epistatic interactions would be helpful to more comprehensively dissect the genetic heterogeneity of this region, and to elucidate the biological relevance of the APOE -adjusted models [70].…”

Section: Resultsmentioning

confidence: 99%

Genome-wide analysis of genetic predisposition to Alzheimer’s disease and related sex disparities

2019

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BackgroundAlzheimer’s disease (AD) is the most common cause of dementia in the elderly and the sixth leading cause of death in the United States. AD is mainly considered a complex disorder with polygenic inheritance. Despite discovering many susceptibility loci, a major proportion of AD genetic variance remains to be explained.MethodsWe investigated the genetic architecture of AD in four publicly available independent datasets through genome-wide association, transcriptome-wide association, and gene-based and pathway-based analyses. To explore differences in the genetic basis of AD between males and females, analyses were performed on three samples in each dataset: males and females combined, only males, or only females.ResultsOur genome-wide association analyses corroborated the associations of several previously detected AD loci and revealed novel significant associations of 35 single-nucleotide polymorphisms (SNPs) outside the chromosome 19q13 region at the suggestive significance level of p < 5E–06. These SNPs were mapped to 21 genes in 19 chromosomal regions. Of these, 17 genes were not associated with AD at genome-wide or suggestive levels of associations by previous genome-wide association studies. Also, the chromosomal regions corresponding to 8 genes did not contain any previously detected AD-associated SNPs with p < 5E–06. Our transcriptome-wide association and gene-based analyses revealed that 26 genes located in 20 chromosomal regions outside chromosome 19q13 had evidence of potential associations with AD at a false discovery rate of 0.05. Of these, 13 genes/regions did not contain any previously AD-associated SNPs at genome-wide or suggestive levels of associations. Most of the newly detected AD-associated SNPs and genes were sex specific, indicating sex disparities in the genetic basis of AD. Also, 7 of 26 pathways that showed evidence of associations with AD in our pathway-bases analyses were significant only in females.ConclusionsOur findings, particularly the newly discovered sex-specific genetic contributors, provide novel insight into the genetic architecture of AD and can advance our understanding of its pathogenesis.Electronic supplementary materialThe online version of this article (10.1186/s13195-018-0458-8) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

Genome-wide analysis of genetic predisposition to Alzheimer’s disease and related sex disparities

2019

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“…PVRL2 ( p -value 4.92 ∗ 10ˆ–34 in Brain (CMC) RNA-seq, also known as NECTIN2) is a well-known gene for AD. This gene encodes a single-pass type I membrane glycoprotein and interact with AOPE gene (Kulminski et al, 2018). TOMM40 [ p -value 1.13 ∗ 10ˆ–25 in Whole Blood (YFS) RNA Array] is also located adjacent to APOE.…”

Section: Resultsmentioning

confidence: 99%

Prediction of Alzheimer’s Disease-Associated Genes by Integration of GWAS Summary Data and Expression Data

2019

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Alzheimer’s disease (AD) is the most common cause of dementia. It is the fifth leading cause of death among elderly people. With high genetic heritability (79%), finding the disease’s causal genes is a crucial step in finding a treatment for AD. Following the International Genomics of Alzheimer’s Project (IGAP), many disease-associated genes have been identified; however, we do not have enough knowledge about how those disease-associated genes affect gene expression and disease-related pathways. We integrated GWAS summary data from IGAP and five different expression-level data by using the transcriptome-wide association study method and identified 15 disease-causal genes under strict multiple testing (α < 0.05), and four genes are newly identified. We identified an additional 29 potential disease-causal genes under a false discovery rate (α < 0.05), and 21 of them are newly identified. Many genes we identified are also associated with an autoimmune disorder.

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“…Owing to the strong LD between variants of the two genes at this locus, we were unable to statistically distinguish the effects of TOMM40 ‐L and APOE ‐ε4 in our series. It has recently been reported that LD structures of genes in the APOE / TOMM40 locus are highly heterogeneous, with significant differences between patients with AD and unaffected controls and that these differing patterns may correspond to heterogenous “molecular signatures” that may denote polygenetically enhanced susceptibility to AD and related diseases [39]. Future work needs to further assess the clinical discriminative value of either variant to distinguish DLB with versus without concomitant AD pathology and to clarify the molecular mechanisms underlying the association between DLB+AD and APOE ‐ε4 or TOMM40 ‐L (or both).…”

Section: Discussionmentioning

confidence: 99%

Alzheimer's disease pathology explains association between dementia with Lewy bodies and APOE‐ε4/TOMM40 long poly‐T repeat allele variants

Prokopenko

Miyakawa

Zheng

et al. 2019

A&D Transl Res & Clin Interv

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IntroductionThe role of TOMM40-APOE 19q13.3 region variants is well documented in Alzheimer's disease (AD) but remains contentious in dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD).MethodsWe dissected genetic profiles within the TOMM40-APOE region in 451 individuals from four European brain banks, including DLB and PDD cases with/without neuropathological evidence of AD-related pathology and healthy controls.ResultsTOMM40-L/APOE-ε4 alleles were associated with DLB (ORTOMM40-L = 3.61; P value = 3.23 × 10−9; ORAPOE-ε4 = 3.75; P value = 4.90 × 10−10) and earlier age at onset of DLB (HRTOMM40-L = 1.33, P value = .031; HRAPOE-ε4 = 1.46, P value = .004), but not with PDD. The TOMM40-L/APOE-ε4 effect was most pronounced in DLB individuals with concomitant AD pathology (ORTOMM40-L = 4.40, P value = 1.15 × 10−6; ORAPOE-ε4 = 5.65, P value = 2.97 × 10−8) but was not significant in DLB without AD. Meta-analyses combining all APOE-ε4 data in DLB confirmed our findings (ORDLB = 2.93, P value = 3.78 × 10−99; ORDLB+AD = 5.36, P value = 1.56 × 10−47).DiscussionAPOE-ε4/TOMM40-L alleles increase susceptibility and risk of earlier DLB onset, an effect explained by concomitant AD-related pathology. These findings have important implications in future drug discovery and development efforts in DLB.

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Apolipoprotein E region molecular signatures of Alzheimer's disease

Cited by 36 publications

References 53 publications

Genome-wide analysis of genetic predisposition to Alzheimer’s disease and related sex disparities

Genome-wide analysis of genetic predisposition to Alzheimer’s disease and related sex disparities

Prediction of Alzheimer’s Disease-Associated Genes by Integration of GWAS Summary Data and Expression Data

Alzheimer's disease pathology explains association between dementia with Lewy bodies and APOE‐ε4/TOMM40 long poly‐T repeat allele variants

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