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

Raghavan, Neha; Brickman, Adam M.; Andrews, Howard; Manly, Jennifer J.; Schupf, Nicole; Lantigua, Rafael; Wolock, Charles J.; Kamalakaran, Sitharthan; Petrovski, Steve; Tosto, Giuseppe; Vardarajan, Badri N.; Goldstein, David B.; Mayeux, Richard

doi:10.1002/acn3.582

Cited by 119 publications

(113 citation statements)

References 33 publications

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“…Of genes with SLPs above 3, a number have previously been implicated by sequencing studies, consisting of TREM2 , ABCA7 , SORL1 , and PSEN1 (Blue et al., ; Guerreiro et al., ; Kim, ; Patel et al., ; Raghavan et al., ). Many of the others did not seem likely to have any plausible role in AD susceptibility but there were some exceptions that we list here.…”

Section: Resultsmentioning

confidence: 99%

Weighted burden analysis of exome‐sequenced late‐onset Alzheimer's cases and controls provides further evidence for a role for PSEN1 and suggests involvement of the PI3K/Akt/GSK‐3β and WNT signalling pathways

Curtis

Bakaya²,

Sharma³

et al. 2020

Annals of Human Genetics

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Previous studies have implicated common and rare genetic variants as risk factors for late‐onset Alzheimer's disease (LOAD). Here, weighted burden analysis was applied to over 10,000 exome‐sequenced subjects from the Alzheimer's Disease Sequencing Project. Analyses were carried out to investigate whether rare variants predicted to have a functional effect within a gene were more commonly seen in cases or in controls. Confirmatory results were obtained for TREM2, ABCA7, and SORL1. Additional support was provided for PSEN1 (p = 0.0002), which previously had been only weakly implicated in LOAD. There was suggestive evidence that functional variants in PIK3R1, WNT7A, C1R, and EXOC5 might increase risk and that variants in TIAF1 and/or NDRG2 might have a protective effect. Overall, there was strong evidence (p = 5 × 10−6) that variants in tyrosine phosphatase genes reduce the risk of developing LOAD. Because PIK3R1 variants are expected to impair PI3K/Akt/GSK‐3β signalling while variants in tyrosine phosphatase genes would enhance it, these findings are in line with those from animal models, suggesting that this pathway is protective against Alzheimer's disease.

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Section: Resultsmentioning

confidence: 99%

Weighted burden analysis of exome‐sequenced late‐onset Alzheimer's cases and controls provides further evidence for a role for PSEN1 and suggests involvement of the PI3K/Akt/GSK‐3β and WNT signalling pathways

Curtis

Bakaya²,

Sharma³

et al. 2020

Annals of Human Genetics

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“…For example, a rare variant in the 3′ UTR of RAB10, a member of the RAB family of small GTPases that are critical regulators of membrane trafficking and vesicular transport , confers resilience to AD 70,71 . Furthermore, coding variants that increase risk for AD have been identified in SORL1 6,72 , a member of the vacuolar protein sorting 10 (VPS10)domain-containing receptor family and the low density lipoprotein receptor (LDLR) family of APOE receptors that is expressed primarily in microglia in the brain 18 and plays important roles in the endolysosomal system and APP processing 68 .…”

Section: Discussionmentioning

confidence: 99%

Integration of Alzheimer’s disease genetics and myeloid genomics reveals novel disease risk mechanisms

Novikova

Kapoor

Tcw

et al. 2019

Preprint

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Genome-wide association studies (GWAS) have identified more than thirty loci associated with Alzheimer's disease (AD), but the causal variants, regulatory elements, genes and pathways remain largely unknown thus impeding a mechanistic understanding of AD pathogenesis. Previously, we showed that AD risk alleles are enriched in myeloid-specific epigenomic annotations. Here, we show that they are specifically enriched in active enhancers of monocytes, macrophages and microglia. We integrated AD GWAS signals with myeloid epigenomic and transcriptomic datasets using novel analytical approaches to link myeloid enhancer activity to target gene expression regulation and AD risk modification. We nominate candidate AD risk enhancers and identify their target causal genes (including AP4E1, AP4M1 , APBB3 , BIN1 , CD2AP , MS4A4A , MS4A6A , PILRA , RABEP1 , SPI1 , SPPL2A , TP53INP1 , ZKSCAN1 , and ZYX ) in sixteen loci. Fine-mapping of these enhancers nominates candidate functional variants that likely modify disease susceptibility by regulating causal gene expression in myeloid cells. In the MS4A locus we identified a single candidate functional variant and validated it experimentally in human induced pluripotent stem cell (hiPSC)-derived microglia. Combined, these results strongly implicate dysfunction of the myeloid endolysosomal system in the etiology of AD. causal gene expression in eight loci, and experimentally validated one of these candidate causal variants in the MS4A locus in human induced pluripotent stem cell (hiPSC)-derived microglia. Results AD risk alleles are specifically enriched in active enhancers of monocytes, macrophages and microgliaOur earlier analyses showed a significant enrichment of AD risk alleles in various myeloid-specific epigenomic annotations, but not in brain or other tissues 15 . To further dissect this enrichment, we used ChIP-Seq profiles of histone modifications that define the chromatin signatures of regulatory elements (H3K27ac for active enhancers and promoters, H3K4me1 for enhancers, and H3K4me2 for active enhancers and promoters) from monocytes, macrophages and microglia to annotate the genome with myeloid active enhancers (AE), active promoters (AP), primed enhancers (PE) and primed promoters (PP) (see Methods) [18][19][20] . To identify which of these myeloid regulatory elements are enriched for AD risk alleles, we performed stratified LD score regression (LDSC) 21 of AD single nucleotide polymorphism (SNP) heritability partitioned by the aforementioned epigenomic annotations using the International Genomics of Alzheimer's Project (IGAP) AD GWAS dataset 22 . This analysis revealed selective enrichment of AD risk alleles in active enhancers of monocytes, macrophages and microglia (Figure 1a). In contrast, schizophrenia SNP heritability (using the Psychiatric Genomics Consortium SCZ GWAS dataset as control 23 ) was not enriched in any of these myeloid regulatory elements (Figure 1a). To identify TFs that likely regulate the activity of myeloid enhancers, we performed de novo motif an...

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“…Of genes with SLPs above 3, a number have previously been implicated by sequencing studies, consisting of TREM2, ABCA7, SORL1 and PSEN1 (Blue et al, 2018;Guerreiro et al, 2013;Kim, 2018;Patel et al, 2019;Raghavan et al, 2018). PIK3R1 codes for a key component of the PI3K/Akt/GSK-3β signalling pathway and in neuronally differentiated PC12 cells activation of this pathway is neuroprotective against Aβ25-35-induced apoptosis and tau hyperphosphorylation (Cheng et al, 2018).…”

Section: Resultsmentioning

confidence: 99%

“…A number of analyses utilising this dataset have been published to date. One study incorporating this dataset with others identified 19 loss of function variants of SORL1 in cases as opposed to 1 in controls and a collapsing test of loss of function ultra-rare variants highlighted other genes including GRID2IP, WDR76 and GRN (Raghavan et al, 2018). A subsequent study used variant-based and gene-based tests of association and followed up significant or suggestive results in other samples to implicate three novel genes, IGHG3, AC099552.4 and ZNF655 as well as novel and predicted functional genetic variants in genes previously associated with Alzheimer's disease (AD) .…”

Section: Introductionmentioning

confidence: 99%

Weighted burden analysis of exome-sequenced late onset Alzheimer’s cases and controls provides further evidence for a role for PSEN1 and suggests involvement of the PI3K/Akt/GSK-3β and WNT signalling pathways

Curtis

Bakaya²,

Sharma³

et al. 2019

Preprint

View full text Add to dashboard Cite

SummaryPrevious studies have implicated common and rare genetic variants as risk factors for late onset Alzheimer’s disease (AD, LOAD). Here, weighted burden analysis was applied to over 10,000 exome sequenced subjects from the Alzheimer’s Disease Sequencing Project. Analyses were carried out to investigate whether rare variants predicted to have a functional effect within a gene were more commonly seen in cases or in controls. Confirmatory results were obtained for TREM2, ABCA7 and SORL1. Additional support was provided for PSEN1 (p = 0.0002), which previously had been only weakly implicated in LOAD. There was suggestive evidence that functional variants in PIK3R1, WNT7A, C1R and EXOC5 might increase risk and that variants in TIAF1 and/or NDRG2 might have a protective effect. Overall, there was strong evidence (p = 5 × 10−6) that variants in tyrosine phosphatase genes reduce the risk of developing LOAD. Since PIK3R1 variants are expected to impair PI3K/Akt/GSK-3β signalling while variants in tyrosine phosphatase genes would enhance it, these findings are in line with those from animal models suggesting that this pathway is protective against AD.

show abstract

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

Cited by 119 publications

References 33 publications

Weighted burden analysis of exome‐sequenced late‐onset Alzheimer's cases and controls provides further evidence for a role for PSEN1 and suggests involvement of the PI3K/Akt/GSK‐3β and WNT signalling pathways

Weighted burden analysis of exome‐sequenced late‐onset Alzheimer's cases and controls provides further evidence for a role for PSEN1 and suggests involvement of the PI3K/Akt/GSK‐3β and WNT signalling pathways

Integration of Alzheimer’s disease genetics and myeloid genomics reveals novel disease risk mechanisms

Weighted burden analysis of exome-sequenced late onset Alzheimer’s cases and controls provides further evidence for a role for PSEN1 and suggests involvement of the PI3K/Akt/GSK-3β and WNT signalling pathways

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