The Alzheimer's Disease Sequencing Project: Study design and sample selection

Beecham, Gary W.; Bis, Joshua C.; Martin, Eden R.; Choi, Seung Hoan; DeStefano, Anita L.; Duijn, Cornelia M. van; Fornage, Myriam; Gabriel, Stacy; Koboldt, Daniel C.; Larson, David E.; Naj, Adam C.; Psaty, Bruce M.; Salerno, William; Bush, William S.; Foroud, Tatiana; Wijsman, Ellen M.; Farrer, Lindsay A.; Goate, Alison; Haines, Jonathan L.; Pericak‐Vance, Margaret A.; Boerwinkle, Eric; Mayeux, Richard; Seshadri, Sudha; Schellenberg, Gerard D.

doi:10.1212/nxg.0000000000000194

Cited by 147 publications

(191 citation statements)

References 6 publications

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“…We used the univariate LD score regression 18 intercept for each study separately as well as for the meta-analysed results to ensure that the test statistics did not include model or structural biases such as population stratification, cryptic relatedness, and model misspecification. To investigate the genetic correlation between POAG and AD, we used bivariate LD score regression 25 using our POAG meta-analysis in Europeans and 71,880 AD cases and 383,378 controls of European descent obtained from metaanalysis of Psychiatric Genomics Consortium (PGC-ALZ) 55 , the International Genomics of Alzheimer's Project (IGAP) 56 , and the Alzheimer's Disease Sequencing Project (ADSP) 57 .…”

Section: Association Testingmentioning

confidence: 99%

A large cross-ancestry meta-analysis of genome-wide association studies identifies 69 novel risk loci for primary open-angle glaucoma and includes a genetic link with Alzheimer’s disease

Gharahkhani

Jorgenson

Hysi

et al. 2020

Preprint

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We conducted a large multi-ethnic meta-analysis of genome-wide association studies for primary open-angle glaucoma (POAG) on a total of 34,179 cases vs 349,321 controls, and identified 127 independent risk loci, almost doubling the number of known loci for POAG. The majority of loci have broadly consistent effect across European, Asian and African ancestries. We identify a link, both genome-wide and at specific loci, between POAG and Alzheimer's disease. Gene expression data and bioinformatic functional analyses provide further support for the functional relevance of the POAG risk genes. Several drug compounds target these risk genes and may be potential candidates for developing novel POAG treatments.Primary open-angle glaucoma (POAG) is the leading cause of irreversible blindness worldwide 1,2 . The disease is characterized by progressive optic nerve degeneration that is usually accompanied by elevated intraocular pressure (IOP). Neuroprotective therapies are not available and current treatments are limited to lowering IOP which can slow disease progression at early disease stages. However over 50% of glaucoma is not diagnosed until irreversible optic nerve damage has occurred 2,3 .

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Section: Association Testingmentioning

confidence: 99%

A large cross-ancestry meta-analysis of genome-wide association studies identifies 69 novel risk loci for primary open-angle glaucoma and includes a genetic link with Alzheimer’s disease

Gharahkhani

Jorgenson

Hysi

et al. 2020

Preprint

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“…Processing of AD data sets: The Alzheimer's Disease Sequencing Project (ADSP) [24] is a multiinstitutional effort to collect and analyze whole-genome and whole-exome data for AD research.…”

Section: Methodsmentioning

confidence: 99%

Unbalanced Sample Size Introduces Spurious Correlations to Genome-wide Heterozygosity Analyses

Liu

Caselli

2020

Preprint

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Excess of heterozygosity (H) is a widely used measure of genetic diversity of a population. As high-throughput sequencing and genotyping data become readily available, it has been applied to investigating the associations of genome-wide genetic diversity with human diseases and traits.However, these studies often report contradictory results. In this paper, we present a metaanalysis of five whole-exome studies to examine the association of H scores with Alzheimer's disease. We show that the mean H score of a group is not associated with the disease status, but is associated with the sample size. Across all five studies, the group with more samples has a significantly lower H score than the group with fewer samples. To remove potential confounders in empirical data sets, we perform computer simulations to create artificial genomes controlled for the number of polymorphic loci, the sample size and the allele frequency. Analyses of these simulated data confirm the negative correlation between the sample size and the H score.Furthermore, we find that genomes with a large number of rare variants also have inflated H scores. These biases altogether can lead to spurious associations between genetic diversity and the phenotype of interest. Based on these findings, we advocate that studies shall balance the sample sizes when using genome-wide H scores to assess genetic diversities of different populations, which helps improve the reproducibility of future research.

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“…Phenotype information and variant calls based on whole exome sequencing using the GRCh37 assembly for the Alzheimer's Disease Sequencing Project (ADSP) Distribution were downloaded from dbGaP (phs000572.v7.p4.c1-c6). As described previously, participants were at least 60 years old and were mostly of European-American ancestry though with a small number of Caribbean Hispanic ancestry and all cases met NINCDS-ADRDA criteria for possible, probable or definite AD based on clinical assessment, or had presence of AD (moderate or high likelihood) upon neuropathology examination (Beecham et al, 2017). The cases were chosen whose AD risk score suggested that their disease was not well explained by age, sex or APOE status.…”

Section: Methodsmentioning

confidence: 99%

“…Analyses of risk genes and pathways showed enrichment for rare variants which remained to be identified. The Alzheimer's Disease Sequencing Project (ADSP) has the aim of identifying rare genetic variants which increase or decrease the risk of Late Onset Alzheimer's Disease (LOAD) and a full description of its membership, support and methodologies is provided on its website (https://www.niagads.org/adsp/content/about) (Beecham et al, 2017). A number of analyses utilising this dataset have been published to date.…”

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

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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.

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The Alzheimer's Disease Sequencing Project: Study design and sample selection

Cited by 147 publications

References 6 publications

A large cross-ancestry meta-analysis of genome-wide association studies identifies 69 novel risk loci for primary open-angle glaucoma and includes a genetic link with Alzheimer’s disease

A large cross-ancestry meta-analysis of genome-wide association studies identifies 69 novel risk loci for primary open-angle glaucoma and includes a genetic link with Alzheimer’s disease

Unbalanced Sample Size Introduces Spurious Correlations to Genome-wide Heterozygosity Analyses

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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