Gene-based analysis in HRC imputed genome wide association data identifies three novel genes for Alzheimer’s disease

Baker, Emily; Sims, Rebecca; Leonenko, Ganna; Frizzati, Aura; Harwood, Janet; Grozeva, Detelina; Morgan, Kevin; Passmore, Peter; Holmes, Clive; Powell, John; Brayne, Carol; Gill, Michael; Mead, Simon; Bossù, Paola; Spalletta, Gianfranco; Goate, Alison; Cruchaga, Carlos; Maier, Wolfgang; Heun, Reinhard; Jessen, Frank; Peters, Oliver; Dichgans, Martin; Frölich, Lutz; Ramı́rez, Alfredo; Jones, Lesley; Hardy, John; Ivanov, Dobril; Hill, Matthew; Holmans, Peter; Allen, Nicholas Denby; Morgan, B. Paul; Seshadri, Sudha; Schellenberg, Gerard D.; Amouyel, Philippe; Williams, Julie; Escott‐Price, Valentina

doi:10.1371/journal.pone.0218111

Cited by 27 publications

(21 citation statements)

References 57 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Building upon IGAP (2013) 26 dataset, single nucleotide 26,[30][31][32][33][34] , gene-wide 35,36 , transethnic 32 and proxy design 31,37,38 (based on reports of parental history) studies have identified numerous novel genome-wide significant (GWS) loci, see Table 1 and Figure 1.…”

Section: Late-onset Ad Genetics: Common Variationmentioning

confidence: 99%

The multiplex model of the genetics of Alzheimer’s disease

2020

Self Cite

View full text Add to dashboard Cite

Genes play a strong role in Alzheimer's disease (AD) with late-onset AD showing heritability of 58-79% and early-onset AD over 90%. Genetic association provides a robust platform to build our understanding of the etiology of this complex disease. Over 40 loci are now implicated for AD, suggesting that AD is a disease of multiple components as supported by pathway analyses (immunity, endocytosis, cholesterol transport, ubiquitination, amyloid-β and tau processing). Over 50% of late-onset AD (LOAD) heritability has been captured and allows the calculation of the accumulation of AD genetic risk through polygenic risk scores (PRS). PRS predicts disease with up to 90% accuracy and is an exciting tool in our research armoury that could allow selection of those with high PRS for clinical trials and precision medicine, as well as the cellular modelling of the combined risk. Here we propose the multiplex model as a new perspective from which to understand AD. The multiplex model reflex's the combination of some, or all, of these model components (genetic and environmental), in a tissue specific manner, to trigger or sustain a disease cascade, which ultimately results in the cell/synaptic loss observed in AD.

show abstract

Section: Late-onset Ad Genetics: Common Variationmentioning

confidence: 99%

The multiplex model of the genetics of Alzheimer’s disease

2020

Self Cite

View full text Add to dashboard Cite

show abstract

“…To illustrate this, we use AD as an example. For AD the R 2 is 0.16 for APOE alone and 0.1 for the PRS excluding APOE locus (in house analysis in GERAD data ( Baker et al, 2019 ) using summary statistics from ( Kunkle et al, 2019 )). AUC is the accuracy of the prediction, comparing the observed case/control status and the predicted classification estimated by a logistic regression model.…”

Section: Risk Prediction In Neurodegeneration With Polygenic Risk Scomentioning

confidence: 99%

Polygenic risk and pleiotropy in neurodegenerative diseases

Bellou

Stevenson-Hoare

Escott‐Price

2020

Neurobiology of Disease

Self Cite

View full text Add to dashboard Cite

In this paper we explore the phenomenon of pleiotropy in neurodegenerative diseases, focusing on Alzheimer's disease (AD). We summarize the various techniques developed to investigate pleiotropy among traits, elaborating in the polygenic risk scores (PRS) analysis. PRS was designed to assess a cumulative effect of a large number of SNPs for association with a disease and, later for disease risk prediction. Since genetic predictions rely on heritability, we discuss SNP-based heritability from genome-wide association studies and its contribution to the prediction accuracy of PRS. We review work examining pleiotropy in neurodegenerative diseases and related phenotypes and biomarkers. We conclude that the exploitation of pleiotropy may aid in the identification of novel genes and provide further insights in the disease mechanisms, and along with PRS analysis, may be advantageous for precision medicine.

show abstract

“…This success can be largely attributed to the extensive collaboration across four genetic consortia; Genetic and Environmental Risk in AD (GERAD), European AD Initiative (EADI), Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) and AD Genetics Consortium (ADGC), badged together as the International Genomics of Alzheimer's Project (IGAP). In addition, genome-wide gene-wide analyses identified five novel genome-wide significant loci, TP53INP1, IGHV1-67, [17] PPARGC1A, RORA and ZNF423 [18] using the IGAP dataset. Building upon the initial IGAP dataset, TRIP4 [19], ECHDC3 [7,20], IQCK, ACE, ADAM10 and ADAMTS1 [7] have more recently been reported as genome-wide susceptibility loci.…”

Section: Identified Common Risk Locimentioning

confidence: 99%

Benefits and Challenges of Rare Genetic Variation in Alzheimer’s Disease

2019

Self Cite

View full text Add to dashboard Cite

Purpose of Review It is well established that sporadic Alzheimer's disease (AD) is polygenic with common and rare genetic variation alongside environmental factors contributing to disease. Here, we review our current understanding of the genetic architecture of disease, paying specific attention to rare susceptibility variants, and explore some of the limitations in rare variant detection and analysis. Recent Findings Rare variation has been shown to robustly associate with disease. These include potentially damaging and loss of function mutations that are easily modelled in silico, in vitro and in vivo, and represent potentially druggable targets. A number of risk genes, including TREM2, SORL1 and ABCA7 show multiple independent associations suggesting that they may influence disease via multiple mechanisms. With transcriptional regulation, inflammatory response and modification of protein production suggested to be of primary importance. Summary We are at the beginning of our journey of rare variant detection in AD. Whole exome sequencing has been the predominant technology of choice. While fruitful, this has introduced a number of challenges with regard to data integration. Ultimately the future of disease-associated rare variant identification lies in whole genome sequencing projects that will allow the testing of the full range of genomic variation.

show abstract

Gene-based analysis in HRC imputed genome wide association data identifies three novel genes for Alzheimer’s disease

Cited by 27 publications

References 57 publications

The multiplex model of the genetics of Alzheimer’s disease

The multiplex model of the genetics of Alzheimer’s disease

Polygenic risk and pleiotropy in neurodegenerative diseases

Benefits and Challenges of Rare Genetic Variation in Alzheimer’s Disease

Contact Info

Product

Resources

About