Identification of genetic heterogeneity of Alzheimer's disease across age.

Published on Dec 1, 2019in Neurobiology of Aging4.347
· DOI :10.1016/J.NEUROBIOLAGING.2019.02.022
Min-Tzu Lo14
Estimated H-index: 14
(UCSD: University of California, San Diego),
Karolina Kauppi17
Estimated H-index: 17
(UCSD: University of California, San Diego)
+ 7 AuthorsChi-Hua Chen34
Estimated H-index: 34
(UCSD: University of California, San Diego)
Abstract The risk of APOE for Alzheimer's disease (AD) is modified by age. Beyond APOE, the polygenic architecture may also be heterogeneous across age. We aim to investigate age-related genetic heterogeneity of AD and identify genomic loci with differential effects across age. Stratified gene-based genome-wide association studies and polygenic variation analyses were performed in the younger (60–79 years, N = 14,895) and older (≥80 years, N = 6559) age-at-onset groups using Alzheimer's Disease Genetics Consortium data. We showed a moderate genetic correlation (rg = 0.64) between the two age groups, supporting genetic heterogeneity. Heritability explained by variants on chromosome 19 (harboring APOE) was significantly larger in younger than in older onset group (p
📖 Papers frequently viewed together
2,546 Citations
562 Citations
2 Citations
#1Kyoko Watanabe (VU: VU University Amsterdam)H-Index: 21
#2Erdogan Taskesen (VU: VU University Amsterdam)H-Index: 19
Last. Danielle Posthuma (VU: VU University Amsterdam)H-Index: 101
view all 4 authors...
A main challenge in genome-wide association studies (GWAS) is to pinpoint possible causal variants. Results from GWAS typically do not directly translate into causal variants because the majority of hits are in non-coding or intergenic regions, and the presence of linkage disequilibrium leads to effects being statistically spread out across multiple variants. Post-GWAS annotation facilitates the selection of most likely causal variant(s). Multiple resources are available for post-GWAS annotation...
830 CitationsSource
#1Rahul S. Desikan (UCSF: University of California, San Francisco)H-Index: 43
#2Chun Chieh Fan (UCSD: University of California, San Diego)H-Index: 26
Last. Anders M. Dale (University of California, Berkeley)H-Index: 166
view all 34 authors...
Background Identifying individuals at risk for developing Alzheimer disease (AD) is of utmost importance. Although genetic studies have identified AD-associated SNPs in APOE and other genes, genetic information has not been integrated into an epidemiological framework for risk prediction. Methods and findings Using genotype data from 17,008 AD cases and 37,154 controls from the International Genomics of Alzheimer’s Project (IGAP Stage 1), we identified AD-associated SNPs (at p < 10−5). We then i...
182 CitationsSource
#1Luke W. Bonham (UCSF: University of California, San Francisco)H-Index: 17
#2Ethan G. Geier (UCSF: University of California, San Francisco)H-Index: 18
Last. Jennifer S. Yokoyama (UCSF: University of California, San Francisco)H-Index: 29
view all 16 authors...
RESEARCH ARTICLE Age-dependent effects of APOE e4 in preclinical Alzheimer’s disease Luke W. Bonham 1 , Ethan G. Geier 1 , Chun C. Fan 2 , Josiah K. Leong 3 , Lilah Besser 4 , Walter A. Kukull 4 , John Kornak 5 , Ole A. Andreassen 6 , Gerard D. Schellenberg 7 , Howard J. Rosen 1 , William P. Dillon 8 , Christopher P. Hess 8 , Bruce L. Miller 1 , Anders M. Dale 2 , Rahul S. Desikan 8,a & Jennifer S. Yokoyama 1,a Memory and Aging Center, Department of Neurology, University of California, San Franc...
22 CitationsSource
#1Jian Yang (UQ: University of Queensland)H-Index: 181
#2Sang Hong Lee (UNE: University of New England (Australia))H-Index: 34
Last. Peter M. Visscher (UQ: University of Queensland)H-Index: 146
view all 5 authors...
In a recent publication in PNAS, Krishna Kumar et al. (1) claim that “GCTA applied to current SNP data cannot produce reliable or stable estimates of heritability.” We show below that those claims are false due to their misunderstanding of the theory and practice of random-effect models underlying genome-wide complex trait analysis (GCTA) (2). GCTA, more precisely, the genomic-relatedness-based restricted maximum-likelihood (GREML) approach (3) implemented in GCTA (4), is a method to estimate th...
26 CitationsSource
#1Zein Al-Atrache (PCOM: Philadelphia College of Osteopathic Medicine)H-Index: 5
#2Ahmad Cader (PCOM: Philadelphia College of Osteopathic Medicine)H-Index: 2
Last. Denah M. Appelt (PCOM: Philadelphia College of Osteopathic Medicine)H-Index: 15
view all 3 authors...
688 CitationsSource
#1Perry G. Ridge (BYU: Brigham Young University)H-Index: 24
#2Kaitlyn B. Hoyt (BYU: Brigham Young University)H-Index: 1
Last. Lei Yu (Rush University Medical Center)H-Index: 66
view all 11 authors...
Alzheimer's disease (AD) is a complex genetic disorder with no effective treatments. More than 20 common markers have been identified, which are associated with AD. Recently, several rare variants have been identified in Amyloid Precursor Protein (APP), Triggering Receptor Expressed On Myeloid Cells 2 (TREM2) and Unc-5 Netrin Receptor C (UNC5C) that affect risk for AD. Despite the many successes, the genetic architecture of AD remains unsolved. We used Genome-wide Complex Trait Analysis to (1) e...
97 CitationsSource
#1Caroline Van Cauwenberghe (University of Antwerp)H-Index: 10
#2Christine Van Broeckhoven (University of Antwerp)H-Index: 110
Last. Kristel Sleegers (University of Antwerp)H-Index: 66
view all 3 authors...
Alzheimer disease (AD) is a devastating neurodegenerative disease and the predominant form of dementia (50–75%). In 2015, ~44 million people worldwide are estimated to have AD or a related dementia. Each year, 4.6 million new cases of dementia are predicted with numbers expected to almost double by 2030.1 AD is pathologically defined by severe neuronal loss, aggregation of amyloid β (Aβ) in extracellular senile plaques, and formation of intraneuronal neurofibrillary tangles consisting of hyperph...
376 CitationsSource
#1Bengt Winblad (KI: Karolinska Institutet)H-Index: 184
#2Philippe Amouyel (Pasteur Institute)H-Index: 72
Last. Henrik Zetterberg (UCL Institute of Neurology)H-Index: 136
view all 34 authors...
Defeating Alzheimer's disease and other dementias : a priority for European science and society
745 CitationsSource
#1Joseph E. GauglerH-Index: 49
#2Bryan D. JamesH-Index: 32
Last. Jennifer WeuveH-Index: 43
view all 5 authors...
3,292 CitationsSource
#1Gyungah Jun (BU: Boston University)H-Index: 34
#2Carla A. Ibrahim-Verbaas (EUR: Erasmus University Rotterdam)H-Index: 18
Last. Lindsay A. Farrer (BU: Boston University)H-Index: 113
view all 117 authors...
APOE ɛ4, the most significant genetic risk factor for Alzheimer disease (AD), may mask effects of other loci. We re-analyzed genome-wide association study (GWAS) data from the International Genomics of Alzheimer's Project (IGAP) Consortium in APOE ɛ4+ (10 352 cases and 9207 controls) and APOE ɛ4- (7184 cases and 26 968 controls) subgroups as well as in the total sample testing for interaction between a single-nucleotide polymorphism (SNP) and APOE ɛ4 status. Suggestive associations (P<1 × 10-4) ...
163 CitationsSource
Cited By11
#1Steven D. TargumH-Index: 26
#2Lisa FosdickH-Index: 3
Last. Gwenn S. Smith (JHUSOM: Johns Hopkins University School of Medicine)H-Index: 52
view all 0 authors...
BACKGROUND Age may affect treatment outcome in trials of mild probable Alzheimer's disease (AD). OBJECTIVE We examined age as a moderator of outcome in an exploratory study of deep brain stimulation targeting the fornix (DBS-f) region in participants with AD. METHODS Forty-two participants were implanted with DBS electrodes and randomized to double-blind DBS-f stimulation ("on") or sham DBS-f ("off") for 12 months. RESULTS The intervention was safe and well tolerated. However, the selected clini...
#1Hiroshi Kumon (Ehime University)H-Index: 1
#2Yuta Yoshino (Ehime University)H-Index: 11
Last. Shu-ichi UenoH-Index: 35
view all 13 authors...
BACKGROUND Phosphatidylinositol-binding clathrin assembly protein (PICALM) is a validated genetic risk factor for late-onset Alzheimer's disease (AD) and is associated with other neurodegenerative diseases. However, PICALM expression in the blood of neurodegenerative diseases remains elusive. OBJECTIVE This study aimed to assess the usefulness of PICALM expression levels in the blood of patients with AD, Parkinson's disease (PD), dementia with Lewy bodies (DLB), and geriatric major depressive di...
1 CitationsSource
#1Bessi Qorri (Queen's University)H-Index: 7
#2Mike TsayH-Index: 1
Last. Joseph Geraci (Queen's University)H-Index: 12
view all 5 authors...
1 CitationsSource
#1Nicolas RuffiniH-Index: 1
Last. Susanne GerberH-Index: 10
view all 4 authors...
Neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS) are heterogeneous, progressive diseases with frequently overlapping symptoms characterized by a loss of neurons. Studies have suggested relations between neurodegenerative diseases for many years (e.g., regarding the aggregation of toxic proteins or triggering endogenous cell death pathways). We gathered publicly available genomic, transcriptom...
2 CitationsSource
#1Jialan Huang (SHU: Shanghai University)H-Index: 1
#2Dong Lu (SHU: Shanghai University)H-Index: 1
Last. Guofeng Meng (SHU: Shanghai University)
view all 3 authors...
The causal mechanism of Alzheimer's disease is extremely complex. Achieving great statistical power in association studies usually requires a large number of samples. In this work, we illustrated a different strategy to identify AD risk genes by clustering AD patients into modules based on their single-patient differential expression signatures. The evaluation suggested that our method could enrich AD patients with similar clinical manifestations. Applying this to a cohort of only 310 AD patient...
#1Qian Zhang (UQ: University of Queensland)H-Index: 111
#1Qian Zhang (UQ: University of Queensland)H-Index: 13
Last. Peter M. VisscherH-Index: 146
view all 22 authors...
Genetic association studies have identified 44 common genome-wide significant risk loci for late-onset Alzheimer’s disease (LOAD). However, LOAD genetic architecture and prediction are unclear. Here we estimate the optimal P-threshold (Poptimal) of a genetic risk score (GRS) for prediction of LOAD in three independent datasets comprising 676 cases and 35,675 family history proxy cases. We show that the discriminative ability of GRS in LOAD prediction is maximised when selecting a small number of...
11 CitationsSource
#1Eftychia Bellou (Cardiff University)H-Index: 5
#2Emily Baker (Cardiff University)H-Index: 6
view all 9 authors...
Abstract Alzheimer’s disease (AD) is a devastating neurodegenerative condition with significant genetic heritability. Several genes have been implicated in the onset of AD with the apolipoprotein E (APOE) gene being the strongest single genetic risk loci. Evidence suggests that the effect of APOE alters with age during disease progression. Here, we aim to investigate the impact of APOE and other variants outside the APOE region on AD risk in younger and older participants. Using data from both t...
5 CitationsSource
#1Emily Baker (Cardiff University)H-Index: 6
#2Valentina Escott-Price (Cardiff University)H-Index: 35
Genome-wide association studies have identified nearly 40 genome-wide significant single nucleotide polymorphisms (SNPs) which are associated with Alzheimer's Disease (AD). Due to the polygenicity of AD, polygenic risk scores (PRS) have shown high potential for AD risk prediction. PRSs have been shown to successfully discriminate between AD cases and controls achieving a prediction accuracy of up to 84% based on area under the receiver operating curve. The prediction accuracy in AD is higher com...
#1Henne HolstegeH-Index: 24
#2Detelina Grozeva (Cardiff University)H-Index: 37
Last. J-C Lambert (Pasteur Institute)H-Index: 10
view all 89 authors...
Background: With the development of next-generation sequencing technologies, it is possible to identify rare genetic variants that influence the risk of complex disorders. To date, whole exome sequencing (WES) strategies have shown that specific clusters of damaging rare variants in the TREM2, SORL1 and ABCA7 genes are associated with an increased risk of developing Alzheimers Disease (AD), reaching odds ratios comparable with the APOE-e4 allele, the main common AD genetic risk factor. Here, we ...
4 CitationsSource
#1Michael E. Belloy (Stanford University)H-Index: 6
#2Valerio Napolioni (Stanford University)H-Index: 26
view all 6 authors...
Importance Identification of genetic factors that interact with the apolipoprotein e4 (APOE4) allele to reduce risk for Alzheimer disease (AD) would accelerate the search for new AD drug targets.Klotho-VS heterozygosity (KL-VSHET+status) protects against aging-associated phenotypes and cognitive decline, but whether it protects individuals who carryAPOE4from AD remains unclear. Objectives To determine ifKL-VSHET+status is associated with reduced AD risk and β-amyloid (Aβ) pathology in individual...
18 CitationsSource