Genome-wide association analysis of dementia and its clinical endophenotypes reveal novel loci associated with Alzheimer’s disease and three causality networks of AD: the GR@ACE project

Moreno‐Grau, Sonia; Rojas, Itziar de; Hernández, Isabel; Quintela, Inés; Montrreal, Laura; Alegret, Montserrat; Hernández-Olasagarre, Begoña; Madrid, Laura; González‐Pérez, Antonio; Maroña, Olalla; Rosende-Roca, Maiteé; Mauleón, Ana; Vargas, Liliana; Lafuente, Asunción; Abdelnour, Carla; Rodríguez-Gómez, Octavio; Gil, Silvia; Santos‐Santos, Miguel A.; Espinosa, Ana; Ortega, Gemma; Sanabria, Ángela; Pérez‐Cordón, Alba; Ruiz, Susana; Aguilera, Núria; Pineda, Juan A; Macı́as, Juan; Alarcon, Emilio I.; Sotolongo-Grau, Óscar; Initiative, Alzheimer’s Disease Neuroimaging; Marquié, Marta; Monté-Rubio, Gemma C.; Valero, Sergi; Clarimón, Jordi; Bullido, María J.; García‐Ribas, Guillermo; Pástor, Pau; Sánchez‐Juan, Pascual; Álvarez, Victoria; Piñol‐Ripoll, Gerard; García‐Alberca, José María; Royo, José Luís; Franco, Emilio; Mir, Pablo; Calero, Miguel; Medina, Miguel Á.; Rábano, Alberto; Ávila, Jesús; Antúnez, Carmen; Real, Luís Miguel; Orellana, Adelina; Carracedo, Ángel; Sáez, María Eugenia; Tárraga, Lluís; Boada, Merçé; Ruiz, Agustín

doi:10.1101/528901

Cited by 8 publications

(12 citation statements)

References 37 publications

(52 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Several loci that are previously well known as associated with the risk of the diseases have been identified in our study. For example, the loci LPA and CELSR2 for IHD 44 , 45 , FGFR2 4 and CASC16 47 for breast cancer, MYOC 48 and TMCO1 49 for glaucoma, and APOE e4 variant for AD 50 . The age-varying predicted risk of disease onset based on the GATE method, and the age-varying disease-free probability by genotypes based on the Kaplan-Meier curve 51 for the exemplary top hits were plotted in Figure 4 and Supplementary Figure 3 , respectively.…”

Section: Resultsmentioning

confidence: 99%

An efficient and accurate frailty model approach for genome-wide survival association analysis controlling for population structure and relatedness in large-scale biobanks

Dey

Zhou

Kiiskinen

et al. 2020

Preprint

View full text Add to dashboard Cite

With decades of electronic health records linked to genetic data, large biobanks provide unprecedented opportunities for systematically understanding the genetics of the natural history of complex diseases. Genome-wide survival association analysis can identify genetic variants associated with ages of onset, disease progression and lifespan. We developed an efficient and accurate frailty (random effects) model approach for genome-wide survival association analysis of censored time-to-event (TTE) phenotypes in large biobanks by accounting for both population structure and relatedness. Our method utilizes state-of-the-art optimization strategies to reduce the computational cost. The saddlepoint approximation is used to allow for analysis of heavily censored phenotypes (>90%) and low frequency variants (down to minor allele count 20). We demonstrated the performance of our method through extensive simulation studies and analysis of five TTE phenotypes, including lifespan, with heavy censoring rates (90.9% to 99.8%) on ~400,000 UK Biobank participants with white British ancestry and ~180,000 samples in FinnGen, respectively. We further performed genome-wide association analysis for 871 TTE phenotypes in UK Biobank and presented the genome-wide scale phenome-wide association (PheWAS) results with the PheWeb browser.

show abstract

Section: Resultsmentioning

confidence: 99%

An efficient and accurate frailty model approach for genome-wide survival association analysis controlling for population structure and relatedness in large-scale biobanks

Dey

Zhou

Kiiskinen

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…This ethnic variability might cause population sub-structure biasing the results in countries with a high degree of population admixture. This is likely to be less problematic in our study as our sample come from a single country, and we have tested population sub-structure in Spain which does not represent a substantial problem for common genetic variants analyses (Moreno-Grau et al, 2019). Additionally, in our sub-haplotype analysis, we controlled for population sub-structure by adjusting for genetic principal components.…”

Section: Discussionmentioning

confidence: 99%

“…A detailed description of the methods and population of the GR@ACE study has been published elsewhere (Moreno-Grau et al, 2019) 1 .…”

Section: Methodsmentioning

confidence: 99%

“…Additionally, we used six tagging variants (rs1467967, rs242557, rs3785883, rs2471738, rs8070723, rs7521), to construct most common MAPT H1 sub-haplotypes as previously described (Pittman et al, 2005; Allen et al, 2014). To control for population sub-structure, results were co-variated by the main four principal components detected in this population (Moreno-Grau et al, 2019). All analyses were performed in PLINK 1.7.…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

The MAPT H1 Haplotype Is a Risk Factor for Alzheimer’s Disease in APOE ε4 Non-carriers

Sánchez‐Juan

Moreno

Rojas

et al. 2019

Front. Aging Neurosci.

Self Cite

View full text Add to dashboard Cite

An ancestral inversion of 900 kb on chromosome 17q21, which includes the microtubule-associated protein tau (MAPT) gene, defines two haplotype clades in Caucasians (H1 and H2). The H1 haplotype has been linked inconsistently with AD. In a previous study, we showed that an SNP tagging this haplotype (rs1800547) was associated with AD risk in a large population from the Dementia Genetics Spanish Consortium (DEGESCO) including 4435 cases and 6147 controls. The association was mainly driven by individuals that were non-carriers of the APOE ε4 allele. Our aim was to replicate our previous findings in an independent sample of 4124 AD cases and 3290 controls from Spain (GR@ACE project) and to analyze the effect of the H1 sub-haplotype structure on the risk of AD. The H1 haplotype was associated with AD risk (OR = 1.12; p = 0.0025). Stratification analysis showed that this association was mainly driven by the APOE ε4 non-carriers (OR = 1.15; p = 0.0022). Pooled analysis of both Spanish datasets (n = 17,996) showed that the highest AD risk related to the MAPT H1/H2 haplotype was in those individuals that were the oldest [third tertile (>77 years)] and did not carry APOE ε4 allele (p = 0.001). We did not find a significant association between H1 sub-haplotypes and AD. H1c was nominally associated but lost statistical significance after adjusting by population sub-structure. Our results are consistent with the hypothesis that genetic variants linked to the MAPT H1/H2 are tracking a genuine risk allele for AD. The fact that this association is stronger in APOE ε4 non-carriers partially explains previous controversial results and might be related to a slower alternative causal pathway less dependent on brain amyloid load.

show abstract

“…Here we aimed to comprehend and expand the knowledge of the genetic landscape underlying AD. We first performed a meta-GWAS integrating all currently published GWAS case-control data, by-proxy case-control data and the data from the Genome Research at Fundació ACE (GR@ACE) study 28 . We confirm the novel observed associations in a large independent replication study.…”

Section: Introductionmentioning

confidence: 99%

Common variants in Alzheimer’s disease: Novel association of six genetic variants with AD and risk stratification by polygenic risk scores

Rojas

Moreno‐Grau

Tesi

et al. 2019

Preprint

Self Cite

View full text Add to dashboard Cite

BACKGROUND:Disentangling the genetic constellation underlying Alzheimer's disease (AD) is important. Doing so allows us to identify biological pathways underlying AD, point towards novel drug targets and use the variants for individualised risk predictions in disease modifying or prevention trials. In the present work we report on the largest genome-wide association study (GWAS) for AD risk to date and show the combined utility of proven AD loci for precision medicine using polygenic risk scores (PRS). METHODS:Three sets of summary statistics were included in our meta-GWAS of AD: an Spanish casecontrol study (GR@ACE/DEGESCO study, n = 12,386), the case-control study of International Genomics of Alzheimer project (IGAP, n = 82,771) and the UK Biobank (UKB) AD-by-proxy case-control study (n=314,278). Using these resources, we performed a fixed-effects inversevariance-weighted meta-analysis. Detected loci were confirmed in a replication study of 19,089 AD cases and 39,101 controls from 16 European-ancestry cohorts not previously used. We constructed a weighted PRS based on the 39 AD variants. PRS were generated by multiplying the genotype dosage of each risk allele for each variant by its respective weight, and then summing across all variants. We first validated it for AD in independent data (assessing effects of subthreshold signal, diagnostic certainty, age at onset and sex) and tested its effect on risk (odds for disease) and age at onset in the GR@ACE/DEGESCO study. FINDINGS:Using our meta-GWAS approach and follow-up analysis, we identified novel genome-wide significant associations of six genetic variants with AD risk (rs72835061-CHRNE, rs2154481-APP, rs876461-PRKD3/NDUFAF7, rs3935877-PLCG2 and two missense variants: rs34173062/rs34674752 in SHARPIN gene) and confirmed a stop codon mutation in the IL34 gene increasing the risk of AD (IL34-Tyr213Ter), and two other variants in PLCG2 and HS3ST1 regions. This brings the total number of genetic variants associated with AD to 39 (excluding APOE). The PRS based on these variants was associated with AD in an independent clinical ADcase control dataset (OR=1.30, per 1-SD increase in the PRS, 95%CI 1.18-1.44, p = 1.1×10 -7 ), a similar effect to that in the GR@ACE/DEGESCO (OR=1.27, 95%CI 1.23-1.32, p = 7.4×10 -39 ). We then explored the combined effects of these 39 variants in a PRS for AD risk and age-at-onset stratification in GR@ACE/DEGESCO. Excluding APOE, we observed a gradual risk increase over the 2% tiles; when comparing the extremes, those with the 2% highest risk had a 2.98-fold (95% CI 2.12-4.18, p = 3.2×10 -10 ) increased risk compared to those with the 2% lowest risk (p = 5.9×10 -10 ). Using the PRS we identified APOE ɛ33 carriers with a similar risk as APOE ɛ4 heterozygotes carriers, as well as APOE ɛ4 heterozygote carriers with a similar risk as APOE ɛ4 homozygote. Considering age at onset; there was a 9-year difference between median onset of AD the lowest risk group and the highest risk group (82 vs 73 years; p = 1.6×10 -6 ); a 4-year median onset diff...

show abstract

Genome-wide association analysis of dementia and its clinical endophenotypes reveal novel loci associated with Alzheimer’s disease and three causality networks of AD: the GR@ACE project

Cited by 8 publications

References 37 publications

An efficient and accurate frailty model approach for genome-wide survival association analysis controlling for population structure and relatedness in large-scale biobanks

An efficient and accurate frailty model approach for genome-wide survival association analysis controlling for population structure and relatedness in large-scale biobanks

The MAPT H1 Haplotype Is a Risk Factor for Alzheimer’s Disease in APOE ε4 Non-carriers

Common variants in Alzheimer’s disease: Novel association of six genetic variants with AD and risk stratification by polygenic risk scores

Contact Info

Product

Resources

About