María Eugenia Sáez

Centro Andaluz de Biología del Desarrollo

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Agustı́n Ruiz

Biomedical Research Networking Center on Neurodegenerative Diseases

Antonio González‐Pérez

Universitat Internacional de Catalunya

Luís Miguel Real

Hospital Universitario de Valme

Merçé Boada

Universitat Internacional de Catalunya

Itziar de Rojas

Biomedical Research Networking Center on Neurodegenerative Diseases

José Luís Royo

Universidad de Málaga

Reposo Ramírez‐Lorca

Universidad de Sevilla

Luis A. Garcı́a Rodrı́guez

University of Colorado System

Sonia Moreno–Grau

Fundació ACE

Lluís Tárraga

Fundació ACE

Cooperative Institutions

Molecular Biology Consortium

238

University of Helsinki

214

Instituto de Salud Carlos III

197

Institute for Molecular Medicine Finland

186

Alzheimer’s Disease Neuroimaging Initiative

185

Boston University

183

Erasmus MC

135

The University of Texas Health Science Center at San Antonio

133

Biomedical Research Networking Center on Neurodegenerative Diseases

128

Centro de Investigación Biomédica en Red

119

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Renal decline in patients with atrial fibrillation treated with rivaroxaban or warfarin: a population-based cohort study in the United Kingdom

European Heart Journal (2021)

Luis A. Garcı́a Rodrı́guez Yanina Balabanova María Eugenia Sáez Gunnar Brobert Antonio González‐Pérez

Abstract Background A recent observational study (1) has suggested that renal decline among patients with non-valvular atrial fibrillation (NVAF) could be faster in users of warfarin vs. rivaroxaban. Purpose To estimate renal decline in patients with NVAF and preserved renal function who started oral anticoagulant (OAC) therapy with rivaroxaban 20 mg or warfarin. Methods Using primary care electronic health records (EHRs) from the United Kingdom (UK), we identified patients with NVAF who initiated rivaroxaban (20 mg/day, N=5338) or warfarin (N=6314) from January 2014–March 2019. Patients were excluded if they had no estimated glomerular filtration rate (eGFR) or serum creatinine (sCr) values recorded in the year before OAC initiation, a history of end-stage renal disease (ESRD), or baseline eGFR <50 ml/min/1.73m2. We identified three renal decline outcomes during follow-up: a) doubling of sCr levels, b) ≥30% decline in eGFR (confirmed by a subsequent measurement), and c) ESRD (code for ESRD/stage 5 CKD/chronic dialysis, or eGFR <15 ml/min/1.73m2 confirmed by subsequent measurement). To identify incident cases of each outcome, we followed patients from OAC initiation to the earliest of a renal decline event, death, or the end of the study period (September 2019). Cox regression was used to calculate adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) for each outcome with rivaroxaban vs. warfarin use, overall and among heart failure and diabetes patient subgroups. We estimated the average eGFR slope using a mixed model regression among the subset of individuals with at least two eGFR measurements during follow-up, where the first was recorded within 120 days of the start of follow-up, and the last was recorded >180 days after the first eGFR measurement (rivaroxaban n=2054, warfarin n=2464). Results After a mean follow-up of 2.5 years, the number of incident cases was: doubling sCr (n=322), ≥30% decline in eGFR (n=1179), and ESRD (n=22). As shown in the Table, after adjusting for age, sex, baseline renal function and comorbidity, HRs for the renal outcomes with rivaroxaban vs. warfarin users were: doubling sCr, 0.63 (95% CI: 0.49–0.81); ≥30% decline in eGFR, 0.76 (95% CI: 0.67–0.86); ESRD, 0.77 (95% CI: 0.29–2.04). Similar results were observed among patients with diabetes or heart failure. Estimated mean loss in renal function during the study period was 2.03 ml/min/1.73 m2 per year among warfarin users and 1.65 ml/min/1.73 m2 among rivaroxaban initiators (p=0.03). Conclusion The risk of renal decline events and rate of decline in renal function among patients with baseline eGFR >50 ml/min/1.73m2 was lower in patients using rivaroxaban 20 mg vs. warfarin. As residual confounding could have been present, further research is needed to confirm/refute our findings. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Bayer AG

10.1093/eurheartj/ehab724.2995

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Multilayer OMICS characterization of APOE‐modulated isogenic hiPSCs elucidates cell‐type–specific mechanisms modified by APOE: A study of the IMI ADAPTED Consortium

Alzheimer s & Dementia (2020)

Janina S. Ried Marco Rocha Curado María Eugenia Sáez Lamiaa Bahnassawy Heyne Lee

Abstract Background Alzheimer’s Disease (AD) is the most common cause of dementia in the elderly and affects over 35 million people worldwide, imposing increasing social and economic burden as the population ages. While it is widely known that the most prominent genetic risk factor for AD is the presence of the Apolipoprotein E (APOE) ε4 allele, the effects of APOE in the development of AD is still poorly understood. As part of the IMI ADAPTED consortium, we aim to clarify the role of APOE as a risk factor in the development of AD. Here we present an in‐depth analysis of the effect of the APOE genotype on the transcriptome of brain cells derived from human‐induced pluripotent stem cells (hiPSCs). Method Isogenic hiPSC lines were modified to carry different APOE genotypes: ε3/ε3, ε4/ε4, ε3/ε4, ε2/ε2, as well as an APOE knock‐out (KO) cell line. Lines carrying each of these genotypes were differentiated into distinct cell types. Differential gene expression (DGE) and protein expression (DPE) was calculated, followed by gene set enrichment. Clustering approaches were used to identify shared and differing gene signatures across genotypes. We further applied upstream regulator and network analysis on the individual cell‐type results and integrated these results across cell types. The results were compared with DGE and DEP results from an APOE mouse model. Finally, the identified genes and mechanisms were combined with the results of data from postmortem human brain samples of AD cases and controls. Results The observed transcriptional changes confirmed phenotypic observations made for the hiPSCs and refined the insight of genes identified human brain OMICS data. Several genes and pathways were identified, which showed consistent gene expression on transcriptome and proteome level. Further, shared patterns of expressions of genes across genotypes and potential mechanisms involved in this were detected. Conclusions In depth transcriptomics and proteomics analysis of APOE modified hiPSCs enabled to study cell type specific effects and contributed with this to the understanding of mechanisms affected by different APOE genotypes.

Apolipoprotein E

10.1002/alz.041206

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No association of a risk variant for severe COVID-19 with HIV protection in three cohorts of highly exposed individuals

PNAS Nexus (2022)

Manuela Sironi Rachele Cagliani Mara Biasin Sergio Lo Caputo Irma Saulle

An extended haplotype on chromosome 3 is the major genetic risk factor for severe COVID-19. The risk haplotype, which was inherited from Neanderthals, decreases the expression of several cytokine receptors, including CCR5. Recently, a study based on three general population cohorts indicated that the minor allele of one of the variants in the haplotype (rs17713054) protects against HIV infection. We thus expected this allele to be over-represented in highly exposed individuals who remain uninfected (exposed seronegative individuals, ESN). To perform a meta-analysis, we genotyped rs17713054 in three ESN cohorts of European ancestry exposed to HIV through different routes. No evidence of association was detected in the single cohorts. The meta-analysis also failed to detect any effect of the variant on protection from HIV-1. The same results were obtained in a Cox-regression analysis for the time to seroconversion. An in-vitro infection assay did not detect differences in viral replication as a function of rs17713054 genotype status. We conclude that the rs17713054 minor allele is not associated with the ESN phenotype and does not modulate HIV infection in vitro.

2019-20 coronavirus outbreak

Betacoronavirus

10.1093/pnasnexus/pgac138

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CDH6 and HAGH protein levels in plasma associate with Alzheimer’s disease in APOE ε4 carriers

Scientific Reports (2020)

Shahzad Ahmad Marta del Campo Oskar Hansson Ayşe Demirkan Agustı́n Ruiz

Abstract Many Alzheimer’s disease (AD) genes including Apolipoprotein E ( APOE ) are found to be expressed in blood-derived macrophages and thus may alter blood protein levels. We measured 91 neuro-proteins in plasma from 316 participants of the Rotterdam Study (incident AD = 161) using Proximity Extension Ligation assay. We studied the association of plasma proteins with AD in the overall sample and stratified by APOE . Findings from the Rotterdam study were replicated in 186 AD patients of the BioFINDER study. We further evaluated the correlation of these protein biomarkers with total tau (t-tau), phosphorylated tau (p-tau) and amyloid-beta (Aβ) 42 levels in cerebrospinal fluid (CSF) in the Amsterdam Dementia Cohort (N = 441). Finally, we conducted a genome-wide association study (GWAS) to identify the genetic variants determining the blood levels of AD-associated proteins. Plasma levels of the proteins, CDH6 (β = 0.638, P = 3.33 × 10 −4 ) and HAGH (β = 0.481, P = 7.20 × 10 −4 ), were significantly elevated in APOE ε4 carrier AD patients. The findings in the Rotterdam Study were replicated in the BioFINDER study for both CDH6 (β = 1.365, P = 3.97 × 10 −3 ) and HAGH proteins (β = 0.506, P = 9.31 × 10 −7 ) when comparing cases and controls in APOE ε4 carriers. In the CSF, CDH6 levels were positively correlated with t-tau and p-tau in the total sample as well as in APOE ε4 stratum ( P < 1 × 10 −3 ). The HAGH protein was not detected in CSF. GWAS of plasma CDH6 protein levels showed significant association with a cis-regulatory locus (rs111283466, P = 1.92 × 10 −9 ). CDH6 protein is implicated in cell adhesion and synaptogenesis while HAGH protein is related to the oxidative stress pathway. Our findings suggest that these pathways may be altered during presymptomatic AD and that CDH6 and HAGH may be new blood-based biomarkers.

Apolipoprotein E

Genome-wide Association Study

10.1038/s41598-020-65038-5

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Citations (22)

High prevalence of the C634Y mutation in the RET proto-oncogene in MEN 2A families in Spain.

PubMed (1999)

Beatríz Sánchez-Hernández Mercedes Robledo Josefina Biarnés María Eugenia Sáez V. Volpini

The RET proto-oncogene encodes a receptor tyrosine kinase expressed in neural crest derived tissues. Germline mutations in the RET proto-oncogene are responsible for three different dominantly inherited cancer syndromes: multiple endocrine neoplasia type 2A (MEN 2A), type 2B (MEN 2B), and familial medullary thyroid carcinoma (FMTC). MTC can also occur sporadically. Molecular characterisation of the RET proto-oncogene has been performed by PCR-SSCP analysis, direct DNA sequencing, and restriction enzyme analysis in 49 unrelated, Spanish, MEN 2 families: 30 MEN 2A families, six FMTC families, and 13 families classified as "other". Germline missense mutations in one of six cysteine codons (609, 611, 618, and 620 in exon 10, and codons 630 and 634 in exon 11), which encode part of the extracellular cysteine rich domain of RET, have been detected in the majority of these families: 100% of MEN 2A families, 67% of FMTC families, and 54% of families classified as "other". No RET mutations in exons 10, 11, 13, 14, 15, or 16 were detected in the remaining families. The most frequent RET mutation in MEN 2A Spanish families is C634Y, occurring in 73% of cases. Haplotype analysis does not exclude the possibility of founder effects in Spanish MEN 2A families with the C634Y mutation.

RET proto-oncogene

Proto-Oncogene Proteins c-ret

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Plant viral elongated nanoparticles modified for log-increases of foreign peptide immunogenicity and specific antibody detection

Journal of Biotechnology (2013)

Flora Sánchez María Eugenia Sáez Pablo Lunello F Ponz

Peptide vaccine

10.1016/j.jbiotec.2013.09.002

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A metagenome-wide association study of HIV disease progression in HIV controllers

iScience (2023)

Luís Miguel Real María Eugenia Sáez Anaïs Corma‐Gómez Antonio González‐Pérez Christian W. Thorball

Some HIV controllers experience immunologic progression with CD4+ T cell decline. We aimed to identify genetic factors associated with CD4+ T cell lost in HIV controllers. A total of 561 HIV controllers were included, 442 and 119 from the International HIV controllers Study Cohort and the Swiss HIV Cohort Study, respectively. No SNP or gene was associated with the long-term non-progressor HIV spontaneous control phenotype in the individual GWAS or in the meta-analysis. However, SNPs previously associated with natural HIV control linked to HLA-B (rs2395029 [p = 0.005; OR = 1.70], rs59440261 [p = 0.003; OR = 1.78]), MICA (rs112243036 [p = 0.011; OR = 1.45]), and PSORS1C1 loci (rs3815087 [p = 0.017; OR = 1.39]) showed nominal association with this phenotype. Genetic factors associated with the long-term HIV controllers without risk of immunologic progression are those previously related to the overall HIV controller phenotype.

Genome-wide Association Study

SNP

Genetic Association

10.1016/j.isci.2023.107214

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A method for detecting epistasis in genome-wide studies using case-control multi-locus association analysis

BMC Genomics (2008)

Javier Gayán Antonio González‐Pérez Fernando Bermudo María Eugenia Sáez José Luís Royo

Abstract Background The difficulty in elucidating the genetic basis of complex diseases roots in the many factors that can affect the development of a disease. Some of these genetic effects may interact in complex ways, proving undetectable by current single-locus methodology. Results We have developed an analysis tool called Hypothesis Free Clinical Cloning (HFCC) to search for genome-wide epistasis in a case-control design. HFCC combines a relatively fast computing algorithm for genome-wide epistasis detection, with the flexibility to test a variety of different epistatic models in multi-locus combinations. HFCC has good power to detect multi-locus interactions simulated under a variety of genetic models and noise conditions. Most importantly, HFCC can accomplish exhaustive genome-wide epistasis search with large datasets as demonstrated with a 400,000 SNP set typed on a cohort of Parkinson's disease patients and controls. Conclusion With the current availability of genetic studies with large numbers of individuals and genetic markers, HFCC can have a great impact in the identification of epistatic effects that escape the standard single-locus association analyses.

Epistasis

Genome-wide Association Study

SNP

Genetic Association

Genetic architecture

10.1186/1471-2164-9-360

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Rare copy number variation in the GR@ACE/DEGESCO dementia dataset of spanish population

Alzheimer s & Dementia (2023)

Itziar de Rojas Guillermo García‐Ribas Pascual Sánchez‐Juan Jordi Pérez‐Tur Pau Pástor

Abstract Background Recent studies have found that duplications or deletions of DNA fragments, known as copy number variants (CNVs), may play a role in missing heritability for complex human diseases. Method In that sense, we conducted a scan for CNVs in the GR@ACE/DEGESCO dementia dataset of Spanish population 1 (n = 20,080 individuals using Axiom 815K Spanish biobank array (Thermo Fisher)). We ran CNV calling algorithms from PennCNV software to obtain high‐confidence calls for CNVs. After extensive quality control (QC) for individuals (sex discrepancies, excess of heterozygosity, high missingness, familiar relations and population outliers were excluded), CNVs (>50kb and nSNPs>10 were included), removing spurious CNVs in telomeric/centromeric regions, gene QC (ANOVA comparisons between DNA origin source evaluated in controls), 8,275 controls and 7,818 dementia cases were selected for following analysis. Result Global burden analyses revealed highly significant differences between dementia cases and controls (dem/ctrl) in CNV rate of deletions (p = 2.69E‐04, mean ctrl‐dem = 1.53‐1.38) but not in duplications (p = 0.535, mean ctrl‐dem = 1.63‐1.61). However, only the number of genes affected by CNVs was significantly different in deletions (p = 0.042, mean ctrl‐dem = 3.62‐3.10; duplications p = 0.448, mean ctrl‐dem = 5.93‐5.68). We also observed a nominal deletion‐gene‐affected association by genes related to nervous system development pathway or intellectual disability such as VPS13B 2 (nine cases affected), PKP3 (Freq ctrl‐dem 0.17‐0.25%) and FBRSL1 3 (Freq ctrl‐dem 0.15‐0.26%). The current study did not detect significant differences in CNVs that affect known Alzheimer’s disease (AD) loci identified by recent genome‐wide association studies 4 (deletions Fisher test p = 0.0875, duplications Fisher Test p = 0.5853). Nevertheless, we found three important AD genes with CNVs potentially associated to dementia. Specifically, we detected MAPT protective deletions (Freq ctrl‐dem 0.16‐0.01%), ABCA7 risk deletions (Freq ctrl‐dem 0.05‐0.14%) and APP CNVs detected in five dementia cases (0.064%). Because the technology used in our study has limitations in detecting small CNVs, future studies must carefully assess the presence of smaller CNVs and their relationship with dementia. Conclusion We have detected potential CNVs in the Spanish population for Alzheimer’s disease, however, because the technology used in our study has limitations in detecting small CNVs, future studies must carefully assess the presence of smaller CNVs and their relationship with dementia.

Missing heritability problem

10.1002/alz.074012

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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

bioRxiv (Cold Spring Harbor Laboratory) (2019)

Sonia Moreno–Grau Itziar de Rojas Isabel Hernández Inés Quintela Laura Montrreal

Abstract Background Genetics plays a major role in Alzheimer’s Disease (AD). To date, 40 genes associated with AD have been identified, although most remain undiscovered. Clinical, neuropathological and genetic variability might impact genetic discoveries and complicate dissection of the biological pathways underlying AD. Methods GR@ACE is a genome-wide study of dementia and its clinical endophenotypes that encompasses 4,120 cases and 3,289 controls from Spain. GR@ACE phenotypes were defined according to AD’s clinical certainty and the presence of vascular co-morbidity. To explore whether clinical endophenotypes reflect variation in underlying biological pathways, we first assessed the impact of known AD loci across endophenotypes to generate three loci categories. Next, we incorporated gene co-expression data and conducted pathway analysis on each category. To assess the impact of heterogeneity in the GWAS findings, the GR@ACE series were meta-analyzed with: 1) genotype-level data from dbGaP (N=21,235); and 2) summary statistics from IGAP Stages I and II (n=61,571 and n=81,455 respectively). Findings We classified known AD loci in three categories, which might reflect the disease clinical heterogeneity, from vascular and mixed forms to pure AD pathology. Immune system pathways were detected in all categories. Intriguingly, vascular processes were only detected as a causal mechanism in probable AD. A meta-analysis of GR@ACE with additional GWAS datasets revealed the ANKRD31-rs4704171 signal in the HMGCR genomic region. We confirmed NDUFAF6-rs10098778 and SCIMP -rs7225151, which were previously detected by IGAP, to be suggestive signals. We also confirmed CD33-rs3865444 to be genome-wide significant. Interpretation The regulation of vasculature is a prominent causal component of probable AD. In that context, cerebral amyloid angiopathy, the unique identified link between the vascular and amyloid hypotheses, deserves further investigation. The GR@ACE meta-analysis revealed novel AD genetic signals. GWAS results are strongly driven by the presence of clinical heterogeneity in the AD series. Funding Grifols SA, Fundación bancaria “La Caixa”, Fundació ACE and ISCIII (Instituto de Salud Carlos III).

Endophenotype

Genome-wide Association Study

Genetic Association

Genetic architecture

10.1101/528901

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Citations (3)