Genome-wide significant risk factors on chromosome 19 and the <i>APOE</i> locus
Bibliographic record
Abstract
// Sonia Moreno-Grau 1 , Isabel Hernández 1 , Stefanie Heilmann-Heimbach 2, 3 , Susana Ruiz 1 , Maitée Rosende-Roca 1 , Ana Mauleón 1 , Liliana Vargas 1 , Octavio Rodríguez-Gómez 1 , Montserrat Alegret 1 , Ana Espinosa 1 , Gemma Ortega 1 , Nuria Aguilera 1 , Carla Abdelnour 1 , Alzheimer’s Disease Neuroimaging Initiative * , Silvia Gil 1 , Wolfgang Maier 4, 5 , Oscar Sotolongo-Grau 1 , Lluís Tárraga 1 , Alfredo Ramirez 2, 4, 6 , Jesús López-Arrrieta 7 , Carmen Antúnez 8 , Manuel Serrano-Ríos 9 , Mercè Boada 1 and Agustín Ruiz 1 1 Research Center and Memory Clinic of Fundació ACE, Institut Català de Neurociències Aplicades, Univesitat Internacional de Catalunya, Barcelona, Spain 2 Institute of Human Genetics, University of Bonn, Bonn, Germany 3 Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany 4 Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany 5 German Center for Neurodegenerative Diseases, DZNE, Bonn, Germany 6 Department of Psychiatry and Psychotherapy, University of Cologne, Cologne, Germany 7 Memory Unit, University Hospital La Paz-Cantoblanco, Madrid, Spain 8 Dementia Unit, University Hospital Virgen de la Arrixaca, Murcia, Spain 9 Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, CIBERDEM, Spain, Hospital Clínico San Carlos, Madrid, Spain * Data used in preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (adni.loni.usc.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or Provided data but did not participate in analysis or writing of this report Correspondence to: Agustín Ruiz, email: aruiz@fundacioace.com Keywords: late onset Alzheimer’s disease; ABCA7; APOE; CD33; linkage disequilibrium; Gerotarget Received: December 13, 2017 Accepted: March 22, 2018 Published: May 15, 2018 ABSTRACT The apolipoprotein E ( APOE ) gene on chromosome 19q13.32, was the first, and remains the strongest, genetic risk factor for Alzheimer’s disease (AD). Additional signals associated with AD have been located in chromosome 19, including ABCA7 (19p13.3) and CD33 (19q13.41). The ABCA7 gene has been replicated in most populations. However, the contribution to AD of other signals close to APOE gene remains controversial. Possible explanations for inconsistency between reports include long range linkage disequilibrium (LRLD). We analysed the contribution of ABCA7 and CD33 loci to AD risk and explore LRLD patterns across APOE region. To evaluate AD risk conferred by ABCA7 rs4147929:G>A and CD33 rs3865444:C>A, we used a large Spanish population (1796 AD cases, 2642 controls). The ABCA7 rs4147929:G>A SNP effect was nominally replicated in the Spanish cohort and reached genome-wide significance after meta-analysis (odds ratio (OR)=1.15, 95% confidence interval (95% CI)=1.12–1.19; P = 1.60 x 10 -19 ). CD33 rs3865444:C>A was not associated with AD in the dataset. The meta-analysis was also negative (OR=0.98, 95% CI=0.93–1.04; P =0.48). After exploring LRLD patterns between APOE and CD33 in several datasets, we found significant LD (D’ >0.20; P <0.030) between APOE -Ɛ2 and CD33 rs3865444C>A in two of five datasets, suggesting the presence of a non-universal long range interaction between these loci affecting to some populations. In conclusion, we provide here evidence of genetic association of the ABCA7 locus in the Spanish population and also propose a plausible explanation for the controversy on the contribution of CD33 to AD susceptibility.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.002 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.001 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.005 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".