Research Papers: Gerotarget (Focus on Aging):

Genome-wide significant risk factors on chromosome 19 and the APOE locus

Sonia Moreno-Grau _, Isabel Hernández, Stefanie Heilmann-Heimbach, Susana Ruiz, Maitée Rosende-Roca, Ana Mauleón, Liliana Vargas, Octavio Rodríguez-Gómez, Montserrat Alegret, Ana Espinosa, Gemma Ortega, Nuria Aguilera, Carla Abdelnour, Alzheimer’s Disease Neuroimaging Initiative, Silvia Gil, Wolfgang Maier, Oscar Sotolongo-Grau, Lluís Tárraga, Alfredo Ramirez, Jesús López-Arrrieta, Carmen Antúnez, Manuel Serrano- Ríos, Mercè Boada and Agustín Ruiz

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Oncotarget. 2018; 9:24590-24600. https://doi.org/10.18632/oncotarget.25083

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Sonia Moreno-Grau1, Isabel Hernández1, Stefanie Heilmann-Heimbach2,3, Susana Ruiz1, Maitée Rosende-Roca1, Ana Mauleón1, Liliana Vargas1, Octavio Rodríguez-Gómez1, Montserrat Alegret1, Ana Espinosa1, Gemma Ortega1, Nuria Aguilera1, Carla Abdelnour1, Alzheimer’s Disease Neuroimaging Initiative*, Silvia Gil1, Wolfgang Maier4,5, Oscar Sotolongo-Grau1, Lluís Tárraga1, Alfredo Ramirez2,4,6, Jesús López-Arrrieta7, Carmen Antúnez8, Manuel Serrano-Ríos9, Mercè Boada1 and Agustín Ruiz1

1Research Center and Memory Clinic of Fundació ACE, Institut Català de Neurociències Aplicades, Univesitat Internacional de Catalunya, Barcelona, Spain

2Institute of Human Genetics, University of Bonn, Bonn, Germany

3Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany

4Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany

5German Center for Neurodegenerative Diseases, DZNE, Bonn, Germany

6Department of Psychiatry and Psychotherapy, University of Cologne, Cologne, Germany

7Memory Unit, University Hospital La Paz-Cantoblanco, Madrid, Spain

8Dementia Unit, University Hospital Virgen de la Arrixaca, Murcia, Spain

9Centro 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


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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