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Linkage analysis for plasma amyloid beta levels in persons with hypertension implicates Aβ-40 levels to presenilin 2

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Abstract

Plasma concentrations of Aβ40 and Aβ42 rise with age and are increased in people with mutations that cause early-onset Alzheimer’s disease (AD). Amyloid beta (Aβ) plasma levels were successfully used as an (endo)phenotype for gene discovery using a linkage approach in families with dominant forms of disease. Here, we searched for loci involved in Aβ plasma levels in a series of non-demented patients with hypertension in the Erasmus Rucphen Family study. Aβ40 and Aβ42 levels were determined in 125 subjects with severe hypertension. All patients were genotyped with a 6,000 single nucleotide polymorphisms (SNPs) illumina array designed for linkage analysis. We conducted linkage analysis of plasma Aβ levels. None of the linkage analyses yielded genome-wide significant logarithm of odds (LOD) score over 3.3, but there was suggestive evidence for linkage (LOD > 1.9) for two regions: 1q41 (LOD = 2.07) and 11q14.3 (LOD = 2.97), both for Aβ40. These regions were followed up with association analysis in the study subjects and in 320 subjects from a population-based cohort. For the Aβ40 region on chromosome 1, association of several SNPs was observed at the presenilin 2 gene (PSEN2) (p = 2.58 × 10−4 for rs6703170). On chromosome 11q14-21, we found some association (p = 3.1 × 10−3 for rs2514299). This linkage study of plasma concentrations of Aβ40 and Aβ42 yielded two suggestive regions, of which one points toward a known locus for familial AD.

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Acknowledgments

This study was financially supported by the Netherlands Organization for Scientific Research (NWO), the Internationale Stichting Alzheimer Onderzoek (ISAO), the Hersenstichting Nederland (HSN) and the Centre for Medical Systems Biology (CMSB) in the framework of the Netherlands Genomics Initiative (NGI) and by the Russian Foundation for Basic Research (RFBR). We thank the participants from the Genetic Research in Isolated Populations, Erasmus Rucphen Family, who made this work possible. Also, we thank Petra Veraart for collecting all genealogical data.

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical statement

All research described in this paper was carried out in compliance with the laws and customs for scientific research in the Netherlands. The Erasmus University Medical Center Medical Ethics Committee approved both the Erasmus Rucphen Family Study and the Rotterdam Study.

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Authors and Affiliations

  1. Department of Neurology, Erasmus University Medical Center, P.O. Box 2040, 3000 CA, Rotterdam, The Netherlands

    Carla A. Ibrahim-Verbaas, Maaike Schuur & John C. van Swieten

  2. Genetic Epidemiology Unit, Department of Epidemiology, Room Ee-2173, Erasmus University Medical Center, P.O. Box 2040, 3000 CA, Rotterdam, The Netherlands

    Carla A. Ibrahim-Verbaas, Najaf Amin, Antonia M. W. Coppus, Aaron Isaacs, Yurii S. Aulchenko, Ben A. Oostra & Cornelia M. van Duijn

  3. Institute of Cytology and Genetics, Russian Academy of Sciences, Lavrentjeva Ave, 10, Novosibirsk, 630090, Russia

    Irina V. Zorkoltseva & Tatiana I. Axenovich

  4. Centre for Medical Systems Biology, LUMC, P.O. Box 9600, 2300 RC, Leiden, The Netherlands

    Aaron Isaacs & Cornelia M. van Duijn

  5. Department of Radiology, Erasmus University Medical Center, P.O. Box 2040, 3000 CA, Rotterdam, The Netherlands

    M. Arfan Ikram

  6. Departments of Neurology and Laboratory Medicine, Alzheimer Centre Nijmegen, and Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen Medical Center, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands

    Marcel M. Verbeek

  7. Department of Epidemiology, Room Ee-2173, Erasmus University Medical Center, P.O. Box 2040, 3000 CA, Rotterdam, The Netherlands

    Monique M. B. Breteler & M. Arfan Ikram

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  1. Carla A. Ibrahim-Verbaas
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  2. Irina V. Zorkoltseva
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Correspondence to Cornelia M. van Duijn.

Electronic supplementary material

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439_2012_1210_MOESM1_ESM.pdf

Online resource 1 Linkage plots Figure 1 shows the genome-wide linkage results for each of the individual Aβ measurements, plotting each SNP’s chromosome and position against its calculated LOD/HLOD. Figure 2 zooms in on the regions reaching suggestive linkage on chromosome 1 and 11 (PDF 779 kb)

439_2012_1210_MOESM2_ESM.doc

Online resource 2 Supplementary table. This table shows the association results under the linkage peak for the SNPs with association p < 0.001 to Aβ40 in the ERF directly genotyped set. Beside SNP details and the association p value to Aβ40, also the association p value to Aβ42 is given (DOC 90 kb)

439_2012_1210_MOESM3_ESM.xls

Online resource 3 Meta-analysis results and eQTL data. For both suggestive linkage regions, all SNPs with a meta-analysis association p value of < 0.001 are given. Beside SNP details and meta-analysis results, the file also contains information on eQTL associations for the SNPs from two different eQTL databases (XLS 126 kb)

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Ibrahim-Verbaas, C.A., Zorkoltseva, I.V., Amin, N. et al. Linkage analysis for plasma amyloid beta levels in persons with hypertension implicates Aβ-40 levels to presenilin 2. Hum Genet 131, 1869–1876 (2012). https://doi.org/10.1007/s00439-012-1210-2

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