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. 2015 Dec;20(12):1588-95.
doi: 10.1038/mp.2015.6. Epub 2015 Feb 17.

Genetic overlap between Alzheimer's disease and Parkinson's disease at the MAPT locus

R S Desikan  1 , A J Schork  2 , Y Wang  3   4 , A Witoelar  4 , M Sharma  5   6 , L K McEvoy  1 , D Holland  3 , J B Brewer  1   3 , C-H Chen  1   7 , W K Thompson  7 , D Harold  8 , J Williams  8 , M J Owen  8 , M C O'Donovan  8 , M A Pericak-Vance  9 , R Mayeux  10 , J L Haines  11 , L A Farrer  12 , G D Schellenberg  13 , P Heutink  14 , A B Singleton  15 , A Brice  16 , N W Wood  17 , J Hardy  18 , M Martinez  19 , S H Choi  20 , A DeStefano  20   21 , M A Ikram  22 , J C Bis  23 , A Smith  24 , A L Fitzpatrick  25 , L Launer  26 , C van Duijn  22 , S Seshadri  21   27 , I D Ulstein  28 , D Aarsland  29   30   31 , T Fladby  32   33 , S Djurovic  4 , B T Hyman  34 , J Snaedal  35 , H Stefansson  36 , K Stefansson  36   37 , T Gasser  5 , O A Andreassen  4   7 , A M Dale  1   2   3   7 ; ADNI, ADGC, GERAD, CHARGE and IPDGC Investigators
Affiliations

Genetic overlap between Alzheimer's disease and Parkinson's disease at the MAPT locus

R S Desikan et al. Mol Psychiatry. 2015 Dec.

Abstract

We investigated the genetic overlap between Alzheimer's disease (AD) and Parkinson's disease (PD). Using summary statistics (P-values) from large recent genome-wide association studies (GWAS) (total n=89 904 individuals), we sought to identify single nucleotide polymorphisms (SNPs) associating with both AD and PD. We found and replicated association of both AD and PD with the A allele of rs393152 within the extended MAPT region on chromosome 17 (meta analysis P-value across five independent AD cohorts=1.65 × 10(-7)). In independent datasets, we found a dose-dependent effect of the A allele of rs393152 on intra-cerebral MAPT transcript levels and volume loss within the entorhinal cortex and hippocampus. Our findings identify the tau-associated MAPT locus as a site of genetic overlap between AD and PD, and extending prior work, we show that the MAPT region increases risk of Alzheimer's neurodegeneration.

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Conflict of interest statement

DISCLOSURES

Dr. Anders M. Dale is a Founder of and holds equity in CorTechs Labs, Inc, and serves on its Scientific Advisory Board. He is also a member of the Scientific Advisory Board of Human Longevity, Inc. (HLI), and receives funding through research agreements with General Electric Healthcare (GEHC) and Medtronic, Inc. The terms of these arrangements have been reviewed and approved by the University of California, San Diego in accordance with its conflict of interest policies.

Dr. Linda K. McEvoy has stock options in CorTechs Labs, Inc.

Dr. James B. Brewer holds stock options in CorTechs Labs, Inc and serves on the advisory board and receives financial support from the Eli Lilly Biomarker Unit (Amyvid). Dr. Brewer also receives research support from General Electric and Janssen Alzheimer Immunotherapy.

Figures

Figure 1
Figure 1
Forest plot for rs393152. Since rs393152 was not available within the Oslo cohort (*), we used a proxy SNP (rs17690703; r2 = .765, D'=1 in Hapmap2).
Figure 2
Figure 2
(a) Regional linkage disequilibrium (LD) plot demonstrating the relationship between rs393152 on chromosome 17 and loci greater than and less than 1 MB. The bottom panel indicates the location of genes in the region. Linkage Disequilibrium measured in the 1000 genomes European Populations using plink v1.07. (b) Regional association plot illustrating the association signal within the MAPT region on chromosome 17. The bottom panel indicates the location of genes in the region. Linkage Disequilibrium measured in the 1000 genomes European Populations using plink v1.07.
Figure 2
Figure 2
(a) Regional linkage disequilibrium (LD) plot demonstrating the relationship between rs393152 on chromosome 17 and loci greater than and less than 1 MB. The bottom panel indicates the location of genes in the region. Linkage Disequilibrium measured in the 1000 genomes European Populations using plink v1.07. (b) Regional association plot illustrating the association signal within the MAPT region on chromosome 17. The bottom panel indicates the location of genes in the region. Linkage Disequilibrium measured in the 1000 genomes European Populations using plink v1.07.
Figure 3
Figure 3
Box plots illustrating the relationship between rs393152 alleles (x-axis) and gene expression levels of MAPT, SYP, and SNCA (y-axis). For each plot, thick black lines show the median value. Regions above and below the black line show the upper and lower quartiles, respectively. The dashed lines extend to the minimum and maximum values with outliers shown as open circles. For MAPT, a proxy SNP was used (please see Results for additional details). As illustrated, the A allele of rs393152 demonstrated a selective dose-dependent effect on the level of intracranial MAPT transcript.
Figure 4
Figure 4
Regional association plot demonstrating the relationship between MAPT transcript expression levels (y-axis) and SNPs in LD with rs393152 on chromosome 17. The bottom panel indicates the location of genes in the region. Linkage Disequilibrium measured in the 1000 genomes European Populations using plink v1.07. As illustrated, SNPs in r2 LD =1 with rs393152 constituted the peak of the association signal with MAPT transcript expression levels.
Figure 5
Figure 5
Bar plots demonstrating the relationship between rs393152 alleles (x-axis) and volume loss (annualized percent change – y-axis) of the hippocampus (blue) and entorhinal cortex (gray) among APOE ε4 carriers (left panel) and APOE ε4 non-carriers (right panel). As illustrated, the A allele of rs393152 demonstrated a selective dose-dependent relationship with medial temporal lobe atrophy only among APOE ε4 non-carriers.
See this image and copyright information in PMC

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