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Meta-Analysis
. 2014 Sep 4;10(9):e1004606.
doi: 10.1371/journal.pgen.1004606. eCollection 2014 Sep.

Genome-wide association meta-analysis of neuropathologic features of Alzheimer's disease and related dementias

Gary W Beecham  1 , Kara Hamilton  1 , Adam C Naj  2 , Eden R Martin  1 , Matt Huentelman  3 , Amanda J Myers  4 , Jason J Corneveaux  3 , John Hardy  5 , Jean-Paul Vonsattel  6 , Steven G Younkin  7 , David A Bennett  8 , Philip L De Jager  9 , Eric B Larson  10 , Paul K Crane  11 , M Ilyas Kamboh  12 , Julia K Kofler  13 , Deborah C Mash  14 , Linda Duque  14 , John R Gilbert  1 , Harry Gwirtsman  15 , Joseph D Buxbaum  16 , Patricia Kramer  17 , Dennis W Dickson  7 , Lindsay A Farrer  18 , Matthew P Frosch  19 , Bernardino Ghetti  20 , Jonathan L Haines  21 , Bradley T Hyman  22 , Walter A Kukull  23 , Richard P Mayeux  24 , Margaret A Pericak-Vance  1 , Julie A Schneider  25 , John Q Trojanowski  26 , Eric M Reiman  27 ; Alzheimer's Disease Genetics Consortium (ADGC); Gerard D Schellenberg  26 , Thomas J Montine  28
Affiliations
Meta-Analysis

Genome-wide association meta-analysis of neuropathologic features of Alzheimer's disease and related dementias

Gary W Beecham et al. PLoS Genet. .

Erratum in

  • PLoS Genet. 2014 Nov;10(11):e1004867

Abstract

Alzheimer's disease (AD) and related dementias are a major public health challenge and present a therapeutic imperative for which we need additional insight into molecular pathogenesis. We performed a genome-wide association study and analysis of known genetic risk loci for AD dementia using neuropathologic data from 4,914 brain autopsies. Neuropathologic data were used to define clinico-pathologic AD dementia or controls, assess core neuropathologic features of AD (neuritic plaques, NPs; neurofibrillary tangles, NFTs), and evaluate commonly co-morbid neuropathologic changes: cerebral amyloid angiopathy (CAA), Lewy body disease (LBD), hippocampal sclerosis of the elderly (HS), and vascular brain injury (VBI). Genome-wide significance was observed for clinico-pathologic AD dementia, NPs, NFTs, CAA, and LBD with a number of variants in and around the apolipoprotein E gene (APOE). GalNAc transferase 7 (GALNT7), ATP-Binding Cassette, Sub-Family G (WHITE), Member 1 (ABCG1), and an intergenic region on chromosome 9 were associated with NP score; and Potassium Large Conductance Calcium-Activated Channel, Subfamily M, Beta Member 2 (KCNMB2) was strongly associated with HS. Twelve of the 21 non-APOE genetic risk loci for clinically-defined AD dementia were confirmed in our clinico-pathologic sample: CR1, BIN1, CLU, MS4A6A, PICALM, ABCA7, CD33, PTK2B, SORL1, MEF2C, ZCWPW1, and CASS4 with 9 of these 12 loci showing larger odds ratio in the clinico-pathologic sample. Correlation of effect sizes for risk of AD dementia with effect size for NFTs or NPs showed positive correlation, while those for risk of VBI showed a moderate negative correlation. The other co-morbid neuropathologic features showed only nominal association with the known AD loci. Our results discovered new genetic associations with specific neuropathologic features and aligned known genetic risk for AD dementia with specific neuropathologic changes in the largest brain autopsy study of AD and related dementias.

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Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Regional association plot for GALNT7 and the neuritic plaque (any vs. none) analysis.
The purple dot indicates the most associated SNP in the region. The x-axis is basepair position, and y-axis is the −log(p-value), base 10.
Figure 2
Figure 2. Regional association plot for ABCG1 and the neuritic plaque (any vs. none) analysis.
The purple dot indicates the most associated SNP in the region. The x-axis is basepair position, and y-axis is the −log(p-value), base 10.
Figure 3
Figure 3. Regional association plot for the chromosome 9:129,280,000–129,380,000 region and the neuritic plaque (any vs. none) analysis.
The purple dot indicates the most associated SNP in the region. The x-axis is basepair position, and y-axis is the −log(p-value), base 10.
Figure 4
Figure 4. Regional association plot for the chromosome 18:6,420,000–6,520,000 region and the hippocampal sclerosis (any vs. none) analysis.
The purple dot indicates the most associated SNP in the region. The x-axis is basepair position and y-axis is the −log(p-value), base 10.
Figure 5
Figure 5. Regional association plot for KCNMB2 and the hippocampal sclerosis (any vs. none) analysis.
The purple dot indicates the most associated SNP in the region. The x-axis is basepair position, and y-axis is the −log(p-value), base 10.
Figure 6
Figure 6. Barplot of OR for known AD risk loci (all 21 loci).
Red indicates the estimated OR previously reported through the IGAP consortium , green indicates the estimated OR from our primary clinico-neuropathologic case-control analysis, and blue indicates the estimated OR from a more restrictive analysis that required complete documentation of all relevant neuropathologic phenotypes.
Figure 7
Figure 7. Correlations of OR for known AD risk loci and the neuropathology phenotypes.
Bottom left indicates the magnitude, direction, and confidence interval of the correlation. Top right shows plots of the data points against each other. The diagonal box indicates the phenotypes; off-diagonal boxes indicate the correlations of the OR for the corresponding phenotypes.
See this image and copyright information in PMC

References

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