Genome-Wide Association Meta-analysis of Neuropathologic Features of Alzheimer's Disease and Related Dementias

Beecham, Gary W.; Hamilton, Kara; Naj, Adam C.; Martin, Eden R.; Huentelman, Matt; Myers, Amanda; Corneveaux, Jason J.; Hardy, John; Vonsattel, Jean Paul; Younkin, Steven G.; Bennett, David A.; Jager, Philip L. De; Larson, Eric B.; Crane, Paul K.; Kamboh, M. Ilyas; Kofler, Julia; Mash, Deborah C.; Duque, Linda; Gilbert, John R.; Gwirtsman, Harry E.; Buxbaum, Joseph D.; Kramer, Patricia L.; Dickson, Dennis W.; Farrer, Lindsay A.; Frosch, Matthew P.; Ghetti, Bernardino; Haines, Jonathan L.; Hyman, Bradley T.; Kukull, Walter A.; Mayeux, Richard; Pericak‐Vance, Margaret A.; Schneider, Julie A.; Trojanowski, John Q.; Reiman, Eric M.; Schellenberg, Gerard D.; Montine, Thomas J.

doi:10.1371/journal.pgen.1004606

Cited by 317 publications

(356 citation statements)

References 29 publications

(34 reference statements)

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“…37 This locus also did not reach genome-wide significance with clinicopathological Alzheimer’s disease dementia (p=5·21 × 10 −6 ). 38 The contact in 1 protein, encoded by CNTN1 , is a glycosylphosphatidylinositol-anchored neuronal membrane protein that functions as a cell-adhesion molecule with important roles in axonal function. 39,40 Mutations in CNTN1 were found to cause a familial form of lethal congenital myopathy.…”

Section: Discussionmentioning

confidence: 99%

“…In addition to performing a genome-wide association study with clinicopathological Alzheimer’s disease dementia, Beecham and colleagues 38 also analysed commonly comorbid neuropathological features seen in elderly individuals with dementia, including Lewy body disease. In this latter analysis, only the APOE locus was found to achieve genome-wide significance.…”

Section: Discussionmentioning

confidence: 99%

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Investigating the genetic architecture of dementia with Lewy bodies: a two-stage genome-wide association study

Guerreiro

Ross

Kun‐Rodrigues

et al. 2018

The Lancet Neurology

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Summary Background Dementia with Lewy bodies is the second most common form of dementia in elderly people but has been overshadowed in the research field, partly because of similarities between dementia with Lewy bodies, Parkinson’s disease, and Alzheimer’s disease. So far, to our knowledge, no large-scale genetic study of dementia with Lewy bodies has been done. To better understand the genetic basis of dementia with Lewy bodies, we have done a genome-wide association study with the aim of identifying genetic risk factors for this disorder. Methods In this two-stage genome-wide association study, we collected samples from white participants of European ancestry who had been diagnosed with dementia with Lewy bodies according to established clinical or pathological criteria. In the discovery stage (with the case cohort recruited from 22 centres in ten countries and the controls derived from two publicly available database of Genotypes and Phenotypes studies [phs000404.v1.p1 and phs000982.v1.p1] in the USA), we performed genotyping and exploited the recently established Haplotype Reference Consortium panel as the basis for imputation. Pathological samples were ascertained following autopsy in each individual brain bank, whereas clinical samples were collected after participant examination. There was no specific timeframe for collection of samples. We did association analyses in all participants with dementia with Lewy bodies, and also only in participants with pathological diagnosis. In the replication stage, we performed genotyping of significant and suggestive results from the discovery stage. Lastly, we did a meta-analysis of both stages under a fixed-effects model and used logistic regression to test for association in each stage. Findings This study included 1743 patients with dementia with Lewy bodies (1324 with pathological diagnosis) and 4454 controls (1216 patients with dementia with Lewy bodies vs 3791 controls in the discovery stage; 527 vs 663 in the replication stage). Results confirm previously reported associations: APOE (rs429358; odds ratio [OR] 2·40, 95% CI 2·14–2·70; p=1·05 × 10−48), SNCA (rs7681440; OR 0·73, 0·66–0·81; p=6·39 × 10−10), and GBA (rs35749011; OR 2·55, 1·88–3·46; p=1·78 × 10−9). They also provide some evidence for a novel candidate locus, namely CNTN1 (rs7314908; OR 1·51, 1·27–1·79; p=2·32 × 10−6); further replication will be important. Additionally, we estimate the heritable component of dementia with Lewy bodies to be about 36%. Interpretation Despite the small sample size for a genome-wide association study, and acknowledging the potential biases from ascertaining samples from multiple locations, we present the most comprehensive and well powered genetic study in dementia with Lewy bodies so far. These data show that common genetic variability has a role in the disease.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Investigating the genetic architecture of dementia with Lewy bodies: a two-stage genome-wide association study

Guerreiro

Ross

Kun‐Rodrigues

et al. 2018

The Lancet Neurology

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207

240

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“…Our results might further explain discrepancies reported across exploratory GWAS studies of AD markers. For instance, the top genome-wide significant loci that emerged from an exploratory GWAS analysis of AD pathologies (Ab plaques and neurofibrillary tangles) were not significant at a liberal statistical significance threshold of p , 0.05 in the IGAP GWAS contrasting AD dementia to CN, 6,29 highlighting that the top loci surpassing GWAS level significance thresholds in analyses examining different AD phenotypes are likely to differ. Thus, although it is necessary to apply stringent criteria in discovery style GWAS analyses to reduce the incidence of false-positives, it is highly likely that relevant signal exists below these stringent criteria.…”

Section: (Pgrs) Discrimination Between Patients With Alzheimer Diseasmentioning

confidence: 99%

Polygenic risk of Alzheimer disease is associated with early- and late-life processes

Sperling²,

et al. 2016

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Objective: To examine associations between aggregate genetic risk and Alzheimer disease (AD) markers in stages preceding the clinical symptoms of dementia using data from 2 large observational cohort studies. Methods:We computed polygenic risk scores (PGRS) using summary statistics from the International Genomics of Alzheimer's Project genome-wide association study of AD. Associations between PGRS and AD markers (cognitive decline, clinical progression, hippocampus volume, and b-amyloid) were assessed within older participants with dementia. Associations between PGRS and hippocampus volume were additionally examined within healthy younger participants (age 18-35 years).Results: Within participants without dementia, elevated PGRS was associated with worse memory (p The asymptomatic stage of Alzheimer disease (AD) is thought to last over a decade, during which the pathophysiologic processes are under way in the absence of clinical symptoms.1 Given that current clinical trials are testing whether antiamyloid therapies slow cognitive decline among clinically normal individuals at risk for AD dementia, 2,3 it is critical to understand the influence of risk factors before overt symptoms of dementia are present. Coinvestigators are listed at Neurology.org.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. A complete listing of ADNI investigators can be found at

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“…The ε4 allele is associated with a higher risk of atherosclerosis and higher plasma levels of total and LDL cholesterol [94]. In addition, several other genes involved in cholesterol metabolism have been associated with AD including adenosine triphosphate (ATP)-binding cassette subfamily A member 7 (ABCA7) [95], clusterin [96] and sortilin-related receptor (SORL1) [97].…”

Section: Lipid Effects On Alzheimer's Diseasementioning

confidence: 99%

Hypercholesterolaemia and vascular dementia

et al. 2017

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Correspondence: Philip Bath (Philip.bath@nottingham.ac.uk) Vascular dementia (VaD) is the second commonest cause of dementia. Stroke is the leading cause of disability in adults in developed countries, the second major cause of dementia and the third commonest cause of death. Traditional vascular risk factors -diabetes, hypercholesterolaemia, hypertension and smoking -are implicated as risk factors for VaD. The associations between cholesterol and small vessel disease (SVD), stroke, cognitive impairment and subsequent dementia are complex and as yet not fully understood. Similarly, the effects of lipids and lipid-lowering therapy on preventing or treating dementia remain unclear; the few trials that have assessed lipid-lowering therapy for preventing (two trials) or treating (four trials) dementia found no evidence to support the use of lipid-lowering therapy for these indications. It is appropriate to treat those patients with vascular risk factors that meet criteria for lipid-lowering therapy for the primary and secondary prevention of cardiovascular and cerebrovascular events, and in line with current guidelines. Managing the individual patient in a holistic manner according to his or her own vascular risk profile is recommended. Although the paucity of randomized controlled evidence makes for challenging clinical decision making, it provides multiple opportunities for on-going and future research, as discussed here.

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Genome-Wide Association Meta-analysis of Neuropathologic Features of Alzheimer's Disease and Related Dementias

Cited by 317 publications

References 29 publications

Investigating the genetic architecture of dementia with Lewy bodies: a two-stage genome-wide association study

Investigating the genetic architecture of dementia with Lewy bodies: a two-stage genome-wide association study

Polygenic risk of Alzheimer disease is associated with early- and late-life processes

Hypercholesterolaemia and vascular dementia

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