Genome‐wide association study of neocortical Lewy‐related pathology

Peuralinna, Terhi; Myllykangas, Liisa; Oinas, Minna; Nalls, Mike A.; Keage, Hannah A.D.; Isoviita, Veli‐Matti; Valori, Miko; Polvikoski, Tuomo; Paetau, Anders; Sulkava, Raimo; Ince, Paul G.; Zaccai, Julia; Brayne, Carol; Traynor, Bryan J.; Hardy, John; Singleton, Andrew B.; Tienari, Pentti J.

doi:10.1002/acn3.231

Cited by 28 publications

(18 citation statements)

References 40 publications

(50 reference statements)

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“…The most significant Alzheimer’s disease or Parkinson’s disease variants at the following loci showed nominal (p<0·05) association levels: MAPT , BIN1 , GAK , HLA-DBQB1 , CD2AP , INPP5D , ECHDC3 , and SCIMP . Additionally, variants previously suggested to be associated with Lewy-related pathology in a Finnish cohort, 28 did not show evidence of association in this study (appendix p 5). See appendix pp 12–70 for colocalisation plots of association between dementia with Lewy bodies and either Parkinson’s disease or Alzheimer’s disease.…”

Section: Discussioncontrasting

confidence: 72%

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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: Discussioncontrasting

confidence: 72%

“…The locus has also been reported to affect the levels of both β-amyloid and Lewy body pathology in brains of patients. 27 In a small Finnish dataset, 28 the ε4 allele association with dementia with Lewy bodies was largely driven by the subgroup with concomitant Alzheimer’s disease pathology.…”

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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213

240

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“…A GWAS based on neuropathologically confirmed elderly cases with neocortical Lewy related pathology (LRP) identified suggestive novel risk factors for neocortical LRP; SPTBN1 which encodes beta‐spectrin, an α‐synuclein binding protein and a component of LBs .…”

Section: Methodsmentioning

confidence: 99%

Review: Clinical, neuropathological and genetic features of Lewy body dementias

Hansen

Ling

Lashley

et al. 2019

Neuropathology Appl Neurobio

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2019) Neuropathology and Applied Neurobiology 45, 635-654 Clinical, neuropathological and genetic features of Lewy body dementias Lewy body dementias are the second most common neurodegenerative dementias after Alzheimer's disease and include dementia with Lewy bodies and Parkinson's disease dementia. They share similar clinical and neuropathological features but differ in the time of dementia and parkinsonism onset. Although Lewy bodies are their main pathological hallmark, several studies have shown the emerging importance of Alzheimer's disease pathology. Clinical amyloid-b imaging using Pittsburgh Compound B (PiB) supports neuropathological studies which found that amyloid-b pathology is more common in dementia with Lewy bodies than in Parkinson's disease dementia. Nevertheless, other co-occurring pathologies, such as cerebral amyloid angiopathy, TDP-43 pathology and synaptic pathology may also influence the development of neurodegeneration and dementia. Recent genetic studies demonstrated an important role of APOE genotype and other genes such as GBA and SNCA which seem to be involved in the pathophysiology of Lewy body dementias. The aim of this article is to review the main clinical, neuropathological and genetic aspects of dementia with Lewy bodies and Parkinson's disease dementia. This is particularly relevant as future management for these two conditions may differ.

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“…Thus, there are both shared and distinct risk SNPs implicated in DLB compared to PD and AD, likely contributing to the clinicopathological spectrum of LBD. These GWAS studies have also highlighted potential roles for other genes coding for proteins related to antigen presentation ( HLA‐DPA1/DPB1 and DRB5 ), tyrosine kinases ( GAK ), cell adhesion molecules ( CNTN1 ), lysosomal degradation ( SCARB2, TMEM175 ), synuclein processing ( SPTBN1 ), vesicular transport ( SYT11 ), and many others in the potential pathogenesis of LBD, although their role in disease progression and neuropathology remains to be seen. Finally, emerging studies highlight SNP associations with cognitive and motor features in sporadic PD, suggesting that common genetic variation may also influence clinical heterogeneity in LBD.…”

Section: Genetic Influencesmentioning

confidence: 99%

Pathological Influences on Clinical Heterogeneity in Lewy Body Diseases

2019

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PD, PD with dementia, and dementia with Lewy bodies are clinical syndromes characterized by the neuropathological accumulation of alpha‐synuclein in the CNS that represent a clinicopathological spectrum known as Lewy body disorders. These clinical entities have marked heterogeneity of motor and nonmotor symptoms with highly variable disease progression. The biological basis for this clinical heterogeneity remains poorly understood. Previous attempts to subtype patients within the spectrum of Lewy body disorders have centered on clinical features, but converging evidence from studies of neuropathology and ante mortem biomarkers, including CSF, neuroimaging, and genetic studies, suggest that Alzheimer's disease beta‐amyloid and tau copathology strongly influence clinical heterogeneity and prognosis in Lewy body disorders. Here, we review previous clinical biomarker and autopsy studies of Lewy body disorders and propose that Alzheimer's disease copathology is one of several likely pathological contributors to clinical heterogeneity of Lewy body disorders, and that such pathology can be assessed in vivo. Future work integrating harmonized assessments and genetics in PD, PD with dementia, and dementia with Lewy bodies patients followed to autopsy will be critical to further refine the classification of Lewy body disorders into biologically distinct endophenotypes. This approach will help facilitate clinical trial design for both symptomatic and disease‐modifying therapies to target more homogenous subsets of Lewy body disorders patients with similar prognosis and underlying biology. © 2019 International Parkinson and Movement Disorder Society

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Genome‐wide association study of neocortical Lewy‐related pathology

Cited by 28 publications

References 40 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

Review: Clinical, neuropathological and genetic features of Lewy body dementias

Pathological Influences on Clinical Heterogeneity in Lewy Body Diseases

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