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

Abstract

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.

Pathological Influences on Clinical Heterogeneity in Lewy Body Diseases

“…Genome‐wide association studies (GWAS) comparing statistical frequencies of single‐nucleotide polymorphisms (SNPs) between disease and control populations are an important mechanism for discovery of novel common risk variants. Two recent GWAS in DLB that had pathological validation in a subsection of their subjects confirmed the strong effect of APOE ε4 alleles, GBA , and SNCA genes in the occurrence of DLB, similar to other studies in PD . SNPs in SNCA have been linked to increased SNCA gene expression in sporadic PD .…”

“…SNPs in SNCA have been linked to increased SNCA gene expression in sporadic PD . Interestingly, SNPs in the SNCA gene that associated with PD in previous studies were different than the ones implicated in the occurrence of DLB . 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.…”

A comprehensive analysis of SNCA‐related genetic risk in sporadic parkinson disease

“…5,6,8,10 Adding to the complexity, the secondary signal from the largest meta-GWAS, but not the top hit, also shows association with dementia with Lewy bodies (DLB), a closely related neurodegenerative disorder. 16 It is generally believed that common risk variants affect gene regulation, causing higher intracellular levels of α-synuclein, consistent with the pathogenic effect of increased gene dosage observed in patients with genomic multiplications. 2 However, investigations of SNCA susceptibility SNPs as expression quantitative trait loci (eQTLs) in brain have thus far not yielded sufficient evidence to firmly corroborate this hypothesis.…”

Clinical and neuropathological differences between Parkinson's disease, Parkinson's disease dementia and dementia with Lewy bodies – current issues and future directions

“…; Guerreiro et al . , ). Despite earlier controversy, it appears clear that an ApoE4 allele also confers a higher risk of developing PDD.…”