Exome sequencing in dementia with Lewy bodies

Mj, Keogh; Kurzawa‐Akanbi, Marzena; Griffin, Helen; Douroudis, Konstantinos; Ayers, Kristin L.; Hussein, RI; Hudson, Gavin; Pyle, Angela; Cordell, Heather J.; Attems, Johannes; McKeith, Ian G.; Jt, O’Brien; Burn, David J.; Morris, Christopher M.; Aparicio, Thomas; Chinnery, Patrick F.

doi:10.1038/tp.2015.220

Cited by 37 publications

(47 citation statements)

References 26 publications

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“…In support of prior evidence (Keogh, et al, 2016; Tsuang, et al, 2013), the frequency of the APOE ε4 risk allele was significantly higher in our DLB cohort compared to Caucasian controls ( p -value < 0.001) and survival was significantly shorter in APOE ε4 carriers (Supplementary Figure 2). Interestingly, we found no pathogenic mutations in LRRK2, MAPT, PSEN2, SCARB2, and SNCA indicating that mutations in these genes are not a frequent cause of DLB.…”

Section: Discussionsupporting

confidence: 91%

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Next-generation sequencing reveals substantial genetic contribution to dementia with Lewy bodies

Geiger

Ding

Crain

et al. 2016

Neurobiology of Disease

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Dementia with Lewy bodies (DLB) is the second most common neurodegenerative dementia after Alzheimer’s disease. Although an increasing number of genetic factors have been connected to this debilitating condition, the proportion of cases that can be attributed to distinct genetic defects is unknown. To provide a comprehensive analysis of the frequency and spectrum of pathogenic missense mutations and coding risk variants in nine genes previously implicated in DLB, we performed exome sequencing in 111 pathologically confirmed DLB patients. All patients were Caucasian individuals from North America. Allele frequencies of identified missense mutations were compared to 222 control exomes. Remarkably, ~25% of cases were found to carry a pathogenic mutation or risk variant in APP, GBA or PSEN1, highlighting that genetic defects play a central role in the pathogenesis of this common neurodegenerative disorder. In total, 13% of our cohort carried a pathogenic mutation in GBA, 10% of cases carried a risk variant or mutation in PSEN1, and 2% were found to carry an APP mutation. The APOE ε4 risk allele was significantly overrepresented in DLB patients (p-value <0.001). Our results conclusively show that mutations in GBA, PSEN1, and APP are common in DLB and consideration should be given to offer genetic testing to patients diagnosed with Lewy body dementia.

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Section: Discussionsupporting

confidence: 91%

“…After completion of our analysis, a candidate gene study of exome data from a British DLB cohort was published (Keogh, et al, 2016). Similar to our findings, this study found an increased frequency of the APOE ε4 risk allele.…”

Section: Discussionmentioning

confidence: 99%

Next-generation sequencing reveals substantial genetic contribution to dementia with Lewy bodies

Geiger

Ding

Crain

et al. 2016

Neurobiology of Disease

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“…3 Third, even the largest cohorts of dementia with Lewy body samples have been generally small, in many instances including as few as 100 patients. 4,5 However, the fact that dementia with Lewy bodies has a strong genetic component is currently indisputable. The ε4 allele of APOE is recognised to be a strong risk factor, 6,7 as are heterozygous mutations and common polymorphisms in the glucocerebrosidase gene ( GBA ).…”

Section: Introductionmentioning

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

212

240

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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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“…Neuropathological diagnosis of DLB is achieved when the presence of Lewy bodies is confirmed in the cortex and the brainstem (McKeith et al, 2005). Little is known about the genetics of DLB, although molecular studies seem to point toward genetic overlaps with other neurodegenerative diseases, mainly with AD and Parkinson’s disease (PD) (Bras et al, 2014; Guerreiro et al, 2016; Keogh et al, 2016; Meeus et al, 2012). …”

Section: Introductionmentioning

confidence: 99%

Analysis of C9orf72 repeat expansions in a large international cohort of dementia with Lewy bodies

Kun‐Rodrigues¹,

Ross

Orme³

et al. 2017

Neurobiology of Aging

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C9orf72 repeat expansions are a common cause of amyotrophic lateral sclerosis and frontotemporal dementia. To date, no large-scale study of dementia with Lewy bodies (DLB) has been undertaken to assess the role of C9orf72 repeat expansions in the disease. Here, we investigated the prevalence of C9orf72 repeat expansions in a large cohort of DLB cases and identified no pathogenic repeat expansions in neuropathologically or clinically defined cases, showing that C9orf72 repeat expansions are not causally associated with DLB.

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Exome sequencing in dementia with Lewy bodies

Cited by 37 publications

References 26 publications

Next-generation sequencing reveals substantial genetic contribution to dementia with Lewy bodies

Next-generation sequencing reveals substantial genetic contribution to dementia with Lewy bodies

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

Analysis of C9orf72 repeat expansions in a large international cohort of dementia with Lewy bodies

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