Analysis of neurodegenerative disease-causing genes in dementia with Lewy bodies

Tatiana Orme,David J Stone,David Mann,Afina W Lemstra ,Owen A Ross,Claire Troakes,Geidy E Serrano,Glenda M Halliday ,Henrik Zetterberg,John Hardy,Stuart Pickering‐Brown ,Elisabet Londos,Tammaryn Lashley,Tamás Révész ,Brad Boeve ,Dena G Hernandez ,Dennis W Dickson,Suzanne Lesage,Minna Oinas,Kevin Morgan,Thomas G Beach,Eliezer Masliah,Pentti J Tienari,Claire E Shepherd,Vivianna M Van Deerlin ,Olaf Ansorge,Valentina Escott‐Price ,Andrew Singleton ,Liisa Myllykangas,Janice L Holton ,John Q Trojanowski,Nigel J Cairns,Peter St George‐Hyslop ,Ekaterina Rogaeva,Lawrence S Honig,Célia Kun‐Rodrigues ,Laura Parkkinen,Isabel Santana,Neill R Graff‐Radford ,Lee Darwent,Rita Guerreiro,Tanis J Ferman,Andrew J Lees ,Lorraine N Clark ,Pau Pástor ,John C Morris,Douglas Galasko,Yaroslau Compta,Safa Al‐Sarraj ,Karen Marder,Ronald C Petersen,José Brás

doi:10.1186/s40478-020-0879-z

Abstract

Dementia with Lewy bodies (DLB) is a clinically heterogeneous disorder with a substantial burden on healthcare. Despite this, the genetic basis of the disorder is not well defined and its boundaries with other neurodegenerative diseases are unclear. Here, we performed whole exome sequencing of a cohort of 1118 Caucasian DLB patients, and focused on genes causative of monogenic neurodegenerative diseases. We analyzed variants in 60 genes implicated in DLB, Alzheimer’s disease, Parkinson’s disease, frontotemporal dementia, and atypical parkinsonian or dementia disorders, in order to determine their frequency in DLB. We focused on variants that have previously been reported as pathogenic, and also describe variants reported as pathogenic which remain of unknown clinical significance, as well as variants associated with strong risk. Rare missense variants of unknown significance were found in APP, CHCHD2, DCTN1, GRN, MAPT, NOTCH3, SQSTM1, TBK1 and TIA1. Additionally, we identified a pathogenic GRN p.Arg493* mutation, potentially adding to the diversity of phenotypes associated with this mutation. The rarity of previously reported pathogenic mutations in this cohort suggests that the genetic overlap of other neurodegenerative diseases with DLB is not substantial. Since it is now clear that genetics plays a role in DLB, these data suggest that other genetic loci play a role in this disease.

Highlights

Dementia with Lewy bodies (DLB) is a neurodegenerative disease that shares clinical and pathological features with both Parkinson’s disease (PD) and Alzheimer’s disease (AD)
DLB shares risk loci that are associated with AD or PD, and we have recently shown the genetic correlation between DLB and PD, and DLB and AD, is approximately equal when disregarding APOE [26]
It has been proposed that rare variants in AD and PD causing genes may play a role in sporadic DLB

Summary

Introduction

Dementia with Lewy bodies (DLB) is a neurodegenerative disease that shares clinical and pathological features with both Parkinson’s disease (PD) and Alzheimer’s disease (AD). Families with the disorder are rare, and SNCA multiplications and point mutations have been shown to cause disease in multiplex families of mixed Parkinson’s disease and dementia [31, 63, 77]. DLB shares risk loci that are associated with AD or PD, and we have recently shown the genetic correlation between DLB and PD, and DLB and AD, is approximately equal when disregarding APOE [26]. It has been proposed that rare variants in AD and PD causing genes may play a role in sporadic DLB. These studies have been small, with sample sizes of approximately 100 cases [36, 37, 51]; it is uncertain whether these findings are merely coincidental

Methods

Results

Conclusion