A comprehensive analysis of dominant and recessive parkinsonism genes in REM sleep behavior disorder

Mufti, Kheireddin; Rudakou, Uladzislau; Yu, Eric; Ruskey, Jennifer A.; Asayesh, Farnaz; Laurent, Sandra B.; Spiegelman, Dan; Arnulf, Isabelle; Hu, Michèle; Montplaisir, Jacques; Gagnon, Jean‐François; Désautels, Alex; Dauvilliers, Yves; Gigli, Gian Luigi; Valente, Mariarosaria; Janes, Francesco; Högl, Birgit; Stefani, Ambra; Holzknecht, Evi; Šonka, Karel; Kemlink, David; Oertel, Wolfgang H.; Janzen, Annette; Plazzi, Giuseppe; Antelmi, Elena; Figorilli, Michela; Puligheddu, Monica; Mollenhauer, Brit; Trenkwalder, Claudia; Sixel‐Döring, Friederike; Cock, Valérie Cochen De; Monaca, Christelle; Heidbreder, Anna; Ferini‐Strambi, Luigi; Dijkstra, Femke; Viaene, Mineke; Abril, Beatriz; Boeve, Bradley F.; Postuma, Ronald B.; Rouleau, Guy A.; Gan‐Or, Ziv

doi:10.1101/2020.03.17.20032664

Cited by 3 publications

(4 citation statements)

References 35 publications

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“…The controls were not examined by polysomnography, but because only 1% of them are expected to develop iRBD, it is unlikely that this can affect the results. Details on age and on sex of the participants have been given previously 15 (data available from Dryad, table e-1, doi.org/10.5061/dryad.vt4b8gtqd ). Differences in age and sex were taken into account as needed in the statistical analysis.…”

Section: Methodsmentioning

confidence: 99%

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Novel Associations of BST1 and LAMP3 With REM Sleep Behavior Disorder

Mufti¹,

Rudakou

et al. 2021

Neurology

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Objective:To examine the role of genes identified through genome-wide association studies (GWASs) of Parkinson disease (PD) in the risk of isolated rapid-eye-movement (REM) sleep behavior disorder (iRBD).Methods:We fully sequenced 25 genes previously identified in GWASs of PD, in a total of 1,039 iRBD patients and 1,852 controls. The role of rare heterozygous variants in these genes was examined using burden tests. The contribution of biallelic variants was further tested. To examine the potential impact of rare nonsynonymous BST1 variants on the protein structure, we performed in silico structural analysis. Finally, we examined the association of common variants using logistic regression adjusted for age and sex.Results:We found an association between rare heterozygous nonsynonymous variants in BST1 and iRBD (p=0.0003 at coverage >50X and 0.0004 at >30X), mainly driven by three nonsynonymous variants (p.V85M, p.I101V and p.V272M) found in 22 (1.2%) controls vs. two (0.2%) patients. All three variants seem to be loss-of-function variants with a potential effect on the protein structure and stability. Rare non-coding heterozygous variants in LAMP3 were also associated with iRBD (p=0.0006 at >30X). We found no association between rare heterozygous variants in the rest of genes and iRBD. Several carriers of biallelic variants were identified, yet there was no overrepresentation in iRBD.Conclusion:Our results suggest that rare coding variants in BST1 and rare non-coding variants in LAMP3 are associated with iRBD. Additional studies are required to replicate these results and examine whether loss-of-function of BST1 could be a therapeutic target.

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Section: Methodsmentioning

confidence: 99%

“…The European ethnicity of the participants was ascertained using GWAS data available in our lab, by performing principle component analysis and clustering with the European cohort available in HapMap v3. Details on age and on sex of the participants have been previously described, 15 and data available from Dryad (Table e-…”

Section: Study Populationmentioning

confidence: 99%

Novel Associations of BST1 and LAMP3 With REM Sleep Behavior Disorder

Mufti¹,

Rudakou

et al. 2021

Neurology

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“…All samples and variants were filtered based on standard quality control process as previously reported [27]. In brief, variants were separated into common and rare by minor allele frequency (MAF) in the cohort.…”

Section: Methodsmentioning

confidence: 99%

Clinical and genetic analysis of Costa Rican patients with Parkinson’s disease

Torrealba‐Acosta

Lobo-Prada

et al. 2020

Preprint

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Background: Parkinson's disease (PD) involves environmental risk and protective factors as well as genetic variance. Most of the research in genomics has been done in subjects of European ancestry leading to sampling bias and leaving Latin American populations underrepresented. Objective: We sought to phenotype and genotype Costa Rican PD cases and controls. Methods: We enrolled 118 PD patients with 97 unrelated controls. Collected information included demographics, exposure to risk and protective factors, motor and cognitive assessments. We sequenced coding and untranslated regions in familial PD and atypical parkinsonism-associated genes including GBA, SNCA, VPS35, LRRK2, GCH1, PRKN, PINK1, DJ-1, VPS13C, ATP13A2. Results: Mean age of PD probands was 62.12 ± 13.51 years, 57.6% were male. Prevalence of risk and protective factors reached 30%. Physical activity significantly correlated with better motor performance despite years of disease. Increased years of education were significantly associated with better cognitive function, whereas hallucinations, falls, mood disorders and coffee consumption correlated with worse cognitive performance. We did not identify an association between tested genes and PD or any damaging homozygous or compound heterozygous variants. Rare variants in LRRK2 were nominally associated with PD, six were located between amino acids p.1620-1623 in the C-terminal-of-ROC (COR) domain of LRRK2. Nonsynonymous GBA variants (p.T369M, p.N370S, p.L444P) were identified in three healthy individuals. One PD patient carried a pathogenic GCH1 variant, p.K224R. Conclusion: This is the first study that reports on sociodemographic, risk factors, clinical presentation and genetics of Costa Rican patients with PD.

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Section: Methodsmentioning

confidence: 99%

Novel associations of BST1 and LAMP3 with rapid eye movement sleep behavior disorder

Mufti

Rudakou

et al. 2020

Preprint

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Isolated rapid-eye-movement (REM) sleep behavior disorder (iRBD) is a parasomnia, characterized by loss of muscle atonia and dream enactment occurring during REM sleep phase. Since a large subgroup of iRBD patients will convert to Parkinson s disease, and since previous genetic studies have suggested common genes, it is likely that there is at least a partial overlap between iRBD and Parkinson s disease genetics. To further examine this potential overlap and to identify genes specifically involved in iRBD, we fully sequenced 25 genes previously identified in genome-wide association studies of Parkinson s disease. The genes were captured and sequenced using targeted next-generation sequencing in a total of 1,039 iRBD patients and 1,852 controls of European ancestry. The role of rare heterozygous variants in these genes was examined using burden tests and optimized sequence Kernel association tests (SKAT-O), adjusted for age and sex. The contribution of biallelic (homozygous and compound heterozygous) variants was further tested in all genes. To examine the association of common variants in the target genes, we used logistic regression adjusted for age and sex. We found a significant association between rare heterozygous nonsynonymous variants in BST1 and iRBD (p=0.0003 at coverage ≥50X and 0.0004 at ≥30X), mainly driven by three nonsynonymous variants (p.V85M, p.I101V and p.V272M) found in a total of 22 (1.2%) controls vs. two (0.2%) patients. Rare non-coding heterozygous variants in LAMP3 were also found to be associated with reduced iRBD risk (p=0.0006 at ≥30X). We found no statistically significant association between rare heterozygous variants in the rest of genes and risk of iRBD. Several carriers of biallelic variants were identified, yet there was no overrepresentation in iRBD patients vs. controls. To examine the potential impact of the rare nonsynonymous BST1 variants on the protein structure, we performed in silico structural analysis. All three variants seem to be loss-of-function variants significantly affecting the protein structure and stability. Our results suggest that rare coding variants in BST1 and rare non-coding variants in LAMP3 are associated with iRBD, and additional studies are required to replicate these results and examine whether loss-of-function of BST1 could be a therapeutic target.

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A comprehensive analysis of dominant and recessive parkinsonism genes in REM sleep behavior disorder

Cited by 3 publications

References 35 publications

Novel Associations of BST1 and LAMP3 With REM Sleep Behavior Disorder

Novel Associations of BST1 and LAMP3 With REM Sleep Behavior Disorder

Clinical and genetic analysis of Costa Rican patients with Parkinson’s disease

Novel associations of BST1 and LAMP3 with rapid eye movement sleep behavior disorder

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