Publications by authors named "Dan Spiegelman"

74 Publications

Fine mapping of the HLA locus in Parkinson's disease in Europeans.

NPJ Parkinsons Dis 2021 Sep 21;7(1):84. Epub 2021 Sep 21.

Department of Human Genetics, McGill University, Montréal, QC, Canada.

We fine mapped the leukocyte antigen (HLA) region in 13,770 Parkinson's disease (PD) patients, 20,214 proxy-cases, and 490,861 controls of European origin. Four HLA types were associated with PD after correction for multiple comparisons, HLA-DQA1*03:01, HLA-DQB1*03:02, HLA-DRB1*04:01, and HLA-DRB1*04:04. Haplotype analyses followed by amino acid analysis and conditional analyses suggested that the association is protective and primarily driven by three specific amino acid polymorphisms present in most HLA-DRB1*04 subtypes-11V, 13H, and 33H (OR = 0.87, 95% CI: 0.83-0.90, p < 8.23 × 10 for all three variants). No other effects were present after adjustment for these amino acids. Our results suggest that specific HLA-DRB1 variants are associated with reduced risk of PD, providing additional evidence for the role of the immune system in PD. Although effect size is small and has no diagnostic significance, understanding the mechanism underlying this association may lead to the identification of new targets for therapeutics development.
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http://dx.doi.org/10.1038/s41531-021-00231-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8455634PMC
September 2021

LRRK2 p.M1646T is associated with glucocerebrosidase activity and with Parkinson's disease.

Neurobiol Aging 2021 07 28;103:142.e1-142.e5. Epub 2021 Feb 28.

Montreal Neurological Institute, McGill University, Montréal, QC, Canada; Department of Neurology and neurosurgery, McGill University, Montréal, QC, Canada. Electronic address:

The LRRK2 p.G2019S Parkinson's disease (PD) variant is associated with elevated glucocerebrosidase (GCase) activity in peripheral blood. We aimed to evaluate the association of other LRRK2 variants with PD and its association with GCase activity. LRRK2 and GBA were fully sequenced in 1123 PD patients and 576 controls from the Columbia and PPMI cohorts, in which GCase activity was measured in dried blood spots by liquid chromatography-tandem mass spectrometry. LRRK2 p.M1646T was associated with increased GCase activity in the Columbia University cohort (β = 1.58, p = 0.0003), and increased but not significantly in the PPMI cohort (β = 0.29, p = 0.58). p.M1646T was associated with PD (odds ratio = 1.18, 95% confidence interval = 1.09-1.28, p = 7.33E-05) in 56,306 PD patients and proxy-cases, and 1.4 million controls. Our results suggest that the p.M1646T variant is associated with risk of PD with a small effect and with increased GCase activity in peripheral blood.
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http://dx.doi.org/10.1016/j.neurobiolaging.2021.02.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8178224PMC
July 2021

Evidence for Non-Mendelian Inheritance in Spastic Paraplegia 7.

Mov Disord 2021 07 17;36(7):1664-1675. Epub 2021 Feb 17.

Department of Human Genetics, McGill University, Montréal, Québec, Canada.

Background: Although the typical inheritance of spastic paraplegia 7 is recessive, several reports have suggested that SPG7 variants may also cause autosomal dominant hereditary spastic paraplegia (HSP).

Objectives: We aimed to conduct an exome-wide genetic analysis on a large Canadian cohort of HSP patients and controls to examine the association of SPG7 and HSP.

Methods: We analyzed 585 HSP patients from 372 families and 1175 controls, including 580 unrelated individuals. Whole-exome sequencing was performed on 400 HSP patients (291 index cases) and all 1175 controls.

Results: The frequency of heterozygous pathogenic/likely pathogenic SPG7 variants (4.8%) among unrelated HSP patients was higher than among unrelated controls (1.7%; OR 2.88, 95% CI 1.24-6.66, P = 0.009). The heterozygous SPG7 p.(Ala510Val) variant was found in 3.7% of index patients versus 0.85% in unrelated controls (OR 4.42, 95% CI 1.49-13.07, P = 0.005). Similar results were obtained after including only genetically-undiagnosed patients. We identified four heterozygous SPG7 variant carriers with an additional pathogenic variant in known HSP genes, compared to zero in controls (OR 19.58, 95% CI 1.05-365.13, P = 0.0031), indicating potential digenic inheritance. We further identified four families with heterozygous variants in SPG7 and SPG7-interacting genes (CACNA1A, AFG3L2, and MORC2). Of these, there is especially compelling evidence for epistasis between SPG7 and AFG3L2. The p.(Ile705Thr) variant in AFG3L2 is located at the interface between hexamer subunits, in a hotspot of mutations associated with spinocerebellar ataxia type 28 that affect its proteolytic function.

Conclusions: Our results provide evidence for complex inheritance in SPG7-associated HSP, which may include recessive and possibly dominant and digenic/epistasis forms of inheritance. © 2021 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28528DOI Listing
July 2021

Novel Associations of and With REM Sleep Behavior Disorder.

Neurology 2021 03 4;96(10):e1402-e1412. Epub 2021 Jan 4.

From the Department of Human Genetics (K.M., E.Y., U.R., L.K., G.A.R., Z.G.-O.), Montreal Neurological Institute (K.M., E.Y., U.R., L.K., J.A.R., F.A., S.B.L., D.S., G.A.R., R.B.P., Z.G.-O.), Department of Neurology and Neurosurgery (J.A.R., F.A., S.B.L., D.S., G.A.R., R.B.P., Z.G.-O.), Centre de Recherche en Biologie Structurale (J.-F.T.), and Department of Pharmacology and Therapeutics (J.-F.T.), McGill University, Montréal, Quebec, Canada; Sleep Disorders Unit (I.A.), Pitié Salpêtrière Hospital, Paris Brain Institute and Sorbonne University, France; Oxford Parkinson's Disease Centre (OPDC) (M.T.M.H.) and Nuffield Department of Clinical Neurosciences (M.T.M.H.), University of Oxford, UK; Center for Advanced Research in Sleep Medicine (J.Y.M., J.-F.G., A.D., R.B.P.), Centre Intégré Universitaire de Santé et de Services Sociaux du Nord-de-l'Île-de-Montréal-Hôpital du Sacré-Coeur de Montréal; Departments of Psychiatry (J.Y.M.) and Neurosciences (A.D.), Université de Montréal; Department of Psychology (J.-F.G.), Université du Québec à Montréal, Canada; National Reference Center for Narcolepsy (Y.D.), Sleep Unit, Department of Neurology, Gui-de-Chauliac Hospital, CHU Montpellier, University of Montpellier, Inserm U1061, France; Clinical Neurology Unit (G.L.G., M.V., F.J., A.B.), Department of Neurosciences, University Hospital of Udine; DMIF (G.L.G.) and Department of Medicine (DAME) (M.V.), University of Udine, Italy; Sleep Disorders Clinic (B.H., A.S., E.H.), Department of Neurology, Medical University of Innsbruck, Austria; Department of Neurology (K.S., D.K.) and Centre of Clinical Neuroscience (K.S., D.K.), Charles University, First Faculty of Medicine and General University Hospital, Prague, Czech Republic; Department of Neurology (W.O., A.J., F.S.-D.), Philipps University, Marburg, Germany; Department of Biomedical, Metabolic and Neural Sciences (G.P.), University of Modena and Reggio-Emilia; IRCCS (G.P.), Institute of Neurological Sciences of Bologna; Neurology Unit (E.A.), Movement Disorders Division, Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona; Department of Medical Sciences and Public Health (M.F., M.P.), Sleep Disorder Research Center, University of Cagliari, Italy; Paracelsus-Elena-Klinik (B.M., C.T., F.S.-D.), Kassel; Department of Neurosurgery (B.M., C.T.), University Medical Centre Göttingen, Germany; Sleep and Neurology Unit (V.C.D.C.), Beau Soleil Clinic; EuroMov Digital Health in Motion (V.C.D.C.), University of Montpellier IMT Mines Ales; University Lille North of France (C.C.M.), Department of Clinical Neurophysiology and Sleep Center, CHU Lille; Department of Sleep Medicine and Neuromuscular Disorders (A.H.), University of Müenster, Germany; Department of Neurological Sciences (L.F.-S.), Università Vita-Salute San Raffaele, Milan, Italy; Laboratory for Sleep Disorders (F.D., M.V.) and Department of Neurology (F.D., M.V.), St. Dimpna Regional Hospital, Geel; Department of Neurology (F.D.), University Hospital Antwerp, Edegem, Belgium; Sleep Disorder Unit (B.A.), Carémeau Hospital, University Hospital of Nîmes, France; and Department of Neurology (B.F.B.), Mayo Clinic, Rochester, MN.

Objective: To examine the role of genes identified through genome-wide association studies (GWASs) of Parkinson disease (PD) in the risk of isolated REM sleep behavior disorder (iRBD).

Methods: We fully sequenced 25 genes previously identified in GWASs of PD in a total of 1,039 patients with iRBD and 1,852 controls. The role of rare heterozygous variants in these genes was examined with burden tests. The contribution of biallelic variants was further tested. To examine the potential effect of rare nonsynonymous 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 and iRBD ( = 0.0003 at coverage >50× and 0.0004 at >30×), driven mainly by 3 nonsynonymous variants (p.V85M, p.I101V, and p.V272M) found in 22 (1.2%) controls vs 2 (0.2%) patients. All 3 variants seem to be loss-of-function variants with a potential effect on the protein structure and stability. Rare noncoding heterozygous variants in were also associated with iRBD ( = 0.0006 at >30×). 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 and rare noncoding variants in are associated with iRBD. Additional studies are required to replicate these results and to examine whether loss of function of could be a therapeutic target.
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http://dx.doi.org/10.1212/WNL.0000000000011464DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8055320PMC
March 2021

Targeted sequencing of Parkinson's disease loci genes highlights SYT11, FGF20 and other associations.

Brain 2021 03;144(2):462-472

Department of Human Genetics, McGill University, Montréal, QC, H3A 1A1, Canada.

Genome-wide association studies (GWAS) have identified numerous loci associated with Parkinson's disease. The specific genes and variants that drive the associations within the vast majority of these loci are unknown. We aimed to perform a comprehensive analysis of selected genes to determine the potential role of rare and common genetic variants within these loci. We fully sequenced 32 genes from 25 loci previously associated with Parkinson's disease in 2657 patients and 3647 controls from three cohorts. Capture was done using molecular inversion probes targeting the exons, exon-intron boundaries and untranslated regions (UTRs) of the genes of interest, followed by sequencing. Quality control was performed to include only high-quality variants. We examined the role of rare variants (minor allele frequency < 0.01) using optimized sequence Kernel association tests. The association of common variants was estimated using regression models adjusted for age, sex and ethnicity as required in each cohort, followed by a meta-analysis. After Bonferroni correction, we identified a burden of rare variants in SYT11, FGF20 and GCH1 associated with Parkinson's disease. Nominal associations were identified in 21 additional genes. Previous reports suggested that the SYT11 GWAS association is driven by variants in the nearby GBA gene. However, the association of SYT11 was mainly driven by a rare 3' UTR variant (rs945006601) and was independent of GBA variants (P = 5.23 × 10-5 after exclusion of all GBA variant carriers). The association of FGF20 was driven by a rare 5' UTR variant (rs1034608171) located in the promoter region. The previously reported association of GCH1 with Parkinson's disease is driven by rare non-synonymous variants, some of which are known to cause dopamine-responsive dystonia. We also identified two LRRK2 variants, p.Arg793Met and p.Gln1353Lys, in 10 and eight controls, respectively, but not in patients. We identified common variants associated with Parkinson's disease in MAPT, TMEM175, BST1, SNCA and GPNMB, which are all in strong linkage disequilibrium with known GWAS hits in their respective loci. A common coding PM20D1 variant, p.Ile149Val, was nominally associated with reduced risk of Parkinson's disease (odds ratio 0.73, 95% confidence interval 0.60-0.89, P = 1.161 × 10-3). This variant is not in linkage disequilibrium with the top GWAS hits within this locus and may represent a novel association. These results further demonstrate the importance of fine mapping of GWAS loci, and suggest that SYT11, FGF20, and potentially PM20D1, BST1 and GPNMB should be considered for future studies as possible Parkinson's disease-related genes.
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http://dx.doi.org/10.1093/brain/awaa401DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7940168PMC
March 2021

Association study of DNAJC13, UCHL1, HTRA2, GIGYF2, and EIF4G1 with Parkinson's disease.

Neurobiol Aging 2021 04 31;100:119.e7-119.e13. Epub 2020 Oct 31.

Montreal Neurological Institute, McGill University, Montréal, Quebec, Canada; Department of Human Genetics, McGill University, Montréal, Quebec, Canada; Department of Neurology and neurosurgery, McGill University, Montréal, Quebec, Canada. Electronic address:

Rare mutations in genes originally discovered in multigenerational families have been associated with increased risk of Parkinson's disease (PD). The involvement of rare variants in DNAJC13, UCHL1, HTRA2, GIGYF2, and EIF4G1 loci has been poorly studied or has produced conflicting results across cohorts. However, they are still being often referred to as "PD genes" and used in different models. To further elucidate the role of these 5 genes in PD, we fully sequenced them using molecular inversion probes in 2408 patients with PD and 3444 controls from 3 different cohorts. A total of 788 rare variants were identified across the 5 genes and 3 cohorts. Burden analyses and optimized sequence Kernel association tests revealed no significant association between any of the genes and PD after correction for multiple comparisons. Our results do not support an association of the 5 tested genes with PD. Combined with previous studies, it is unlikely that any of these genes plays an important role in PD. Their designation as "PARK" genes should be reconsidered.
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http://dx.doi.org/10.1016/j.neurobiolaging.2020.10.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7940813PMC
April 2021

Expanded CAG Repeats in ATXN1, ATXN2, ATXN3, and HTT in the 1000 Genomes Project.

Mov Disord 2021 02 7;36(2):514-518. Epub 2020 Nov 7.

Department of Human Genetics, McGill University, Montréal, Québec, Canada.

Background: Spinocerebellar ataxia types 1, 2, 3 and Huntington disease are neurodegenerative disorders caused by expanded CAG repeats.

Methods: We performed an in-silico analysis of CAG repeats in ATXN1, ATXN2, ATXN3, and HTT using 30× whole-=genome sequencing data of 2504 samples from the 1000 Genomes Project.

Results: Seven HTT-positive, 3 ATXN2-positive, 1 ATXN3-positive, and 6 possibly ATXN1-positive samples were identified. No correlation was found between the repeat sizes of the different genes. The distribution of CAG alleles varied by ethnicity.

Conclusion: Our results suggest that there may be asymptomatic small expanded repeats in almost 0.5% of these populations. © 2020 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28341DOI Listing
February 2021

Comprehensive Analysis of Familial Parkinsonism Genes in Rapid-Eye-Movement Sleep Behavior Disorder.

Mov Disord 2021 01 1;36(1):235-240. Epub 2020 Oct 1.

Paracelsus-Elena-Klinik, Kassel, Germany.

Background: There is only partial overlap in the genetic background of isolated rapid-eye-movement sleep behavior disorder (iRBD) and Parkinson's disease (PD).

Objective: To examine the role of autosomal dominant and recessive PD or atypical parkinsonism genes in the risk of iRBD.

Methods: Ten genes, comprising the recessive genes PRKN, DJ-1 (PARK7), PINK1, VPS13C, ATP13A2, FBXO7, and PLA2G6 and the dominant genes LRRK2, GCH1, and VPS35, were fully sequenced in 1039 iRBD patients and 1852 controls of European ancestry, followed by association tests.

Results: We found no association between rare heterozygous variants in the tested genes and risk of iRBD. Several homozygous and compound heterozygous carriers were identified, yet there was no overrepresentation in iRBD patients versus controls.

Conclusion: Our results do not support a major role for variants in these genes in the risk of iRBD. © 2020 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28318DOI Listing
January 2021

Analysis of Heterozygous PRKN Variants and Copy-Number Variations in Parkinson's Disease.

Mov Disord 2021 01 24;36(1):178-187. Epub 2020 Sep 24.

Department of Human Genetics, McGill University, Montréal, Quebec, Canada.

Background: Biallelic PRKN mutation carriers with Parkinson's disease (PD) typically have an earlier disease onset, slow disease progression, and, often, different neuropathology compared to sporadic PD patients. However, the role of heterozygous PRKN variants in the risk of PD is controversial.

Objectives: Our aim was to examine the association between heterozygous PRKN variants, including single-nucleotide variants and copy-number variations (CNVs), and PD.

Methods: We fully sequenced PRKN in 2809 PD patients and 3629 healthy controls, including 1965 late-onset (63.97 ± 7.79 years, 63% men) and 553 early-onset PD patients (43.33 ± 6.59 years, 68% men). PRKN was sequenced using targeted next-generation sequencing with molecular inversion probes. CNVs were identified using a combination of multiplex ligation-dependent probe amplification and ExomeDepth. To examine whether rare heterozygous single-nucleotide variants and CNVs in PRKN are associated with PD risk and onset, we used optimized sequence kernel association tests and regression models.

Results: We did not find any associations between all types of PRKN variants and risk of PD. Pathogenic and likely-pathogenic heterozygous single-nucleotide variants and CNVs were less common among PD patients (1.52%) than among controls (1.8%, false discovery rate-corrected P = 0.55). No associations with age at onset and in stratified analyses were found.

Conclusions: Heterozygous single-nucleotide variants and CNVs in PRKN are not associated with PD. Molecular inversion probes allow for rapid and cost-effective detection of all types of PRKN variants, which may be useful for pretrial screening and for clinical and basic science studies targeting specifically PRKN patients. © 2020 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28299DOI Listing
January 2021

Transcriptomic Changes Resulting From Overexpression Identify Pathways Potentially Relevant to Essential Tremor.

Front Genet 2020 31;11:813. Epub 2020 Jul 31.

Department of Human Genetics, McGill University, Montreal, QC, Canada.

Essential tremor (ET) is a common movement disorder that has a high heritability. A number of genetic studies have associated different genes and loci with ET, but few have investigated the biology of any of these genes. was significantly associated with ET in a large genome-wide association study (GWAS) and was found to be overexpressed in ET cerebellar tissue. The objective of this study is to determine the effects of overexpressed in cerebellar DAOY cells. Here, we overexpressed RNA in human cerebellar DAOY cells and used an RNA-Seq approach to identify differentially expressed genes (DEGs) by comparing the transcriptome profile of these cells to one of the control DAOY cells. Pathway and gene ontology enrichment identified axon guidance, olfactory signaling, and calcium-voltage channels as significant. Additionally, we show that overexpressing affects transcript levels of previously implicated ET genes such as . Our results investigate the effects of overexpressed and suggest that it may be involved in relevant ET pathways and genes.
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http://dx.doi.org/10.3389/fgene.2020.00813DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7413243PMC
July 2020

Evolution of a Human-Specific Tandem Repeat Associated with ALS.

Am J Hum Genet 2020 09 3;107(3):445-460. Epub 2020 Aug 3.

Division of Medical Genetics, University of Washington School of Medicine, Seattle, WA 98195, USA; Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA. Electronic address:

Tandem repeats are proposed to contribute to human-specific traits, and more than 40 tandem repeat expansions are known to cause neurological disease. Here, we characterize a human-specific 69 bp variable number tandem repeat (VNTR) in the last intron of WDR7, which exhibits striking variability in both copy number and nucleotide composition, as revealed by long-read sequencing. In addition, greater repeat copy number is significantly enriched in three independent cohorts of individuals with sporadic amyotrophic lateral sclerosis (ALS). Each unit of the repeat forms a stem-loop structure with the potential to produce microRNAs, and the repeat RNA can aggregate when expressed in cells. We leveraged its remarkable sequence variability to align the repeat in 288 samples and uncover its mechanism of expansion. We found that the repeat expands in the 3'-5' direction, in groups of repeat units divisible by two. The expansion patterns we observed were consistent with duplication events, and a replication error called template switching. We also observed that the VNTR is expanded in both Denisovan and Neanderthal genomes but is fixed at one copy or fewer in non-human primates. Evaluating the repeat in 1000 Genomes Project samples reveals that some repeat segments are solely present or absent in certain geographic populations. The large size of the repeat unit in this VNTR, along with our multiplexed sequencing strategy, provides an unprecedented opportunity to study mechanisms of repeat expansion, and a framework for evaluating the roles of VNTRs in human evolution and disease.
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http://dx.doi.org/10.1016/j.ajhg.2020.07.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7477013PMC
September 2020

SKOR1 has a transcriptional regulatory role on genes involved in pathways related to restless legs syndrome.

Eur J Hum Genet 2020 11 22;28(11):1520-1528. Epub 2020 Jun 22.

Department of Human Genetics, McGill University, Montréal, QC, Canada.

Restless legs syndrome (RLS) is a common sleep-related sensory-motor disorder. It is characterized by uncomfortable sensations in the legs during the evening or at night. The symptoms can be partially relieved by movement, so typically affected individual needs to walk during rest time; this interferes with sleep. GWAS have identified 19 RLS-associated loci. Among the first to be reported and most significant and robustly replicated reports are variants in the SKOR1 noncoding regions. SKOR1 is highly expressed in the CNS of humans and mice. Skor1 acts as a corepressor of Lbx1 transcription factor in mice and these two genes act together to regulate the cell fate of interneurons in the dorsal horn of the spinal cord. Based on this data we investigated the regulatory role of SKOR1 using a global RNA-sequencing approach in human cell lines where SKOR1 was either overexpressed or silenced. For this work we generated and validated a new poly-clonal anti-SKOR1. Pathway and gene set enrichment analyses of the differentially expressed genes showed, among others, enrichment of genes involved in neurodevelopment and iron metabolism, two RLS relevant pathways that were previously found to be enriched in the latest RLS GWAS meta-analysis. Analysis of our different datasets further supports and highlights the regulatory role of SKOR1, which when dysregulated might represent a key pathogenic element of RLS. A better understanding of SKOR1 and its activity could open new avenues of investigation for the development of a much-needed therapy.
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http://dx.doi.org/10.1038/s41431-020-0670-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7576175PMC
November 2020

Oligogenicity, C9orf72 expansion, and variant severity in ALS.

Neurogenetics 2020 07 8;21(3):227-242. Epub 2020 May 8.

Department of Human Genetics, McGill University, Montréal, QC, Canada.

"Oligogenic inheritance" is used to describe cases where more than one rare pathogenic variant is observed in the same individual. While multiple variants can alter disease presentation, the necessity of multiple variants to instigate pathogenesis has not been addressed in amyotrophic lateral sclerosis (ALS). We sequenced ALS-associated genes in C9orf72-expansion-positive and negative ALS patients, alongside unaffected controls, to test the importance of oligogenicity and variant deleteriousness in ALS. We found that all groups had similar numbers of rare variants, but that variant severity was significantly higher in C9orf72-negative ALS cases, suggesting sufficiency of C9orf72 expansion to cause ALS alone.
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http://dx.doi.org/10.1007/s10048-020-00612-7DOI Listing
July 2020

Variants in the Niemann-Pick type C gene NPC1 are not associated with Parkinson's disease.

Neurobiol Aging 2020 09 8;93:143.e1-143.e4. Epub 2020 Apr 8.

Montreal Neurological Institute, McGill University, Montréal, Quebec, Canada; Department of Neurology and neurosurgery, McGill University, Montréal, Quebec, Canada; Department of Human Genetics, McGill University, Montréal, Quebec, Canada. Electronic address:

Biallelic variants in NPC1, a gene coding for a lysosomal transmembrane protein involved in cholesterol trafficking, may cause Niemann-Pick disease type C (NPC). A few cases of NPC1 variant carriers with Parkinson's disease (PD) have been reported. In addition, pathologic studies have demonstrated phosphorylated alpha-synuclein and Lewy pathology in brains of NPC patients. Therefore, we aimed to examine whether NPC1 genetic variants may be associated with PD. Full sequencing of NPC1 was performed in 2657 PD patients and 3647 controls from 3 cohorts, using targeted sequencing with molecular inversion probes. A total of 9 common variants and 126 rare variants were identified across the 3 cohorts. To examine their association with PD, regression models adjusted for age, sex, and origin were performed for common variants, and optimal sequence Kernel association test (SKAT-O) was performed for rare variants. After correction for multiple comparisons, common and rare NPC1 variants were not associated with PD. Our results do not support a link between heterozygous variants in NPC1 and PD.
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http://dx.doi.org/10.1016/j.neurobiolaging.2020.03.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7302975PMC
September 2020

Multiomics Analyses Identify Genes and Pathways Relevant to Essential Tremor.

Mov Disord 2020 07 6;35(7):1153-1162. Epub 2020 Apr 6.

Department of Human Genetics, McGill University, Montréal, Quebec, Canada.

Introduction: The genetic factors and molecular mechanisms predisposing to essential tremor (ET) remains largely unknown.

Objective: The objective of this study was to identify pathways and genes relevant to ET by integrating multiomics approaches.

Methods: Case-control RNA sequencing of 2 cerebellar regions was done for 64 samples. A phenome-wide association study (pheWAS) of the differentially expressed genes was conducted, and a genome-wide gene association study (GWGAS) was done to identify pathways overlapping with the transcriptomic data. Finally, a transcriptome-wide association study (TWAS) was done to identify novel risk genes for ET.

Results: We identified several novel dysregulated genes, including CACNA1A and SHF. Pathways including axon guidance, olfactory loss, and calcium channel activity were significantly enriched. The ET GWGAS data found calcium ion-regulated exocytosis of neurotransmitters to be significantly enriched. The TWAS also found calcium and olfactory pathways enriched. The pheWAS identified that the underexpressed differentially expressed gene, SHF, is associated with a blood pressure medication (P = 9.3E-08), which is used to reduce tremor in ET patients. Treatment of cerebellar DAOY cells with the ET drug propranolol identified increases in SHF when treated, suggesting it may rescue the underexpression.

Conclusion: We found that calcium-related pathways were enriched across the GWGAS, TWAS, and transcriptome. SHF was shown to have significantly decreased expression, and the pheWAS showed it was associated with blood pressure medication. The treatment of cells with propranolol showed that the drug restored levels of SHF. Overall, our findings highlight the power of integrating multiple different approaches to prioritize ET pathways and genes. © 2020 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28031DOI Listing
July 2020

Analysis of common and rare variants in late-onset Parkinson disease.

Neurol Genet 2020 Feb 9;6(1):385. Epub 2020 Jan 9.

Department of Human Genetics (U.R., L.K., G.A.R, Z.G.-O.), McGill University, Montréal; Montreal Neurological Institute (U.R., J.A.R., L.K., S.B.L., D.S., G.A.R., E.A.F.Z.G.-O.), McGill University; Department of Neurology and Neurosurgery (J.A.R., S.B.L., D.S., G.A.R., E.A.F., Z.G.-O.), McGill University, Montréal, Québec, Canada; The Danek Gertner Institute of Human Genetics, Sheba Medical Center (L.G.); The Joseph Sagol Neuroscience Center (L.G., S.H.-B.), Sheba Medical Center, Tel Hashomer, Ramat Gan; Sackler School of Medicine (L.G., G.Y., S.H.-B.), Tel-Aviv University; Department of Neurology (G.Y., S.H.-B.), Sheba Medical Center; Movement Disorders Institute (G.Y., S.H.-B.), Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel; Centre d'Études Avancées en Médecine du Sommeil (A.D., J.Y.M.), Hôpital du Sacré-Cœur de Montréal; Department of Neurosciences (A.D.), Université de Montréal; Department of Psychiatry (J.Y.M.), Université de Montréal, Québec, Canada; Department of Neurology (S.F., C.H.W., O.L., C.M.K., S.N., R.N.A.), College of Physicians and Surgeons, Columbia University Medical Center, New York; Department of Neurology (Y.D.), National Reference Center for Narcolepsy, Sleep Unit, Gui-de-Chauliac Hospital, CHU Montpellier, University of Montpellier, Inserm, France; Division of Neurosciences (N.D.), CHU de Québec, Université Laval; Department of Medicine (N.D.), Faculty of Medicine, Université Laval, Québec City, Canada; and Taub Institute for Research on Alzheimer's Disease and the Aging Brain (R.N.A.), College of Physicians and Surgeons, Columbia University Medical Center, New York.

Objective: We aimed to study the role of coding variants in a large cohort of patients with late-onset Parkinson disease (PD) (LOPD).

Methods: and its untranslated regions were sequenced using targeted next-generation sequencing in 1,567 patients with PD and 1,667 controls from 3 cohorts. Association tests of rare potential homozygous and compound heterozygous variants and burden tests for rare heterozygous variants were performed. Common variants were analyzed using logistic regression adjusted for age and sex in each of the cohorts, followed by a meta-analysis.

Results: No biallelic carriers of rare variants were found among patients, and 2 carriers of compound heterozygous variants were found in 2 controls. There was no statistically significant burden of rare (minor allele frequency [MAF] <1%) or very rare (MAF <0.1%) coding variants in PD. A haplotype including the p.R153H-p.I398I-p.I1132V-p.Q2376Q variants was nominally associated with a reduced risk for PD (meta-analysis of the tagging SNP p.I1132V [odds ratio = 0.48, 95% confidence interval = 0.28-0.82, = 0.0052]). This haplotype was not in linkage disequilibrium with the known genome-wide association study top hit.

Conclusions: Our results do not support a role for rare heterozygous or biallelic variants in LOPD. Additional genetic replication and functional studies are needed to examine the role of the haplotype identified here associated with reduced risk for PD.
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http://dx.doi.org/10.1212/NXG.0000000000000385DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6984134PMC
February 2020

Clinical and genetic analysis of ATP13A2 in hereditary spastic paraplegia expands the phenotype.

Mol Genet Genomic Med 2020 03 15;8(3):e1052. Epub 2020 Jan 15.

Department of Human Genetics, McGill University, Montréal, QC, Canada.

Background: Hereditary spastic paraplegias (HSP) are neurodegenerative disorders characterized by lower limb spasticity and weakness, with or without additional symptoms. Mutations in ATP13A2, known to cause Kufor-Rakeb syndrome (KRS), have been recently implicated in HSP.

Methods: Whole-exome sequencing was done in a Canada-wide HSP cohort.

Results: Three additional patients with homozygous ATP13A2 mutations were identified, representing 0.7% of all HSP families. Spastic paraplegia was the predominant feature, all patients suffered from psychiatric symptoms, and one patient had developed seizures. Of the identified mutations, c.2126G>C;(p.[Arg709Thr]) is novel, c.2158G>T;(p.[Gly720Trp]) has not been reported in ATP13A2-related diseases, and c.2473_2474insAAdelC;p.[Leu825Asnfs*32]) has been previously reported in KRS but not in HSP. Structural analysis of the mutations suggested a disruptive effect, and enrichment analysis suggested the potential involvement of specific pathways.

Conclusion: Our study suggests that in HSP patients with psychiatric symptoms, ATP13A2 mutations should be suspected, especially if they also have extrapyramidal symptoms.
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http://dx.doi.org/10.1002/mgg3.1052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7057081PMC
March 2020

Genetic, Structural, and Functional Evidence Link TMEM175 to Synucleinopathies.

Ann Neurol 2020 01 18;87(1):139-153. Epub 2019 Nov 18.

Center for Advanced Research in Sleep Medicine, Sacred Heart Hospital of Montreal, Montreal, Quebec, Canada.

Objective: The TMEM175/GAK/DGKQ locus is the 3rd strongest risk locus in genome-wide association studies of Parkinson disease (PD). We aimed to identify the specific disease-associated variants in this locus, and their potential implications.

Methods: Full sequencing of TMEM175/GAK/DGKQ followed by genotyping of specific associated variants was performed in PD (n = 1,575) and rapid eye movement sleep behavior disorder (RBD) patients (n = 533) and in controls (n = 1,583). Adjusted regression models and a meta-analysis were performed. Association between variants and glucocerebrosidase (GCase) activity was analyzed in 715 individuals with available data. Homology modeling, molecular dynamics simulations, and lysosomal localization experiments were performed on TMEM175 variants to determine their potential effects on structure and function.

Results: Two coding variants, TMEM175 p.M393T (odds ratio [OR] = 1.37, p = 0.0003) and p.Q65P (OR = 0.72, p = 0.005), were associated with PD, and p.M393T was also associated with RBD (OR = 1.59, p = 0.001). TMEM175 p.M393T was associated with reduced GCase activity. Homology modeling and normal mode analysis demonstrated that TMEM175 p.M393T creates a polar side-chain in the hydrophobic core of the transmembrane, which could destabilize the domain and thus impair either its assembly, maturation, or trafficking. Molecular dynamics simulations demonstrated that the p.Q65P variant may increase stability and ion conductance of the transmembrane protein, and lysosomal localization was not affected by these variants.

Interpretation: Coding variants in TMEM175 are likely to be responsible for the association in the TMEM175/GAK/DGKQ locus, which could be mediated by affecting GCase activity. ANN NEUROL 2020;87:139-153.
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http://dx.doi.org/10.1002/ana.25629DOI Listing
January 2020

Transcriptome-wide association study of attention deficit hyperactivity disorder identifies associated genes and phenotypes.

Nat Commun 2019 10 1;10(1):4450. Epub 2019 Oct 1.

Department of Human Genetics, McGill University, Montréal, QC, Canada.

Attention deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental psychiatric disorder. Genome-wide association studies (GWAS) have identified several loci associated with ADHD. However, understanding the biological relevance of these genetic loci has proven to be difficult. Here, we conduct an ADHD transcriptome-wide association study (TWAS) consisting of 19,099 cases and 34,194 controls and identify 9 transcriptome-wide significant hits, of which 6 genes were not implicated in the original GWAS. We demonstrate that two of the previous GWAS hits can be largely explained by expression regulation. Probabilistic causal fine-mapping of TWAS signals prioritizes KAT2B with a posterior probability of 0.467 in the dorsolateral prefrontal cortex and TMEM161B with a posterior probability of 0.838 in the amygdala. Furthermore, pathway enrichment identifies dopaminergic and norepinephrine pathways, which are highly relevant for ADHD. Overall, our findings highlight the power of TWAS to identify and prioritize putatively causal genes.
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http://dx.doi.org/10.1038/s41467-019-12450-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6773763PMC
October 2019

SPTAN1 variants as a potential cause for autosomal recessive hereditary spastic paraplegia.

J Hum Genet 2019 Nov 12;64(11):1145-1151. Epub 2019 Sep 12.

Department of Human Genetics, McGill University, Montréal, QC, Canada.

More than 80 known or suspected genes/loci have been reported to be involved in hereditary spastic paraplegia (HSP). Genetic and clinical overlap have been reported between HSP and other neurological condition, yet about 50% of HSP patients remain genetically undiagnosed. To identify novel genes involved in HSP, we performed a genetic analysis of 383 HSP patients from 289 families with HSP. Two patients with biallelic SPTAN1 variants were identified; one carried the c.2572G>T p.(Ala858Ser) and c.4283C>G p.(Ala1428Gly) variants, and the second also carried the c.2572G>T p.(Ala858Ser) variant, and an additional variant, c.6990G>C p.(Met2330Ile). In silico predictive and structural analyses suggested that these variants are likely to be deleterious. SPTAN1 was highly intolerant for functional variants (in the top 0.31% of intolerant genes) with much lower observed vs. expected number of loss-of-function variants (8 vs. 142.7, p < 5 × 10). Using public databases of animal models and previously published data, we have found previously described zebrafish, mouse, and rat animal models of SPTAN1 deficiency, all consistently showing axonal degeneration, fitting the pathological features of HSP in humans. This study expands the phenotype of SPTAN1 mutations, which at the heterozygous state, when occurred de novo, may cause early infantile epileptic encephalopathy-5 (EIEE5). Our results further suggest that SPTAN1 may cause autosomal recessive HSP, and that it should be included in genetic screening panels for genetically undiagnosed HSP patients.
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http://dx.doi.org/10.1038/s10038-019-0669-2DOI Listing
November 2019

Genetic architecture and adaptations of Nunavik Inuit.

Proc Natl Acad Sci U S A 2019 08 22;116(32):16012-16017. Epub 2019 Jul 22.

Montreal Neurological Institute and Hospital, McGill University, Montréal, Québec, Canada H3A 2B4;

The Canadian Inuit have a distinct population background that may entail particular implications for the health of its individuals. However, the number of genetic studies examining this Inuit population is limited, and much remains to be discovered in regard to its genetic characteristics. In this study, we generated whole-exome sequences and genomewide genotypes for 170 Nunavik Inuit, a small and isolated founder population of Canadian Arctic indigenous people. Our study revealed the genetic background of Nunavik Inuit to be distinct from any known present-day population. The majority of Nunavik Inuit show little evidence of gene flow from European or present-day Native American peoples, and Inuit living around Hudson Bay are genetically distinct from those around Ungava Bay. We also inferred that Nunavik Inuit have a small effective population size of 3,000 and likely split from Greenlandic Inuit ∼10.5 kya. Nunavik Inuit went through a bottleneck at approximately the same time and might have admixed with a population related to the Paleo-Eskimos. Our study highlights population-specific genomic signatures in coding regions that show adaptations unique to Nunavik Inuit, particularly in pathways involving fatty acid metabolism and cellular adhesion (, , , and ). Subsequent analyses in selection footprints and the risk of intracranial aneurysms (IAs) in Nunavik Inuit revealed an exonic variant under weak negative selection to be significantly associated with IA (rs77470587; = 4.6 × 10).
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http://dx.doi.org/10.1073/pnas.1810388116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6689950PMC
August 2019

SMPD1 mutations, activity, and α-synuclein accumulation in Parkinson's disease.

Mov Disord 2019 04 20;34(4):526-535. Epub 2019 Feb 20.

Montreal Neurological Institute, McGill University, Montréal, QC, Canada.

Background: SMPD1 (acid-sphingomyelinase) variants have been associated with Parkinson's disease in recent studies. The objective of this study was to further investigate the role of SMPD1 mutations in PD.

Methods: SMPD1 was sequenced in 3 cohorts (Israel Ashkenazi Jewish cohort, Montreal/Montpellier, and New York), including 1592 PD patients and 975 controls. Additional data were available for 10,709 Ashkenazi Jewish controls. Acid-sphingomyelinase activity was measured by a mass spectrometry-based assay in the New York cohort. α-Synuclein levels were measured in vitro following CRISPR/Cas9-mediated knockout and siRNA knockdown of SMPD1 in HeLa and BE(2)-M17 cells. Lysosomal localization of acid-sphingomyelinase with different mutations was studied, and in silico analysis of their effect on acid-sphingomyelinase structure was performed.

Results: SMPD1 mutations were associated with PD in the Ashkenazi Jewish cohort, as 1.4% of PD patients carried the p.L302P or p.fsP330 mutation, compared with 0.37% in 10,709 Ashkenazi Jewish controls (OR, 3.7; 95%CI, 1.6-8.2; P = 0.0025). In the Montreal/Montpellier cohort, the p.A487V variant was nominally associated with PD (1.5% versus 0.14%; P = 0.0065, not significant after correction for multiple comparisons). Among PD patients, reduced acid-sphingomyelinase activity was associated with a 3.5- to 5.8-year earlier onset of PD in the lowest quartile versus the highest quartile of acid-sphingomyelinase activity (P = 0.01-0.001). We further demonstrated that SMPD1 knockout and knockdown resulted in increased α-synuclein levels in HeLa and BE(2)-M17 dopaminergic cells and that the p.L302P and p.fsP330 mutations impair the traffic of acid-sphingomyelinase to the lysosome.

Conclusions: Our results support an association between SMPD1 variants, acid-sphingomyelinase activity, and PD. Furthermore, they suggest that reduced acid-sphingomyelinase activity may lead to α-synuclein accumulation. © 2019 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.27642DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6469643PMC
April 2019

Screening of novel restless legs syndrome-associated genes in French-Canadian families.

Neurol Genet 2018 Dec 20;4(6):e296. Epub 2018 Dec 20.

Department of Human Genetics (F.A., Z.G.-O., G.A.R.), McGill University; Montreal Neurological Institute (F.A., D.S., A.D.-L., Z.G.-O., P.A.D., G.A.R.), McGill University; and Department of Neurology and Neurosurgery (Z.G.-O., P.A.D., G.A.R.), McGill University, Montréal, Quebec, Canada.

Objective: To examine whether any rare, protein-altering variants could be identified across 13 recently identified restless legs syndrome (RLS) loci in familial French-Canadian cases.

Methods: Whole-exome sequences from 7 large French-Canadian families (4-8 affected per family for a total of 38 cases) were examined for variants in any genes located within 1 Mb on either side of each locus.

Results: Among the 43 rare protein-altering variants identified, none segregated with RLS in the families.

Conclusions: Our study does not support a role for causative protein-altering variants in the genes that are located either in the previously or newly identified RLS loci. It is therefore possible that noncoding regulatory variants within these loci or yet unidentified loci could be the cause of RLS in our families.
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http://dx.doi.org/10.1212/NXG.0000000000000296DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6305992PMC
December 2018

Whole exome sequencing identifies novel predisposing genes in neural tube defects.

Mol Genet Genomic Med 2019 01 10;7(1):e00467. Epub 2018 Nov 10.

IRCCS Istituto Giannina Gaslini, Genoa, Italy.

Background: Neural tube defects (NTD) are among the most common defects affecting 1:1000 births. They are caused by a failure of neural tube closure during development. Their clinical presentation is diverse and dependent on the site and severity of the original defect on the embryonic axis. The etiology of NTD is multifactorial involving environmental factors and genetic variants that remain largely unknown.

Methods: We have conducted a whole exome sequencing (WES) study in five new NTD families and pooled the results with WES data from three NTD families and 43 trios that were previously investigated by our group. We analyzed the data using biased candidate gene and unbiased gene burden approaches.

Results: We identified four novel loss-of-function variants in three genes, MTHFR, DLC1, and ITGB1, previously associated with NTD. Notably, DLC1 carried two protein truncating variants in two independent cases. We also demonstrated an enrichment of variants in MYO1E involved in cytoskeletal remodeling. This enrichment reached borderline significance in a replication cohort supporting the association of this new candidate gene to NTD.

Conclusion: These data provide some key insights into the pathogenic mechanisms of human NTD and demonstrate the power of next-generation sequencing in deciphering the genetics of this complex trait.
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http://dx.doi.org/10.1002/mgg3.467DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6382446PMC
January 2019

Triple A syndrome presenting as complicated hereditary spastic paraplegia.

Mol Genet Genomic Med 2018 11 31;6(6):1134-1139. Epub 2018 Oct 31.

Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada.

Background: Hereditary spastic paraplegia (HSP) is a group of rare disorders characterized by spastic paraparesis and other symptoms. Often, other diseases can mimic HSP, which may delay diagnosis and treatment.

Methods: Whole exome sequencing was performed in families with clinically suspected HSP without a genetic diagnosis.

Results: We report three patients from two families who presented with lower limb spasticity, muscular atrophy, and other neurological symptoms, who were clinically diagnosed with complicated HSP. Whole exome sequencing revealed bi-allelic AAAS nonsense mutations; one individual was homozygous for the p.(Arg478*) mutation, and two siblings were homozygous for the p.(Arg286*) mutation, leading to the diagnosis of triple A syndrome. This rare syndrome is typically characterized by a triad of symptoms: achalasia, adrenal insufficiency, and alacrima, and is often accompanied by other neurological abnormalities.

Conclusions: Our findings suggest that triple A syndrome should be suspected in complicated HSP patients without a known genetic cause, especially if at least one of the main triad of triple A syndrome symptoms is present.
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http://dx.doi.org/10.1002/mgg3.492DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6305671PMC
November 2018

Exome sequencing of sporadic childhood-onset schizophrenia suggests the contribution of X-linked genes in males.

Am J Med Genet B Neuropsychiatr Genet 2019 09 30;180(6):335-340. Epub 2018 Oct 30.

Department of Neurology and Neurosurgery, McGill University, Montreal, Canada.

Childhood-onset schizophrenia (COS) is a rare and severe form of schizophrenia, defined as having an onset before the age of 13. The male COS cases have a slightly younger age of onset than female cases. They also present with a higher rate of comorbid developmental disorders. These sex differences are not explained by the frequency of chromosomal abnormalities, and the contribution of other forms of genetic variations remains unestablished. Using a whole-exome sequencing approach, we examined 12 COS trios where the unaffected parents had an affected male child. The sequencing data enabled us to test if the hemizygous variants, transmitted from the unaffected carrying mother, could mediate the phenotype (X-linked recessive inheritance model). Our results revealed that affected children have a significantly greater number of X-linked rare variants than their unaffected fathers. The variants identified in the male probands were mostly found in genes previously linked to other neuropsychiatric diseases like autism, intellectual disability, and epilepsy, including LUZP4, PCDH19, RPS6KA3, and OPHN1. The level of expression of the genes was assessed at different developmental periods in normal brain using the BrainSpan database. This approach revealed that some of them were expressed earlier in males than in females, consistent with the younger age of onset in male COS. In conclusion, this article suggests that X-linked genes might play a role in the pathophysiology of COS. Candidate genes detailed here could explain the higher level of comorbidities and the earlier age of onset observed in a subset of the male COS cases.
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http://dx.doi.org/10.1002/ajmg.b.32683DOI Listing
September 2019

Absence of Mutation Enrichment for Genes Phylogenetically Conserved in the Olivocerebellar Motor Circuitry in a Cohort of Canadian Essential Tremor Cases.

Mol Neurobiol 2019 Jun 12;56(6):4317-4321. Epub 2018 Oct 12.

Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada.

Essential Tremor is a prevalent neurological disorder of unknown etiology. Studies suggest that genetic factors contribute to this pathology. To date, no causative mutations in a gene have been reproducibly reported. All three structures of the olivocerebellar motor circuitry have been linked to Essential Tremor. We postulated that genes enriched for their expression in the olivocerebellar circuitry would be more susceptible to harbor mutations in Essential Tremor patients. A list of 11 candidate genes, enriched for their expression in the olivocerebellar circuitry, was assessed for their variation spectrum and frequency in a cohort of Canadian Essential Tremor cases. Our results from this list of 11 candidate genes do not support an association for Essential Tremor in our cohort of Canadian cases. The heterogenic nature of ET and modest size of the cohort used in this study are two confounding factors that could explain these results.
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http://dx.doi.org/10.1007/s12035-018-1369-1DOI Listing
June 2019

Common and rare GCH1 variants are associated with Parkinson's disease.

Neurobiol Aging 2019 01 15;73:231.e1-231.e6. Epub 2018 Sep 15.

Department of Human Genetics, McGill University, Montréal, Quebec, Canada; Montreal Neurological Institute, McGill University, Montréal, Quebec, Canada; Department of Neurology and Neurosurgery, McGill University, Montréal, Quebec, Canada. Electronic address:

GCH1 encodes the enzyme guanosine triphospahte (GTP) cyclohydrolase 1, essential for dopamine synthesis in nigrostriatal cells, and rare mutations in GCH1 may lead to Dopa-responsive dystonia (DRD). While GCH1 is implicated in genomewide association studies in Parkinson's disease (PD), only a few studies examined the role of rare GCH1 variants in PD, with conflicting results. In the present study, GCH1 and its 5' and 3' untranslated regions were sequenced in 1113 patients with PD and 1111 controls. To examine the association of rare GCH1 variants with PD, burden analysis was performed. Three rare GCH1 variants, which were previously reported to be pathogenic in DRD, were found in five patients with PD and not in controls (sequence Kernel association test, p = 0.024). A common haplotype, tagged by rs841, was associated with a reduced risk for PD (OR = 0.71, 95% CI = 0.61-0.83, p = 1.24 × 10), and with increased GCH1 expression in brain regions relevant for PD (www.gtexportal.org). Our results support a role for rare, DRD-related variants, and common GCH1 variants in the pathogenesis of PD.
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http://dx.doi.org/10.1016/j.neurobiolaging.2018.09.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6251729PMC
January 2019

Sequencing of the GBA coactivator, Saposin C, in Parkinson disease.

Neurobiol Aging 2018 12 2;72:187.e1-187.e3. Epub 2018 Jul 2.

Montreal Neurological Institute, McGill University, Montréal, QC, Canada; Department of Neurology and Neurosurgery, McGill University, Montréal, QC, Canada; McGill Parkinson Program and Neurodegenerative Diseases Group, Montreal Neurological Institute, McGill University, Montréal, QC, Canada; Department of Human Genetics, McGill University, Montréal, QC, Canada. Electronic address:

Saposin C (SapC), encoded by PSAP, is required for the activity of glucocerebrosidase, encoded by GBA. Although GBA mutations have been studied thoroughly in Parkinson disease (PD), genetic studies on SapC are still lacking. PSAP was sequenced in 1123 PD patients and 1153 controls, and data from additional 1167 patients and 1685 controls were examined. A total of 6 patients had SapC mutations in the 2 combined cohorts, but no statistically significant association after correction for multiple comparisons was found. Larger studies are necessary to examine the role of very rare SapC variants in PD.
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http://dx.doi.org/10.1016/j.neurobiolaging.2018.06.034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6215722PMC
December 2018
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