Lynne Krohn
A5054839291- Parkinson's Disease Mechanisms and Treatments
- Lysosomal Storage Disorders Research
- Neurological diseases and metabolism
- RNA regulation and disease
- Genetics and Neurodevelopmental Disorders
- Genetic Associations and Epidemiology
- Genomic variations and chromosomal abnormalities
- Autism Spectrum Disorder Research
- Cellular transport and secretion
- Carbohydrate Chemistry and Synthesis
- Genomics and Rare Diseases
- Nuclear Receptors and Signaling
- Restless Legs Syndrome Research
- Neurogenetic and Muscular Disorders Research
- Genomics and Chromatin Dynamics
- Sleep and Wakefulness Research
- Biochemical Analysis and Sensing Techniques
- Child Nutrition and Feeding Issues
- RNA modifications and cancer
- Trypanosoma species research and implications
- Neuroinflammation and Neurodegeneration Mechanisms
- Amyotrophic Lateral Sclerosis Research
- Studies on Chitinases and Chitosanases
- T-cell and B-cell Immunology
- T-cell and Retrovirus Studies
McGill University
2018-2024
Montreal Neurological Institute and Hospital
2018-2024
Alnylam Pharmaceuticals (United States)
2023-2024
Genomics England
2021
Centre For Human Genetics
2018-2020
Abstract Background Increasing evidence supports an extensive and complex genetic contribution to PD. Previous genome‐wide association studies (GWAS) have shed light on the basis of risk for this disease. However, determinants PD age at onset are largely unknown. Objectives To identify onset. Methods Using data 28,568 cases, we performed a study based Results We estimated that heritability attributed common variation was ∼0.11, lower than overall (∼0.27), likely, in part, because subjective...
Parkinson's disease is a genetically complex disorder. Multiple genes have been shown to contribute the risk of disease, and currently 90 independent variants identified by genome-wide association studies. Thus far, number (including SNCA, LRRK2, GBA) contain variability across spectrum frequency effect, from rare, highly penetrant common alleles with small effect sizes. Variants in GBA, encoding enzyme glucocerebrosidase, are associated Lewy body diseases such as dementia. These variants,...
<h3>Importance</h3> Substantial genome-wide association study (GWAS) work in Parkinson disease (PD) has led to the discovery of an increasing number loci shown reliably be associated with increased risk disease. Improved understanding underlying genes and mechanisms at these will key pathogenesis PD. <h3>Objective</h3> To investigate what genomic processes underlie sporadic <h3>Design Setting</h3> This genetic used bioinformatic tools Coloc transcriptome-wide (TWAS) integrate PD case-control...
Parkinson's disease is a neurodegenerative movement disorder that currently has no disease-modifying treatment, partly owing to inefficiencies in drug target identification and validation. We use Mendelian randomization investigate over 3,000 genes encode druggable proteins predict their efficacy as targets for disease. expression protein quantitative trait loci mimic exposure medications, we examine the causal effect on risk (in two large cohorts), age at onset progression. propose 23...
Abstract We performed the largest genome-wide association study of PD to date, involving analysis 7.8M SNPs in 37.7K cases, 18.6K UK Biobank proxy-cases, and 1.4M controls. identified 90 independent significant signals across 78 loci, including 38 risk 37 novel loci. These variants explained 26-36% heritable PD. Tests causality within a Mendelian randomization framework putatively causal genes for 70 signals. Tissue expression enrichment suggested that signatures loci were heavily...
The TMEM175/GAK/DGKQ locus is the 3rd strongest risk in genome-wide association studies of Parkinson disease (PD). We aimed to identify specific disease-associated variants this locus, and their potential implications.Full sequencing followed by genotyping associated was performed PD (n = 1,575) rapid eye movement sleep behavior disorder (RBD) patients 533) controls 1,583). Adjusted regression models a meta-analysis were performed. Association between glucocerebrosidase (GCase) activity...
Abstract Background Parkinson's disease (PD) is a neurodegenerative with an often complex component identifiable by genome‐wide association studies. The most recent large‐scale PD studies have identified more than 90 independent risk variants for and progression across 80 genomic regions. One major challenge in current genomics the identification of causal gene(s) variant(s) at each study locus. objective was to create tool that would display data relevant loci provide guidance...
Abstract Background Parkinson’s disease (PD) is a neurodegenerative movement disorder affecting 1–5% of the general population for which neither effective cure nor early diagnostic tools are available that could tackle pathology in phase. Here we report multi-stage procedure to identify candidate genes likely involved etiopathogenesis PD. Methods The study includes discovery stage based on analysis whole exome data from 26 dominant late onset PD families, validation performed 1542...
Abstract 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, *04:04. Haplotype analyses followed by amino acid analysis conditional suggested that association is protective primarily driven three specific polymorphisms present most *04 subtypes—11V, 13H, 33H...
Rapid-eye movement (REM) sleep behavior disorder (RBD), enactment of dreams during REM sleep, is an early clinical symptom alpha-synucleinopathies and defines a more severe subtype. The genetic background RBD its underlying mechanisms are not well understood. Here, we perform genome-wide association study RBD, identifying five risk loci near SNCA, GBA, TMEM175, INPP5F, SCARB2. Expression analyses highlight SNCA-AS1 potentially SCARB2 differential expression in different brain regions with...
To study the role of GBA variants in risk for isolated REM sleep behavior disorder (iRBD) and conversion to overt neurodegeneration.A total 4,147 individuals were included: 1,061 patients with iRBD 3,086 controls. was fully sequenced using molecular inversion probes Sanger sequencing. We analyzed effects on iRBD, age at onset (AAO), rates.GBA found 9.5% compared 4.1% controls (odds ratio, 2.45; 95% confidence interval [CI], 1.87-3.22; p = 1 × 10-10). The estimated OR mild p.N370S variant...
Understanding how different parts of the immune system contribute to pathogenesis in Parkinson's disease is a burning challenge with important therapeutic implications. We studied enrichment common variant heritability for stratified by and brain cell types.We used summary statistics from most recent meta-analysis genomewide association studies partitioned using linkage disequilibrium score regression, specific types, as defined open chromatin regions. also validated results polygenic risk...
Rapid eye movement sleep behavior disorder (RBD) is a prodromal synucleinopathy, as >80% will eventually convert to overt synucleinopathy. We performed an in-depth analysis of the SNCA locus identify RBD-specific risk variants.Full sequencing and genotyping was in isolated/idiopathic RBD (iRBD, n = 1,076), Parkinson disease (PD, 1,013), dementia with Lewy bodies (DLB, 415), control subjects (n 6,155). The iRBD cases were diagnosed prior neurodegeneration, although some have since converted....
Parkinson's disease (PD) is a complex neurodegenerative disorder. Men are on average ~ 1.5 times more likely to develop PD compared women with European ancestry. Over the years, genomewide association studies (GWAS) have identified numerous genetic risk factors for PD, however, it unclear whether genetics contribute etiology in sex-specific manner.In an effort study associated we explored 2 large datasets from International Disease Genomics Consortium and UK Biobank consisting of 13,020 male...
Background Classical randomisation of clinical trial patients creates a source genetic variance that may be contributing to the high failure rate seen in neurodegenerative disease trials. Our objective was quantify difference between randomised arms and determine how imbalance can affect outcomes. Methods 5851 with Parkinson’s European ancestry data two simulated virtual cohorts based on public were used. Data resampled at different sizes for 1000 iterations randomly assigned trial....
Biallelic PRKN mutation carriers with Parkinson's disease (PD) typically have an earlier onset, slow progression, and, often, different neuropathology compared to sporadic PD patients. However, the role of heterozygous variants in risk is controversial.Our aim was examine association between variants, including single-nucleotide and copy-number variations (CNVs), PD.We fully sequenced 2809 patients 3629 healthy controls, 1965 late-onset (63.97 ± 7.79 years, 63% men) 553 early-onset (43.33...
Genome-wide association studies (GWAS) have identified numerous loci associated with Parkinson's disease. The specific genes and variants that drive the associations within vast majority of these are unknown. We aimed to perform a comprehensive analysis selected determine potential role rare common genetic loci. fully sequenced 32 from 25 previously disease in 2657 patients 3647 controls three cohorts. Capture was done using molecular inversion probes targeting exons, exon-intron boundaries...
Background:Both genetic and environmental factors contribute to Parkinson's disease (PD) risk. Objective:We investigated the potential association of several relevant variables with PD age at onset (AAO), focusing on LRRK2 p.G2019S GBA p.N370S mutations. Methods:Ashkenazi Jewish (AJ) patient s, screened for mutations, underwent an interview regarding exposure following lifestyle factors: cigarette smoking, consumption coffee, tea alcohol, head injury rural living. Multivariate linear...
Loss-of-function mutations in hepatocyte nuclear factor 1A (HNF1A) are known to cause rare forms of diabetes and alter hepatic physiology through unclear mechanisms. In the general population, 1:100 individuals carry a rare, protein-coding