Allele-specific expression of Parkinson’s disease susceptibility genes in human brain

Langmyhr, Margrete; Henriksen, Sandra Pilar; Cappelletti, Chiara; Berg, Wilma D. J. van de; Pihlstrøm, Lasse; Toft, Mathias

doi:10.1038/s41598-020-79990-9

Cited by 17 publications

(14 citation statements)

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“…Allele-specific approaches are used to investigate gene regulation by detecting differences in expression of each allele at a particular locus ( 1 ). While previous studies have investigated the specific genomic location, tissue specificity, and disease phenotype impact of allele-specific expression (ASE) ( 2 – 7 ), few have documented how evolutionary forces, such as natural selection and genetic drift, regulate gene expression evolution genome wide ( 8 , 9 ). In addition to evolutionary forces and population demographics, variability in gene expression explained by genic interactions with the environment has been limited to only a few instances where external environmental exposures have been measured ( 10 – 14 ).…”

Section: Introductionmentioning

confidence: 99%

Recombination affects allele-specific expression of deleterious variants in human populations

et al. 2022

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How the genetic composition of a population changes through stochastic processes, such as genetic drift, in combination with deterministic processes, such as selection, is critical to understanding how phenotypes vary in space and time. Here, we show how evolutionary forces affecting selection, including recombination and effective population size, drive genomic patterns of allele-specific expression (ASE). Integrating tissue-specific genotypic and transcriptomic data from 1500 individuals from two different cohorts, we demonstrate that ASE is less often observed in regions of low recombination, and loci in high or normal recombination regions are more efficient at using ASE to underexpress harmful mutations. By tracking genetic ancestry, we discriminate between ASE variability due to past demographic effects, including subsequent bottlenecks, versus local environment. We observe that ASE is not randomly distributed along the genome and that population parameters influencing the efficacy of natural selection alter ASE levels genome wide.

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Section: Introductionmentioning

confidence: 99%

Recombination affects allele-specific expression of deleterious variants in human populations

et al. 2022

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“…For the other six probable fast motor progression associated genes, allele-specific expression of TMEM175 is identified in human brain [43], and TMEM175 deficiency could lead to lysosomal and mitochondrial dysfunction, as well as α-synuclein deposition [44]. In the PD risk protein coding genetic interaction network (Fig.…”

Section: Discussionmentioning

confidence: 99%

Rapid motor progression of Parkinson’s disease associates with clinical and genetic variants

Cao¹,

Jiang²,

Piao³

et al. 2021

Front Biosci (Landmark Ed)

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Introduction 3. Material and methods 3.1 Participants 3.2 Baseline evaluations 3.3 Five-year follow-up evaluation 3.4 Genotyping and selection of SNPs 3.5 Statistical analysis 3.6 Bioinformatics analysis 4. Results 4.1 Clinical observations 4.2 Genetic associations with longitudinal motor progression 4.3 ROC curve analysis 4.4 Analysis of molecular pathways related to rapid motor decline 5. Discussion 6. Conclusions 7. Author contributions 8. Ethics approval and consent to participate 9. Acknowledgment 10. Funding 11. Conflict of interest 12. References

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“…The following findings are notable: LRRK2 is associated with a prior diagnosis of essential tremor (ET). NUCKS1, a gene that shows allele-specific gene expression in the human brain (51), is significantly associated with UPDRS-III motor scores and with UPDRS-V (H&Y stage). Of note, the PD-risk SNP rs823118 in the same gene was associated with higher MMSE scores in males when disease duration was not included as a covariate (Supplementary Table 5).…”

Section: Gene-level Association Analysismentioning

confidence: 99%

“…GPNMB, demonstrating genome-wide significance, is also associated with bradykinesia at baseline, as are THSD4, which attenuates TGFβ signaling, and MCCC1, which is used in NFκB signaling (58). STK39, which encodes a protein kinase that may mediate stress-activated signals (51), is associated with RLS.…”

Section: Gene-level Association Analysismentioning

confidence: 99%

Variable Effects of PD-Risk Associated SNPs and Variants in Parkinsonism-Associated Genes on Disease Phenotype in a Community-Based Cohort

et al. 2021

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Genetic risk factors for Parkinson's disease (PD) risk and progression have been identified from genome-wide association studies (GWAS), as well as studies of familial forms of PD, implicating common variants at more than 90 loci and pathogenic or likely pathogenic variants at 16 loci. With the goal of understanding whether genetic variants at these PD-risk loci/genes differentially contribute to individual clinical phenotypic characteristics of PD, we used structured clinical documentation tools within the electronic medical record in an effort to provide a standardized and detailed clinical phenotypic characterization at the point of care in a cohort of 856 PD patients. We analyzed common SNPs identified in previous GWAS studies, as well as low-frequency and rare variants at parkinsonism-associated genes in the MDSgene database for their association with individual clinical characteristics and test scores at baseline assessment in our community-based PD patient cohort: age at onset, disease duration, Unified Parkinson's Disease Rating Scale I-VI, cognitive status, initial and baseline motor and non-motor symptoms, complications of levodopa therapy, comorbidities and family history of neurological disease with one or more than one affected family members. We find that in most cases an individual common PD-risk SNP identified in GWAS is associated with only a single clinical feature or test score, while gene-level tests assessing low-frequency and rare variants reveal genes associated in either a unique or partially overlapping manner with the different clinical features and test scores. Protein-protein interaction network analysis of the identified genes reveals that while some of these genes are members of already identified protein networks others are not. These findings indicate that genetic risk factors for PD differentially affect the phenotypic presentation and that genes associated with PD risk are also differentially associated with individual disease phenotypic characteristics at baseline. These findings raise the intriguing possibility that different SNPs/gene effects impact discrete phenotypic characteristics. Furthermore, they support the hypothesis that different gene and protein-protein interaction networks that underlie PD risk, the PD phenotype, and the neurodegenerative process leading to the disease phenotype, and point to the significance of the genetic background on disease phenotype.

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Allele-specific expression of Parkinson’s disease susceptibility genes in human brain

Cited by 17 publications

References 50 publications

Recombination affects allele-specific expression of deleterious variants in human populations

Recombination affects allele-specific expression of deleterious variants in human populations

Rapid motor progression of Parkinson’s disease associates with clinical and genetic variants

Variable Effects of PD-Risk Associated SNPs and Variants in Parkinsonism-Associated Genes on Disease Phenotype in a Community-Based Cohort

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