Genome-wide Analysis of Copy Number Variation in Latin American Parkinson's Disease Patients

Background: Parkinson's disease is the second most common neurodegenerative disorder and affects people from all ethnic backgrounds, yet little is known about the genetics of Parkinson's disease in non-European populations. In addition, the overall identification of copy number variants at a genome-wide level has been understudied in Parkinson's disease patients. Objectives: To understand the genome-wide burden of copy number variants in Latinos and its association with Parkinson's disease. Methods: We used genome-wide genotyping data from 747 Parkinson's disease patients and 632 ancestry matched controls from the Latin American Research Consortium on the Genetics of Parkinson's disease. Results: Genome-wide copy number burden analysis showed no difference between patients vs. controls, whereas patients were significantly enriched for copy number variants overlapping known Parkinson's disease genes compared to controls (Odds Ratio: 3.97 [1.69 - 10.5], P = 0.018). PARK2 showed the strongest copy number burden, with 20 copy number variant carriers. These patients presented an earlier age of disease onset compared to patients with other copy number variants (median age at onset: 31 years vs. 57 years, P = 7.46 x 10-7). Conclusions: We found that Parkinson's disease patients are significantly enriched with copy number variants affecting known Parkinson's disease genes. We also identified that out of 250 patients with early-onset disease, 5.6% carried a copy number variant on PARK2 in our cohort. Our study is the first to analyze genome-wide copy number variants association in Latino Parkinson's disease patients and provides insights about this complex disease in this understudied population.

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Genome‐Wide Analysis of Copy Number Variation in Latin American Parkinson's Disease Patients

Movement Disorders ◽

10.1002/mds.28353 ◽

2020 ◽

Author(s):

Elif Irem Sarihan ◽

Eduardo Pérez‐Palma ◽

Lisa‐Marie Niestroj ◽

Douglas Loesch ◽

Miguel Inca‐Martinez ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Copy Number Variation ◽

Latin American ◽

Copy Number ◽

Genome Wide Analysis ◽

Genome Wide ◽

Number Variation

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α-Synuclein BAC transgenic mice exhibit RBD-like behaviour and hyposmia: a prodromal Parkinson’s disease model

Brain ◽

10.1093/brain/awz380 ◽

2019 ◽

Vol 143 (1) ◽

pp. 249-265 ◽

Cited By ~ 8

Author(s):

Tomoyuki Taguchi ◽

Masashi Ikuno ◽

Mari Hondo ◽

Laxmi Kumar Parajuli ◽

Katsutoshi Taguchi ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Transgenic Mice ◽

Rem Sleep ◽

Genome Wide Association Study ◽

Artificial Chromosome ◽

Genome Wide Association ◽

Genome Wide ◽

A Genome ◽

Familial Parkinson’S Disease

Abstract Parkinson’s disease is one of the most common movement disorders and is characterized by dopaminergic cell loss and the accumulation of pathological α-synuclein, but its precise pathogenetic mechanisms remain elusive. To develop disease-modifying therapies for Parkinson’s disease, an animal model that recapitulates the pathology and symptoms of the disease, especially in the prodromal stage, is indispensable. As subjects with α-synuclein gene (SNCA) multiplication as well as point mutations develop familial Parkinson’s disease and a genome-wide association study in Parkinson’s disease has identified SNCA as a risk gene for Parkinson’s disease, the increased expression of α-synuclein is closely associated with the aetiology of Parkinson’s disease. In this study we generated bacterial artificial chromosome transgenic mice harbouring SNCA and its gene expression regulatory regions in order to maintain the native expression pattern of α-synuclein. Furthermore, to enhance the pathological properties of α-synuclein, we inserted into SNCA an A53T mutation, two single-nucleotide polymorphisms identified in a genome-wide association study in Parkinson’s disease and a Rep1 polymorphism, all of which are causal of familial Parkinson’s disease or increase the risk of sporadic Parkinson’s disease. These A53T SNCA bacterial artificial chromosome transgenic mice showed an expression pattern of human α-synuclein very similar to that of endogenous mouse α-synuclein. They expressed truncated, oligomeric and proteinase K-resistant phosphorylated forms of α-synuclein in the regions that are specifically affected in Parkinson’s disease and/or dementia with Lewy bodies, including the olfactory bulb, cerebral cortex, striatum and substantia nigra. Surprisingly, these mice exhibited rapid eye movement (REM) sleep without atonia, which is a key feature of REM sleep behaviour disorder, at as early as 5 months of age. Consistent with this observation, the REM sleep-regulating neuronal populations in the lower brainstem, including the sublaterodorsal tegmental nucleus, nuclei in the ventromedial medullary reticular formation and the pedunculopontine nuclei, expressed phosphorylated α-synuclein. In addition, they also showed hyposmia at 9 months of age, which is consistent with the significant accumulation of phosphorylated α-synuclein in the olfactory bulb. The dopaminergic neurons in the substantia nigra pars compacta degenerated, and their number was decreased in an age-dependent manner by up to 17.1% at 18 months of age compared to wild-type, although the mice did not show any related locomotor dysfunction. In conclusion, we created a novel mouse model of prodromal Parkinson’s disease that showed RBD-like behaviour and hyposmia without motor symptoms.

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Linking a genome-wide association study signal to aLRRK2coding variant in Parkinson's disease

Movement Disorders ◽

10.1002/mds.26495 ◽

2015 ◽

Vol 31 (4) ◽

pp. 484-487 ◽

Cited By ~ 4

Author(s):

Jia Nee Foo ◽

Sun Ju Chung ◽

Louis C. Tan ◽

Herty Liany ◽

Ho-Sung Ryu ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Association Study ◽

Genome Wide Association Study ◽

Genome Wide Association ◽

Genome Wide ◽

A Genome

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Detection and characterization of copy number variants based on whole-genome sequencing by DNBSEQ platforms

10.1101/786962 ◽

2019 ◽

Author(s):

Junhua Rao ◽

Lihua Peng ◽

Fang Chen ◽

Hui Jiang ◽

Chunyu Geng ◽

...

Keyword(s):

Whole Genome Sequencing ◽

Genome Sequencing ◽

Copy Number ◽

Copy Number Variants ◽

Copy Number Variant ◽

Whole Genome ◽

Genome Wide ◽

Wide Range ◽

Distribution Sensitivity ◽

Cnv Detection

AbstractBackgroundNext-generation sequence (NGS) has rapidly developed in past years which makes whole-genome sequencing (WGS) becoming a more cost- and time-efficient choice in wide range of biological researches. We usually focus on some variant detection via WGS data, such as detection of single nucleotide polymorphism (SNP), insertion and deletion (Indel) and copy number variant (CNV), which playing an important role in many human diseases. However, the feasibility of CNV detection based on WGS by DNBSEQ™ platforms was unclear. We systematically analysed the genome-wide CNV detection power of DNBSEQ™ platforms and Illumina platforms on NA12878 with five commonly used tools, respectively.ResultsDNBSEQ™ platforms showed stable ability to detect slighter more CNVs on genome-wide (average 1.24-fold than Illumina platforms). Then, CNVs based on DNBSEQ™ platforms and Illumina platforms were evaluated with two public benchmarks of NA12878, respectively. DNBSEQ™ and Illumina platforms showed similar sensitivities and precisions on both two benchmarks. Further, the difference between tools for CNV detection was analyzed, and indicated the selection of tool for CNV detection could affected the CNV performance, such as count, distribution, sensitivity and precision.ConclusionThe major contribution of this paper is providing a comprehensive guide for CNV detection based on WGS by DNBSEQ™ platforms for the first time.

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DEFINING CANDIDATE PARKINSON’S DISEASE GENES THROUGH THE ANALYSIS OF GENOME-WIDE HOMOZYGOSITY

10.1101/2020.11.23.20235671 ◽

2020 ◽

Author(s):

Steven J Lubbe ◽

Yvette C. Wong ◽

Bernabe Bustos ◽

Soojin Kim ◽

Jana Vandrovcova ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Autosomal Recessive Inheritance ◽

Homozygosity Mapping ◽

Disease Genes ◽

Compound Heterozygous ◽

Genome Wide ◽

Biallelic Mutations ◽

Functional Analyses

ABSTRACTEarly-onset Parkinson’s disease (EOPD) can be caused by biallelic mutations in PRKN, DJ1 and PINK1. However, while the identification of novel genes is becoming increasingly challenging, new insights into EOPD genetics have important relevance for understanding the pathways driving disease pathogenesis. Here, using extended runs of homozygosity (ROH) >8Mb as a marker for possible autosomal recessive inheritance, we identified 90 EOPD patients with extended ROH. Investigating rare, damaging homozygous variants to identify candidate genes for EOPD, 81 genes were prioritised. Through the assessment of biallelic (homozygous and compound heterozygous) variant frequencies in cases and controls from three independent cohorts totalling 3,381 PD patients and 2,463 controls, we identified two biallelic MIEF1 variant carriers among EOPD patients. We further investigated the role of disease-associated variants in MIEF1 which encodes for MID51, an outer mitochondrial membrane protein, and found that putative EOPD-associated variants in MID51 preferentially disrupted its oligomerization state. These findings provide further support for the role of mitochondrial dysfunction in the development of PD. Together, we have used genome-wide homozygosity mapping to identify potential EOPD genes, and future studies incorporating expanded datasets and further functional analyses will help to determine their roles in disease aetiology.

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PO184 Analysis of copy number variants in familial and sporadic parkinson’s disease

Journal of Neurology Neurosurgery & Psychiatry ◽

10.1136/jnnp-2017-abn.205 ◽

2017 ◽

Vol 88 (Suppl 1) ◽

pp. A59.4-A60

Author(s):

Theresita Joseph ◽

Jason Hehir ◽

Manuela Tan ◽

Wei Zhang ◽

Henry Houlden ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Copy Number ◽

Copy Number Variants ◽

Sporadic Parkinson’S Disease

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A genome-wide study shows a limited contribution of rare copy number variants to Alzheimer's disease risk

Human Molecular Genetics ◽

10.1093/hmg/dds476 ◽

2012 ◽

Vol 22 (4) ◽

pp. 816-824 ◽

Cited By ~ 20

Author(s):

Jade Chapman ◽

Elliott Rees ◽

Denise Harold ◽

Dobril Ivanov ◽

Amy Gerrish ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Copy Number ◽

Disease Risk ◽

Copy Number Variants ◽

Genome Wide ◽

A Genome ◽

Genome Wide Study

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Evaluation of copy number burden in specific epilepsy types from a genome-wide study of 18,564 subjects

10.1101/651299 ◽

2019 ◽

Cited By ~ 2

Author(s):

Lisa-Marie Niestroj ◽

Daniel P. Howrigan ◽

Eduardo Perez-Palma ◽

Elmo Saarentaus ◽

Peter Nürnberg ◽

...

Keyword(s):

Copy Number ◽

Genetic Architecture ◽

Focal Epilepsy ◽

Copy Number Variants ◽

Epileptic Encephalopathy ◽

Additional Risk ◽

Genome Wide ◽

A Genome ◽

Generalized Epilepsy ◽

Genome Wide Study

AbstractRare and large copy number variants (CNVs) around known genomic ‘hotspots’ are strongly implicated in epilepsy etiology. But it remains unclear whether the observed associations are specific to an epilepsy phenotype, and if additional risk signal can be found outside hotspots. Here, we present the largest CNV burden and first CNV breakpoint level association analysis in epilepsy to date with 11,246 European epilepsy cases and 7,318 ancestry-matched controls. We studied five epilepsy phenotypes: genetic generalized epilepsy, lesional focal epilepsy, non-acquired focal epilepsy, epileptic encephalopathy, and unclassified epilepsy. We discovered novel epilepsy-associated CNV loci and further characterized the CNV burden enrichment among phenotype-specific epilepsies. Finally, we provide evidence for deletion burden outside of known hotspot regions and show that CNVs play a significant role in the genetic architecture of lesional focal epilepsies.

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Genomic Association Study for Cognitive Impairment in Parkinson's Disease

Frontiers in Neurology ◽

10.3389/fneur.2020.579268 ◽

2021 ◽

Vol 11 ◽

Author(s):

Kye Won Park ◽

Sungyang Jo ◽

Mi Sun Kim ◽

Sang Ryong Jeon ◽

Ho-Sung Ryu ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Cognitive Impairment ◽

Association Study ◽

Mmse Score ◽

Genome Wide Association ◽

Functional Study ◽

Genome Wide ◽

A Genome ◽

Moca Score

Background: Cognitive impairment is very common in Parkinson's disease (PD) and constitutes the most debilitating complication of this disease. However, to date, few studies have investigated a genome-wide association in the development of cognitive impairment of PD. We aimed to identify the genetic loci associated with cognitive impairment in patients with sporadic PD by ethnicity-specific genotyping.Materials and methods: We recruited 1,070 patients with PD and performed a genome-wide association study using the Korean Chip, a microarray chip containing 827,400 single-nucleotide polymorphisms (SNPs) optimized for the Korean population. Multiple logistic regression models adjusting for age, sex, years of education, and disease duration were used to compare between patients with and without cognitive impairment, which was defined using the Mini-Mental Status Examination (MMSE) score (MMSE score ≥ 26 vs. < 26) or the Montreal Cognitive Assessment (MoCA) score (MoCA score ≥24 vs. < 24).Results:RYR2 SNP rs10495397 was most significantly associated with cognitive impairment based on the MMSE scores (OR = 3.21; 95% CI = 1.96–5.25, P = 3.36 × 10−6) and CASC17 showed the strongest association with cognitive impairment based on the MoCA scores. However, none of the SNPs were statistically significant after Bonferroni correction.Conclusion:RYR2 may play a role in cognitive impairment in PD by the pathogenic mechanism of neuroinflammation. However, more studies are needed to replicate and validate the results of our functional study.

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