Integrated Analysis of Whole Exome Sequencing and Copy Number Evaluation in Parkinson’s Disease

Yemni, Eman A.A. Al; Monies, Dorota; Alkhairallah, Thamer; Bohlega, Saeed; Abouelhoda, Mohamed; Magrashi, Amna; Mustafa, Abeer E.; AlAbdulaziz, Basma S.; Al‐Hamed, Mohamed H.; Baz, Batoul; Goljan, Ewa; Albar, Renad; Jabaan, Amjad; Faquih, Tariq; Subhani, Shazia; Ali, Wafa Bel Haj; Shinwari, Jameela; Al-Mubarak, Bashayer; Tassan, Nada Al

doi:10.1038/s41598-019-40102-x

Cited by 40 publications

(33 citation statements)

References 73 publications

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“…Synaptosome associated protein 91 (SNAP91), also known as AP180, has been shown to be significantly increased in schizophrenia compared with normal controls (Fromer et al, 2016). In an integrated analysis of whole exome sequencing and copy number evaluation in Parkinson's disease (PD), loss of function and missense changes in SNAP91 were observed in PD patients (Yemni et al, 2019). SNAP91 was also found to promote release site clearance and clathrin-dependent vesicle reformation in mouse cochlear inner hair cells (Kroll et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

Co-expression Network Analysis Reveals Novel Genes Underlying Alzheimer’s Disease Pathogenesis

Hu¹,

Zhou³

et al. 2020

Front. Aging Neurosci.

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Background: The pathogenesis of Alzheimer’s disease (AD) remains to be elucidated. This study aimed to identify the hub genes in AD pathogenesis and determine their functions and pathways.Methods: A co-expression network for an AD gene dataset with 401 samples was constructed, and the AD status-related genes were screened. The hub genes of the network were identified and validated by an independent cohort. The functional pathways of hub genes were analyzed.Results: The co-expression network revealed a module that related to the AD status, and 101 status-related genes were screened from the trait-related module. Gene enrichment analysis indicated that these status-related genes are involved in synaptic processes and pathways. Four hub genes (ENO2, ELAVL4, SNAP91, and NEFM) were identified from the module, and these hub genes all participated in AD-related pathways, but the associations of each gene with clinical features were variable. An independent dataset confirmed the different expression of hub genes between AD and controls.Conclusions: Four novel genes associated with AD pathogenesis were identified and validated, which provided novel therapeutic targets for AD.

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Section: Discussionmentioning

confidence: 99%

Co-expression Network Analysis Reveals Novel Genes Underlying Alzheimer’s Disease Pathogenesis

Hu¹,

Zhou³

et al. 2020

Front. Aging Neurosci.

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“…For the majority of cases, at least two variants were found per proband. The presence of multiple candidate variants per case, is something that we and others have encountered in similar complex disorders (ASD and Parkinson's disease) [22,34,35]. This reinforces the plausibility of a polygenic model whereby several genes/loci may harbor risk variants collectively contributing to the disease burden.…”

Section: Discussionmentioning

confidence: 52%

Whole exome sequencing in ADHD trios from single and multi-incident families implicates new candidate genes and highlights polygenic transmission

et al. 2020

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Several types of genetic alterations occurring at numerous loci have been described in attention deficit hyperactivity disorder (ADHD). However, the role of rare single nucleotide variants (SNVs) remains under investigated. Here, we sought to identify rare SNVs with predicted deleterious effect that may contribute to ADHD risk. We chose to study ADHD families (including multi-incident) from a population with a high rate of consanguinity in which genetic risk factors tend to accumulate and therefore increasing the chance of detecting risk alleles. We employed whole exome sequencing (WES) to interrogate the entire coding region of 16 trios with ADHD. We also performed enrichment analysis on our final list of genes to identify the overrepresented biological processes. A total of 32 rare variants with predicted damaging effect were identified in 31 genes. At least two variants were detected per proband, most of which were not exclusive to the affected individuals. In addition, the majority of our candidate genes have not been previously described in ADHD including five genes (NEK4, NLE1, PSRC1, PTP4A3, and TMEM183A) that were not previously described in any human condition. Moreover, enrichment analysis highlighted brain-relevant biological themes such as "Glutamatergic synapse", "Cytoskeleton organization", and "Ca 2+ pathway". In conclusion, our findings are in keeping with prior studies demonstrating the highly challenging genetic architecture of ADHD involving low penetrance, variable expressivity and locus heterogeneity.

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“…These genes have been previously linked to PD in different studies. As an example, CLSTN1 overlapped a significantly hypomethylated CpG (Chuang et al 2017), was differentially expressed (Kong et al 2018) and carried a missense mutation (Yemni et al 2019) in PD cases. Several dynein and kinesin proteins also appear to be relevant in PD.…”

Section: Germline Variants Are Associated With the Diseasementioning

confidence: 99%

Somatic mutations in Parkinson disease are enriched in synaptic and neuronal processes

Lobón

Solís-Moruno

Juan

et al. 2020

Preprint

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The role of somatic mutations in complex diseases, including neurodevelopmental and neurodegenerative disorders, is becoming increasingly clear. To explore their relevance in sporadic Parkinson disease, we performed whole-exome sequencing in blood and four brain regions of ten patients. We identified 59 candidate somatic single nucleotide variants (sSNVs) through sensitive calling and extensive filtering. We validated 27 of them with amplicon-based deep sequencing, with a 70% validation rate for the highest-confidence variants. Most of the sSNVs were exclusively called in blood but were also found in the brain tissues with the ultra-deep amplicon sequencing, demonstrating the strength of multi-tissue sampling designs. We could confirm between 0 and 6 sSNVs per patient and generally those with a shorter lifespan carried more variants. Remarkably, the validated sSNVs are enriched in genes with synaptic functions that are co-expressed with genes previously associated with Parkinson disease.

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Integrated Analysis of Whole Exome Sequencing and Copy Number Evaluation in Parkinson’s Disease

Cited by 40 publications

References 73 publications

Co-expression Network Analysis Reveals Novel Genes Underlying Alzheimer’s Disease Pathogenesis

Co-expression Network Analysis Reveals Novel Genes Underlying Alzheimer’s Disease Pathogenesis

Whole exome sequencing in ADHD trios from single and multi-incident families implicates new candidate genes and highlights polygenic transmission

Somatic mutations in Parkinson disease are enriched in synaptic and neuronal processes

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