Mutation analysis of LRRK2, SCNA, UCHL1, HtrA2 and GIGYF2 genes in Chinese patients with autosomal dorminant Parkinson's disease

Tian, Jing; Guo, Jifeng; Wang, Lei; Sun, Qiying; Yao, Lingyan; Luo, Lin-zi; Shi, Changhe; Hu, Yacen; Yan, Xinxiang; Tang, Beisha

doi:10.1016/j.neulet.2012.03.086

Cited by 17 publications

(7 citation statements)

References 32 publications

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“…Several rare variants and candidate genes have been identified among familial and sporadic cases of PD (Blauwendraat et al, 2019b;Deng et al, 2016;Farlow et al, 2016;Funayama et al, 2015;Guo et al, 2018;Kalia and Lang, 2015;Lesage et al, 2016;Mok et al, 2016;Quadri et al, 2018). Previously, we have replicated PRKN (Guo et al, 2008), PINK1 (Guo et al, 2008;Tang et al, 2006), PARK7 (Guo et al, 2008;Tang et al, 2006), ATP13A2 (Guo et al, 2008), PLA2G6 (Shi et al, 2011), CHCHD2 (Liu et al, 2015), RAB39B (Kang et al, 2016), TMEM230 (Yan et al, 2017), GCH1 (Xu et al, 2017), and other genes (Tian et al, 2012;Yang et al, 2019) in patients with PD in China. Copy number variations (CNVs), particularly in PRKN and SNCA, have also been highlighted to play a vital role in the development of heritable or sporadic PD (Konno et al, 2016;Mok et al, 2016;Taghavi et al, 2018) and several genes, such as ATP13A2 (Ramirez et al, 2006), PLA2G6 (Paisan-Ruiz et al, 2009, FBXO7 (Di Fonzo et al, 2009), PRKN (Djarmati et al, 2004;Lucking et al, 2000), PINK1 (Bonifati et al, 2005;Kumazawa et al, 2008), and PARK7 (Djarmati et al, 2004) were reported to be strongly associated with an early-onset age of PD (Searles Nielsen et al, 2013).…”

Section: Introductionmentioning

confidence: 82%

Gene4PD: A Comprehensive Genetic Database of Parkinson’s Disease

Zhao

Zhou

et al. 2021

Front. Neurosci.

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Parkinson’s disease (PD) is a complex neurodegenerative disorder with a strong genetic component. A growing number of variants and genes have been reported to be associated with PD; however, there is no database that integrate different type of genetic data, and support analyzing of PD-associated genes (PAGs). By systematic review and curation of multiple lines of public studies, we integrate multiple layers of genetic data (rare variants and copy-number variants identified from patients with PD, associated variants identified from genome-wide association studies, differentially expressed genes, and differential DNA methylation genes) and age at onset in PD. We integrated five layers of genetic data (8302 terms) with different levels of evidences from more than 3,000 studies and prioritized 124 PAGs with strong or suggestive evidences. These PAGs were identified to be significantly interacted with each other and formed an interconnected functional network enriched in several functional pathways involved in PD, suggesting these genes may contribute to the pathogenesis of PD. Furthermore, we identified 10 genes were associated with a juvenile-onset (age ≤ 30 years), 11 genes were associated with an early-onset (age of 30–50 years), whereas another 10 genes were associated with a late-onset (age > 50 years). Notably, the AAOs of patients with loss of function variants in five genes were significantly lower than that of patients with deleterious missense variants, while patients with VPS13C (P = 0.01) was opposite. Finally, we developed an online database named Gene4PD (http://genemed.tech/gene4pd) which integrated published genetic data in PD, the PAGs, and 63 popular genomic data sources, as well as an online pipeline for prioritize risk variants in PD. In conclusion, Gene4PD provides researchers and clinicians comprehensive genetic knowledge and analytic platform for PD, and would also improve the understanding of pathogenesis in PD.

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Section: Introductionmentioning

confidence: 82%

Gene4PD: A Comprehensive Genetic Database of Parkinson’s Disease

Zhao

Zhou

et al. 2021

Front. Neurosci.

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“…GIGYF2 was initially reported in a cohort composed of Italian and French PD patients (Lautier et al, 2008), yet subsequent studies in Portuguese and US cohorts did not find evidence of association with PD (Bras et al, 2009). Numerous additional studies, including in a different Italian cohort and multiple other ethnicities, also failed to identify an association of GIGYF2 variants with PD (Bartonikova et al, 2018; Bonetti et al, 2009; Di Fonzo et al, 2009; Guo et al, 2009; Huo et al, 2017; Lesage et al, 2010; Li et al, 2010; Meeus et al, 2011; Nichols et al, 2009; Samaranch et al, 2010; Tan et al, 2009; Tan and Schapira, 2010; Tian et al, 2012; Vilarino-Guell et al, 2009; Wang, L. et al, 2010; Wang, L. et al, 2011; Yang et al, 2019; Zhang et al, 2015; Zhang et al, 2009; Zimprich et al, 2009). It is therefore very unlikely that GIGYF2 is associated with PD.…”

Section: Discussionmentioning

confidence: 99%

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

Saini

Rudakou

et al. 2020

Preprint

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Rare mutations in genes originally discovered in multi-generational 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 have been poorly studied or 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 five genes in PD, we fully sequenced them using molecular inversion probes in 2,408 PD patients and 3,444 controls from 3 different cohorts. A total of 788 rare variants were identified across the five genes and three 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 five 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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“…Several rare variants and candidate genes have been identi ed among familial and sporadic cases of PD (Funayama et al, 2015;Kalia and Lang, 2015;Deng et al, 2016;Farlow et al, 2016;Lesage et al, 2016;Mok et al, 2016;Guo et al, 2018;Quadri et al, 2018;Blauwendraat et al, 2019b). Previously, we have replicated PRKN (Guo et al, 2008), PINK1 (Tang et al, 2006;Guo et al, 2008), PARK7 (Tang et al, 2006;Guo et al, 2008), ATP13A2 (Guo et al, 2008), PLA2G6 (Shi et al, 2011), CHCHD2 (Liu et al, 2015), RAB39B (Kang et al, 2016), TMEM230 (Yan et al, 2017), GCH1 (Xu et al, 2017), and other genes (Tian et al, 2012;Yang et al, 2019) in patients with PD in China. Copy number variations (CNVs), particularly in PRKN and SNCA, have also been highlighted to play a vital role in the development of heritable or sporadic PD (Konno et al, 2016;Mok et al, 2016;Taghavi et al, 2018) and several genes, such as ATP13A2 (Ramirez et al, 2006), PLA2G6 (Paisan-Ruiz et al, 2009), FBXO7 (Di Fonzo et al, 2009), PRKN (Lucking et al, 2000;Djarmati et al, 2004), PINK1 (Bonifati et al, 2005;Kumazawa et al, 2008), and PARK7 (Djarmati et al, 2004) were reported to be strongly associated with an early-onset age of PD (Searles Nielsen et al, 2013).…”

mentioning

confidence: 82%

Gene4PD: a comprehensive genetic database of Parkinson's disease

Zhao

Zhou

et al. 2020

Preprint

View full text Add to dashboard Cite

BackgroundParkinson's disease (PD) is a complex neurodegenerative disorder with a strong genetic component. A growing number of variants and genes have been reported to be associated with PD; however, there is no database that integrate different type of genetic data, and support analyzing of PD-associated genes (PAGs).MethodsBy systematic review and curation of multiple lines of public studies, we integrate multiple layers of genetic data (rare variants and copy-number variants identified from patients with PD, associated variants identified from genome-wide association studies, differential expression genes, and differential DNA methylation genes) and clinical data in PD. A weighted scoring system was employed to prioritize PAGs. Permutation test and protein-protein interaction network was used to evaluate the interconnectivity and functional correlation among the PAGs. The relationship between AAO and PAGs was further analyzed. A PHP-based web framework was used to construct a database. ResultWe integrated five layers of genetic data with different levels of evidences from more than 3,000 studies and prioritized 124 PAGs with strong or suggestive evidences. These PAGs were identified to be significantly interacted with each other and formed an interconnected functional network enriched in several functional pathways involved in PD, suggesting these genes may contribute to the pathogenesis of PD, which also highlighting the reliability of these genetic data for PD. Furthermore, we identified 10 genes were associated with a juvenile-onset (age ≤ 30 years), 11 genes were associated with an early-onset (age of 30–50 years), whereas another 10 genes were associated with a late-onset (age > 50 years). Notably, the AAOs of patients with loss of function variants in five genes (GCH1, PINK1, PRKN, FBXO7, ATP13A2) were significantly lower than that of patients with deleterious missense variants, while patients with VPS13C (P = 0.01) was opposite. Finally, we developed an online database named Gene4PD (http://genemed.tech/gene4pd) which integrated published genetic data in PD, the PAGs, and 63 popular genomic data sources, as well as an online pipeline for prioritize risk variants in PD.ConclusionGene4PD provides researchers and clinicians comprehensive genetic knowledge and analytic platform for PD, and would also improve the understanding of pathogenesis in PD.Availability and Implementation: Gene4PD can be freely accessed at http://genemed.tech/gene4pd.

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Mutation analysis of LRRK2, SCNA, UCHL1, HtrA2 and GIGYF2 genes in Chinese patients with autosomal dorminant Parkinson's disease

Cited by 17 publications

References 32 publications

Gene4PD: A Comprehensive Genetic Database of Parkinson’s Disease

Gene4PD: A Comprehensive Genetic Database of Parkinson’s Disease

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

Gene4PD: a comprehensive genetic database of Parkinson's disease

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