The mutation spectrum of <scp>Parkinson‐disease</scp>‐related genes in early‐onset Parkinson's disease in ethnic Chinese

Chen, Yongping; Yu, Shihui; Zhang, Guohui; Hou, Yanbing; Gu, Xiaojing; Ou, Ruwei; Shen, Ying; Song, Wei; Chen, xueping; Zhao, Bi; Cao, Bei; Zhang, Ling‐Yu; Sun, Mingming; Liu, Fei‐Fei; Wei, Qianqian; Liu, Kuncheng; Lin, Junyu; Yang, Tianmi; Yang, Jing; Wu, Ying; Jiang, Zheng; Liu, Jiao; Cheng, Yiming; Xiao, Yi; Su, Wei‐Ming; Fu, Feng; Cai, Yingying; Liu, Shirong; Hu, Tao; Yuan, Xianglei; Zhou, Qingqing; Shao, Ningsheng; Ma, Sha; Shang, Huifang

doi:10.1111/ene.15509

Cited by 19 publications

(13 citation statements)

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“…The examination of known PD genes revealed strong rare variant drivers, and the diagnostic yield (∼8%) in our patient population matches that of similar studies in East Asian populations 20,33,34 (7.9% to 11.6%). Homozygous deletions in PRKN comprised the majority of pathogenic variants identified in this cohort, consistent with previous studies demonstrating that homozygous or compound heterozygous PRKN variants are the major driver of young- or early- onset PD 51–53 .…”

Section: Discussionsupporting

confidence: 86%

“…Several such "pleomorphic" risk loci/genes are known already: SNCA, GBA1, LRRK2, and VPS13C 3,21 . Previous genetic studies of early-onset PD have been conducted in a wide variety of ancestral populations, including European [22][23][24][25][26] , East Asian 20,[27][28][29][30][31][32][33][34][35] , and South Asian 12,16,17 groups. However, most of these early-onset studies were limited by the same factors that have hindered South Asian PD genetics studies generally: small sample sizes, analysis of only a small number of previously known PD genes, and/or lack of control populations to allow for genetic association studies.…”

Section: Introductionmentioning

confidence: 99%

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The genetic drivers of juvenile, young, and early-onset Parkinson’s Disease in India

Andrews

Kukkle

Menon

et al. 2023

Preprint

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ImportanceRecent studies have advanced our understanding of the genetic drivers of Parkinson’s Disease (PD). Rare variants in more than 20 genes are generally accepted to be causal for PD, and the latest PD GWAS study identified 90 independent risk loci. However, there remains a gap in our understanding of PD genetics outside of the European populations in which the vast majority of these studies were focused.ObjectiveTo identify genetic risk factors for PD in a South Asian population and therefore increase understanding of PD genetics more broadly.DesignThis study included common variant (minor allele frequency, MAF > 5%) genome-wide association studies (GWAS) for PD diagnosis (case-control analysis) and age of onset of motor symptoms (case-only analysis). In addition, rare variant (MAF < 1%) analyses delimiting the presence of pathogenic or likely pathogenic variants in previously known PD genes (case-only) and evaluating differential burden of predicted deleterious variants at the gene level (case-control) were performed. Finally, rare and common variants were combined to examine the distribution of a PD polygenic risk score within groups defined by presence of a PD gene mutation.Setting10 specialty movement disorder centers across India.Participants674 PD subjects predominantly with age of onset ≤ 50 years (encompassing juvenile, young, or early-onset PD) were recruited from the contributing centers over a 2-year period. 1,376 control subjects were selected from the reference population GenomeAsia, Phase 2.Main Outcomes & MeasuresDiagnosis of PD, age of onset of motor symptoms.ResultsCommon variant GWAS of PD diagnosis yielded a genome-wide significant signal (lead SNP p-value = 4.11E-11) in theSNCAregion, strongly colocalized (posterior probability = 1) withSNCAregion signal from European PD GWAS. PD cases with pathogenic mutations in PD genes exhibited, on average, lower PD polygenic risk scores than PD cases lacking any PD gene mutations. The top-ranked gene from gene burden studies of rare predicted loss-of-function and deleterious variants wasBSN, which encodes Bassoon, a presynaptic protein previously associated with neurodegenerative disease.Conclusions & RelevanceThis study constitutes the largest genetic investigation of PD and first demonstration ofSNCAassociation with PD in an Indian population to date. Ongoing work seeks to expand this cohort, enabling improved statistical power to detect PD genes in this understudied group.

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Section: Discussionsupporting

confidence: 86%

Section: Introductionmentioning

confidence: 99%

The genetic drivers of juvenile, young, and early-onset Parkinson’s Disease in India

Andrews

Kukkle

Menon

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…The examination of known PD genes revealed strong rare variant drivers, and the diagnostic yield (~8%) in our patient population matches that of similar studies in East Asian populations 20,33,34 (7.9%–11.6%). Homozygous deletions in PRKN comprised the majority of pathogenic variants identified in this cohort, consistent with previous studies demonstrating that homozygous or compound heterozygous PRKN variants are the major drivers of YOPD or EOPD 51–53 .…”

Section: Discussionsupporting

confidence: 85%

“…Several such "pleomorphic" risk loci/genes are known already: SNCA, GBA1, LRRK2, and VPS13C. 3,21 Previous genetics studies of early-onset PD have been conducted in a wide variety of ancestral populations, including European, [22][23][24][25][26] East Asian, 20,[27][28][29][30][31][32][33][34][35] and South Asian 12,16,17 groups. However, most of these early-onset studies were limited by the same factors that have hindered South Asian PD genetics studies generally: small sample sizes, analysis of only a small number of previously known PD genes, and/or lack of control populations to allow for genetic association studies.…”

mentioning

confidence: 99%

The Genetic Drivers of Juvenile, Young, and Early‐Onset Parkinson's Disease in India

Andrews,

Kukkle,

Menon

et al. 2023

Movement Disorders

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BackgroundRecent studies have advanced our understanding of the genetic drivers of Parkinson's disease (PD). Rare variants in more than 20 genes are considered causal for PD, and the latest PD genome‐wide association study (GWAS) identified 90 independent risk loci. However, there remains a gap in our understanding of PD genetics outside of the European populations in which the vast majority of these studies were focused.ObjectiveThe aim was to identify genetic risk factors for PD in a South Asian population.MethodsA total of 674 PD subjects predominantly with age of onset (AoO) ≤50 years (encompassing juvenile, young, or early‐onset PD) were recruited from 10 specialty movement disorder centers across India over a 2‐year period; 1376 control subjects were selected from the reference population GenomeAsia, Phase 2. We performed various case‐only and case–control genetic analyses for PD diagnosis and AoO.ResultsA genome‐wide significant signal for PD diagnosis was identified in the SNCA region, strongly colocalizing with SNCA region signal from European PD GWAS. PD cases with pathogenic mutations in PD genes exhibited, on average, lower PD polygenic risk scores than PD cases lacking any PD gene mutations. Gene burden studies of rare, predicted deleterious variants identified BSN, encoding the presynaptic protein Bassoon that has been previously associated with neurodegenerative disease.ConclusionsThis study constitutes the largest genetic investigation of PD in a South Asian population to date. Future work should seek to expand sample numbers in this population to enable improved statistical power to detect PD genes in this understudied group. © 2023 Denali Therapeutics and The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

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“…[76][77][78][79] SNCA duplications and triplications have also been identified in Asian populations, 80,81 and SNCA p.A53V has been found exclusively in this ancestry. 82 In contrast, pathogenic variants in the SNCA gene have not been frequently reported as a cause of PD in Latin American people. 83 Even so, the prevalence of SNCA mutations in the general population is very rare, and the penetrance is variable.…”

Section: Parkinson's Disease Heterogeneity On the Phenotypic And Geno...mentioning

confidence: 99%

Towards a Global View of Parkinson's Disease Genetics

Khani,

Cerquera‐Cleves,

Kekenadze

et al. 2024

Annals of Neurology

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Parkinson's disease (PD) is a global health challenge, yet historically studies of PD have taken place predominantly in European populations. Recent genetics research conducted in non‐European populations has revealed novel population‐specific genetic loci linked to PD risk, highlighting the importance of studying PD globally. These insights have broadened our understanding of PD etiology, which is crucial for developing disease‐modifying interventions. This review comprehensively explores the global genetic landscape of PD, emphasizing the scientific rationale for studying underrepresented populations. It underscores challenges, such as genotype–phenotype heterogeneity and inclusion difficulties for non‐European participants, emphasizing the ongoing need for diverse and inclusive research in PD. ANN NEUROL 2024

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The mutation spectrum of Parkinson‐disease‐related genes in early‐onset Parkinson's disease in ethnic Chinese

Cited by 19 publications

References 34 publications

The genetic drivers of juvenile, young, and early-onset Parkinson’s Disease in India

The genetic drivers of juvenile, young, and early-onset Parkinson’s Disease in India

The Genetic Drivers of Juvenile, Young, and Early‐Onset Parkinson's Disease in India

Towards a Global View of Parkinson's Disease Genetics

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