Parkinson's disease (PD) is a neurodegenerative disorder caused by a complex interplay of genetic and environmental factors. For the stratification of PD patients and the development of advanced clinical trials, including causative treatments, a better understanding of the underlying genetic architecture of PD is required. Despite substantial efforts, genome-wide association studies have not been able to explain most of the observed heritability. The majority of PD-associated genetic variants are located in non-coding regions of the genome. A systematic assessment of their functional role is hampered by our incomplete understanding of genotype-phenotype correlations, for example through differential regulation of gene expression. Here, the recent progress and remaining challenges for the elucidation of the role of non-coding genetic variants is reviewed with a focus on PD as a complex disease with multifactorial origins. The function of gene regulatory elements and the impact of non-coding variants on them, and the means to map these elements on a genome-wide level, will be delineated. Moreover, examples of how the integration of functional genomic annotations can serve to identify disease-associated pathways and to prioritize disease- and cell type-specific regulatory variants will be given. Finally, strategies for functional validation and considerations for suitable model systems are outlined. Together this emphasizes the contribution of rare and common genetic variants to the complex pathogenesis of PD and points to remaining challenges for the dissection of genetic complexity that may allow for better stratification, improved diagnostics and more targeted treatments for PD in the future.

https://link.springer.com/content/pdf/10.1007/s00702-020-02184-0.pdf

Missing heritability in Parkinson's disease: the emerging role of non-coding genetic variation.

Over the past two decades, our understanding of Parkinson's disease (PD) has been gleaned from the discoveries made in familial and/or sporadic forms of PD in the Caucasian population The transferability and the clinical utility of genetic discoveries to other ethnically diverse populations are unknown The Indian population has been under-represented in PD research The Genetic Architecture of PD in India (GAP-India) project aims to develop one of the largest clinical/genomic bio-bank for PD in India Specifically, GAP-India project aims to: (1) develop a pan-Indian deeply phenotyped clinical repository of Indian PD patients; (2) perform whole-genome sequencing in 500 PD samples to catalog Indian genetic variability and to develop an Indian PD map for the scientific community; (3) perform a genome-wide association study to identify novel loci for PD and (4) develop a user-friendly web-portal to disseminate results for the scientific community Our "hub-spoke" model follows an integrative approach to develop a pan-Indian outreach to develop a comprehensive cohort for PD research in India The alignment of standard operating procedures for recruiting patients and collecting biospecimens with international standards ensures harmonization of data/bio-specimen collection at the beginning and also ensures stringent quality control parameters for sample processing Data sharing and protection policies follow the guidelines established by local and national authoritiesWe are currently in the recruitment phase targeting recruitment of 10,200 PD patients and 10,200 healthy volunteers by the end of 2020 GAP-India project after its completion will fill a critical gap that exists in PD research and will contribute a comprehensive genetic catalog of the Indian PD population to identify novel targets for PD

/pdf/genetic-architecture-of-parkinson-s-disease-in-the-indian-5dpphnbh0l.pdf

Genetic Architecture of Parkinson's Disease in the Indian Population: Harnessing Genetic Diversity to Address Critical Gaps in Parkinson's Disease Research

Novel and reported variants in Parkinson's disease genes confer high disease burden among Indians.

Variants of leucine-rich repeat kinase 2 (LRRK2) are the most common genetic cause of familial Parkinson's disease (PD). We aimed to investigate the genetic and clinical features of patients with PD and LRRK2 variants in Japan by screening for LRRK2 variants in three exons (31, 41, and 48), which include the following pathogenic mutations: p.R1441C, p.R1441G, p.R1441H, p.G2019S, and p.I2020T. Herein, we obtained data containing LRRK2 variants derived from 1402 patients with PD (653 with sporadic PD and 749 with familial PD). As a result, we successfully detected pathogenic variants (four with p.R1441G, five with p.R1441H, seven with p.G2019S, and seven with p.I2020T) and other rare variants (two with p.V1447M, one with p.V1450I, one with p.T1491delT, and one with p.H2391Q). Two risk variants, p.P1446L and p.G2385R, were found in 10 and 146 patients, respectively. Most of the patients presented the symptoms resembling a common type of PD, such as middle-aged onset, tremor, akinesia, rigidity, and gait disturbance. Dysautonomia, cognitive decline, and psychosis were rarely observed. Each known pathogenic variant had a different founder in our cohort proven by haplotype analysis. The generation study revealed that the LRRK2 variants p.G2019S and p.I2020T were derived 3500 and 1300 years ago, respectively. Our findings present overviews of the prevalence and distribution of LRRK2 variants in Japanese cohorts.

Clinical characterization of patients with leucine-rich repeat kinase 2 genetic variants in Japan

What have we learned from genome-wide association studies (GWAS) in Parkinson's disease?

BACKGROUND Genetic variability in LRRK2 has been unequivocally established as a major risk factor for familial and sporadic forms of PD in ethnically diverse populations. OBJECTIVES To resolve the role of LRRK2 in the Indian population. METHODS We performed targeted resequencing of the LRRK2 locus in 288 cases and 298 controls and resolved the haplotypic structure of LRRK2 in a combined cohort of 800 cases and 402 controls in the Indian population. We assessed the frequency of novel missense variants in the white and East Asian population by leveraging exome sequencing and densely genotype data, respectively. We did computational modeling and biochemical approach to infer the potential role of novel variants impacting the LRRK2 protein function. Finally, we assessed the phosphorylation activity of identified novel coding variants in the LRRK2 gene. RESULTS We identified four novel missense variants with frequency ranging from 0.0008% to 0.002% specific for the Indian population, encompassing armadillo and kinase domains of the LRRK2 protein. A common genetic variability within LRRK2 may contribute to increased risk, but it was nonsignificant after correcting for multiple testing, because of small cohort size. The computational modeling showed destabilizing effect on the LRRK2 function. In comparison to the wild-type, the kinase domain variant showed 4-fold increase in the kinase activity. CONCLUSIONS Our study, for the first time, identified novel missense variants for LRRK2, specific for the Indian population, and showed that a novel missense variant in the kinase domain modifies kinase activity in vitro. © 2018 International Parkinson and Movement Disorder Society.

Understanding the role of genetic variability in LRRK2 in Indian population

Aicardi-Goutières syndrome (AGS) is a genetic disorder caused by mutations in several genes with a spectrum of clinical phenotypes. The typical clinical presentation is characterized by early-onset encephalopathy with intellectual decline and motor abnormalities, including spasticity and dystonia, and multisystem inflammation. Aypical and late-onset cases with milder phenotypes have been described. We report here the case of a 20-year-old woman with a milder clinico-radiological phenotype of AGS presenting as childhood-onset isolated generalized dystonia and improving remarkably with bilateral globus pallidus interna (GPi) deep brain stimulation (DBS).

Childhood-Onset Dystonia Attributed to Aicardi-Goutières Syndrome and Responsive to Deep Brain Stimulation

Anti Zic4 Paraneoplastic Neurological Syndrome Presenting as Oscillopsia

Propriospinal myoclonus (PSM) is characterized by predominant axial jerk-like movements. To date, most of the PSM cases reported in the literature are considered to be functional (psychogenic) in origin. The “huffing and puffing sign” is a clinical clue with high diagnostic specificity for a functional etiology in gait disorders. However, this sign has not yet been described in patients with PSM. Here, we report a case of PSM of functional etiology, with coexisting gait disorder and the “huffing and puffing sign.” Our case adds to the list of clinical diagnostic clues that suggest a functional etiology of PSM.

Huffing and puffing sign in functional axial jerks with secondary gait impairment

Hemifacial spasm is a common peripheral movement disorder that usually results from neurovascular conflict involving the facial nerve motor root exit zone. Although it is a sporadic disease, some cases of familial clustering have been reported. In this case report, we present a case of familial occurrence of hemifacial spasm with dolichoectasia of the vertebrobasilar system in three siblings. The patients responded well to botulinum toxin therapy. A genetic mechanism predisposing them to vascular abnormalities is likely to be responsible for the clinical–radiological picture in our patients.

Divya Kalikavil Puthenveedu

Papers

Understanding the role of genetic variability in LRRK2 in Indian population

Childhood-Onset Dystonia Attributed to Aicardi-Goutières Syndrome and Responsive to Deep Brain Stimulation

Anti Zic4 Paraneoplastic Neurological Syndrome Presenting as Oscillopsia

Huffing and puffing sign in functional axial jerks with secondary gait impairment

Hemifacial spasm resulting from vertebrobasilar dolichoectasia in three siblings: A case report