Hunting for Familial Parkinson’s Disease Mutations in the Post Genome Era

Parkinson’s disease (PD) is typically sporadic; however, multi-incident families provide a powerful platform to discover novel genetic forms of disease. Their identification supports deciphering molecular processes leading to disease and may inform of new therapeutic targets. The LRRK2 p.G2019S mutation causes PD in 42.5–68% of carriers by the age of 80 years. We hypothesise similarly intermediately penetrant mutations may present in multi-incident families with a generally strong family history of disease. We have analysed six multiplex families for missense variants using whole exome sequencing to find 32 rare heterozygous mutations shared amongst affected members. Included in these mutations was the KCNJ15 p.R28C variant, identified in five affected members of the same family, two elderly unaffected members of the same family, and two unrelated PD cases. Additionally, the SIPA1L1 p.R236Q variant was identified in three related affected members and an unrelated familial case. While the evidence presented here is not sufficient to assign causality to these rare variants, it does provide novel candidates for hypothesis testing in other modestly sized families with a strong family history. Future analysis will include characterisation of functional consequences and assessment of carriers in other familial cases.

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Identification of sixteen novel candidate genes for late onset Parkinson’s disease

Molecular Neurodegeneration ◽

10.1186/s13024-021-00455-2 ◽

2021 ◽

Vol 16 (1) ◽

Author(s):

Alessandro Gialluisi ◽

Mafalda Giovanna Reccia ◽

Nicola Modugno ◽

Teresa Nutile ◽

Alessia Lombardi ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Candidate Genes ◽

Rare Variants ◽

Late Onset ◽

High Specificity ◽

Diagnostic Tools ◽

Multi Stage ◽

Whole Exome ◽

Family Based

Abstract Background Parkinson’s disease (PD) is a neurodegenerative movement disorder affecting 1–5% of the general population for which neither effective cure nor early diagnostic tools are available that could tackle the pathology in the early phase. Here we report a multi-stage procedure to identify candidate genes likely involved in the etiopathogenesis of PD. Methods The study includes a discovery stage based on the analysis of whole exome data from 26 dominant late onset PD families, a validation analysis performed on 1542 independent PD patients and 706 controls from different cohorts and the assessment of polygenic variants load in the Italian cohort (394 unrelated patients and 203 controls). Results Family-based approach identified 28 disrupting variants in 26 candidate genes for PD including PARK2, PINK1, DJ-1(PARK7), LRRK2, HTRA2, FBXO7, EIF4G1, DNAJC6, DNAJC13, SNCAIP, AIMP2, CHMP1A, GIPC1, HMOX2, HSPA8, IMMT, KIF21B, KIF24, MAN2C1, RHOT2, SLC25A39, SPTBN1, TMEM175, TOMM22, TVP23A and ZSCAN21. Sixteen of them have not been associated to PD before, were expressed in mesencephalon and were involved in pathways potentially deregulated in PD. Mutation analysis in independent cohorts disclosed a significant excess of highly deleterious variants in cases (p = 0.0001), supporting their role in PD. Moreover, we demonstrated that the co-inheritance of multiple rare variants (≥ 2) in the 26 genes may predict PD occurrence in about 20% of patients, both familial and sporadic cases, with high specificity (> 93%; p = 4.4 × 10− 5). Moreover, our data highlight the fact that the genetic landmarks of late onset PD does not systematically differ between sporadic and familial forms, especially in the case of small nuclear families and underline the importance of rare variants in the genetics of sporadic PD. Furthermore, patients carrying multiple rare variants showed higher risk of manifesting dyskinesia induced by levodopa treatment. Conclusions Besides confirming the extreme genetic heterogeneity of PD, these data provide novel insights into the genetic of the disease and may be relevant for its prediction, diagnosis and treatment.

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Family history of hand tremor in patients with early Parkinson’s disease

Journal of Clinical Neuroscience ◽

10.1016/j.jocn.2021.05.041 ◽

2021 ◽

Vol 90 ◽

pp. 161-164

Author(s):

Seong-Min Choi ◽

Soo Hyun Cho ◽

Kyung Wook Kang ◽

Jae-Myung Kim ◽

Byeong C. Kim

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Family History ◽

Hand Tremor ◽

History Of ◽

Early Parkinson’S Disease

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Parkinson’s disease determinants, prediction and gene–environment interactions in the UK Biobank

Journal of Neurology Neurosurgery & Psychiatry ◽

10.1136/jnnp-2020-323646 ◽

2020 ◽

Vol 91 (10) ◽

pp. 1046-1054 ◽

Cited By ~ 2

Author(s):

Benjamin Meir Jacobs ◽

Daniel Belete ◽

Jonathan Bestwick ◽

Cornelis Blauwendraat ◽

Sara Bandres-Ciga ◽

...

Keyword(s):

Risk Factors ◽

Parkinson’S Disease ◽

Parkinson's Disease ◽

Family History ◽

Genetic Risk ◽

Positive Family History ◽

Risk Scores ◽

Uk Biobank ◽

Gene Environment ◽

History Of

ObjectiveTo systematically investigate the association of environmental risk factors and prodromal features with incident Parkinson’s disease (PD) diagnosis and the interaction of genetic risk with these factors. To evaluate whether existing risk prediction algorithms are improved by the inclusion of genetic risk scores.MethodsWe identified individuals with an incident diagnosis of PD (n=1276) and controls (n=500 406) in UK Biobank. We determined the association of risk factors with incident PD using adjusted logistic regression models. We constructed polygenic risk scores (PRSs) using external weights and selected the best PRS from a subset of the cohort (30%). The PRS was used in a separate testing set (70%) to examine gene–environment interactions and compare predictive models for PD.ResultsStrong evidence of association (false discovery rate <0.05) was found between PD and a positive family history of PD, a positive family history of dementia, non-smoking, low alcohol consumption, depression, daytime somnolence, epilepsy and earlier menarche. Individuals with the highest 10% of PRSs had increased risk of PD (OR 3.37, 95% CI 2.41 to 4.70) compared with the lowest risk decile. A higher PRS was associated with earlier age at PD diagnosis and inclusion of the PRS in the PREDICT-PD algorithm led to a modest improvement in model performance. We found evidence of an interaction between the PRS and diabetes.InterpretationHere, we used UK Biobank data to reproduce several well-known associations with PD, to demonstrate the validity of a PRS and to demonstrate a novel gene–environment interaction, whereby the effect of diabetes on PD risk appears to depend on background genetic risk for PD.

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Whole-exome analysis in Parkinson’s disease reveals a high burden of ultra rare variants in early onset cases

10.1101/2020.06.06.137299 ◽

2020 ◽

Cited By ~ 1

Author(s):

Bernabe I. Bustos ◽

Dimitri Krainc ◽

Steven J. Lubbe ◽

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Early Onset ◽

Rare Variants ◽

Neurodegenerative Disorder ◽

Age Of Onset ◽

Late Onset ◽

Genetic Component ◽

Genetic Risk Assessment ◽

Whole Exome

ABSTRACTParkinson’s disease (PD) is a complex neurodegenerative disorder with a strong genetic component. We performed a “hypothesis-free” exome-wide burden-based analysis of different variant frequencies, predicted functional impact and age of onset classes, in order to expand the understanding of rare variants in PD. Analyzing whole-exome data from a total of 1,425 PD cases and 596 controls, we found a significantly increased burden of ultra-rare (URV= private variants absent from gnomAD) protein altering variants (PAV) in early-onset PD cases (EOPD, <40 years old; P=3.95×10−26, beta=0.16, SE=0.02), compared to LOPD cases (>60 years old, late-onset), where more common PAVs (allele frequencies <0.001) showed the highest significance and effect (P=0.026, beta=0.15, SE=0.07). Gene-set burden analysis of URVs in EOPD highlighted significant disease- and tissue-relevant genes, pathways and protein-protein interaction networks that were different to that observed in non-EOPD cases. Heritability estimates revealed that URVs account for 15.9% of the genetic component in EOPD individuals. Our results suggest that URVs play a significant role in EOPD and that distinct etiological bases may exist for EOPD and sporadic PD. By providing new insights into the genetic architecture of PD, our study may inform approaches aimed at novel gene discovery and provide new directions for genetic risk assessment based on disease age of onset.

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Factors Influencing Development of Depressive Illness among Parkinson’s Disease Patients

Journal of National Institute of Neurosciences Bangladesh ◽

10.3329/jninb.v5i2.43013 ◽

2019 ◽

Vol 5 (2) ◽

pp. 106-110

Author(s):

Provat Kumar Sarkar ◽

Hasan Zahidur Rahman ◽

Mahua Chandra ◽

Anis Ahmed ◽

Md Enayet Ul Islam ◽

...

Keyword(s):

Diabetes Mellitus ◽

Parkinson’S Disease ◽

Parkinson's Disease ◽

Family History ◽

Depression Scale ◽

Depressive Illness ◽

Age Group ◽

Cross Sectional ◽

History Of ◽

Axis I

Background: Depressive illness is present among Parkinson’s disease (PD) patients. Objective: The purpose of the present study was to see the influencing factors of development of depressive illness among Parkinson’s disease patients. Methodology: This comparative cross-sectional study was carried out in the Department of Neurology and Department of Psychiatry at Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, Bangladesh from July 2009 to June 2011 for a period of two (2) years. Parkinson’s disease patients who were attended at the movement disorder clinic and general OPD of Department of Neurology and in-patient department of Neurology at BSMMU, Dhaka were selected as study population. Patients with Parkinson’s plus syndrome, with dementia or other causes of parkinsonism like vascular or drug induced parkinsonism were excluded from this study. Data were collected by filling structured clinical questionnaire, then filling up of ‘structured clinical interview for DSM-IV Axis I disorders’ (SCID-CV) and self-reported ‘Depression scale` questionnaire. Parkinson disease was diagnosed by neurologist by the presence of two or more of the four cardinal criteria namely tremor, rigidity, bradykinesia and postural instability. Then patients were screened for depression by a psychiatrist of Department of Psychiatry at BSMMU, Dhaka. Result: A total of 100 Parkinson’s disease patients were interviewed and 80 patients ultimately participated in the study. The mean age of total Parkinson’s disease patients was 57.71±12.36 years ranging from 35 to 82 years with highest percentage (35%) had age group 65 years or above, 28.7% in 55 to 64 years, 22.5% in 45 to 54 years and lowest percentage (13.8%) in age group less than 45 years. Among 80 Parkinson’s disease patients, depression was present in 34 (42%) patients and was absent in 46 (58%) patients. Diabetes mellitus (p=0.125), hypertension (p=0.097), hypothyroidism (p=1.000), other illness (p=0.595), family history of PD (p=0.758) and levodopa use (p=0.661) were not significantly associated with the development of depressive illness in Parkinson’s disease. Conclusion: Diabetes mellitus (DM), hypertension (HTN), hypothyroidism, other illness, family history of PD and levodopa use do not significantly influence in the development of depressive illness among the Parkinson’s disease. Journal of National Institute of Neurosciences Bangladesh, 2019;5(2): 106-110

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Genetic Insights into Early-onset Parkinson’s Disease

US Neurology ◽

10.17925/usn.2010.06.01.41 ◽

2010 ◽

Vol 06 (01) ◽

pp. 41

Author(s):

Roy N Alcalay ◽

Cheryl Waters ◽

◽

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Family History ◽

Early Onset ◽

Late Onset ◽

Positive Family History ◽

Disease Onset ◽

Leucine Rich Repeat ◽

Strong Family History ◽

Early Onset Parkinson’S Disease

Early-onset Parkinson’s disease (EOPD) is defined as disease onset before 40 or 50 years of age. The clinical characteristics of EOPD are very similar to those of late-onset PD, but dystonia is more often a presenting symptom, dementia is rare, and disease progression may be slower. Mutations in several genes have been described in cases with EOPD, often with strong family history, including mutations in α-synuclein (SNCA),DJ-1, PTEN-induced kinase-1 (PINK-1), andATP13A2. However, the most common mutations identified in EOPD are in Parkin (PRKN), leucine-rich repeat kinase 2 (LRRK2), and glucocerebrosidase (GBA). With the exception ofSNCAandATP13A2carriers, mutation carriers are often indistinguishable from non-carriers. Large series of EOPD cases that are not ascertained by family history estimate mutation frequency at 4–16%. Given that the frequency of positive family history is much higher, we believe that many genetic risk factors are yet to be discovered.

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Younger age at onset of sporadic Parkinson’s disease among subjects occupationally exposed to metals and pesticides

Interdisciplinary Toxicology ◽

10.2478/intox-2014-0017 ◽

2014 ◽

Vol 7 (3) ◽

pp. 123-133 ◽

Cited By ~ 16

Author(s):

Marcia H. Ratner ◽

David H. Farb ◽

Josef Ozer ◽

Robert G. Feldman ◽

Raymon Durso

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Family History ◽

Occupational Exposure ◽

Age At Onset ◽

Disease Onset ◽

Occupational Exposures ◽

High Exposure ◽

Younger Age ◽

History Of

ABSTRACT An earlier age at onset of Parkinson’s disease (PD) has been reported to be associated with occupational exposures to manganese and hydrocarbon solvents suggesting that exposure to neurotoxic chemicals may hasten the progression of idiopathic PD. In this study the role of occupational exposure to metals and pesticides in the progression of idiopathic PD was assessed by looking at age at disease onset. The effects of heritable genetic risk factors, which may also influence age at onset, was minimized by including only sporadic cases of PD with no family history of the disease (n=58). Independent samples Student t-test revealed that subjects with occupational exposure to metals and/or pesticides (n=36) were significantly (p=0.013) younger than unexposed controls (n=22). These subjects were then divided into three groups [high (n=18), low (n=18), and unexposed (n=22)] to ascertain if duration of exposure further influenced age at onset of PD. One-way ANOVA revealed that subjects in the high exposure group were significantly (p=0.0121) younger (mean age: 50.33 years) than unexposed subjects (mean age: 60.45 years). Subjects were also stratified by exposure type (metals vs. pesticides). These results suggest that chronic exposure to metals and pesticides is associated with a younger age at onset of PD among patients with no family history of the disease and that duration of exposure is a factor in the magnitude of this effect.

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Rare Variants Analysis of Lysosomal Related Genes in Early-Onset and Familial Parkinson’s Disease in a Chinese Cohort

Journal of Parkinson s Disease ◽

10.3233/jpd-212658 ◽

2021 ◽

pp. 1-11

Author(s):

Yong-Ping Chen ◽

Xiao-Jing Gu ◽

Wei Song ◽

Yan-Bing Hou ◽

Ru-Wei Ou ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Early Onset ◽

Rare Variants ◽

Lysosomal Storage ◽

Asian Populations ◽

Whole Exome ◽

Gene Level ◽

Chinese Cohort

Background: Genetic studies have indicated that variants in several lysosomal genes are risk factors for idiopathic Parkinson’s disease (PD). However, the role of lysosomal genes in PD in Asian populations is largely unknown. Objective: This study aimed to analyze rare variants in lysosomal related genes in Chinese population with early-onset and familial PD. Methods: In total, 1,136 participants, including 536 and 600 patients with sporadic early-onset PD (SEOPD) and familial PD, respectively, underwent whole-exome sequencing to assess the genetic etiology. Rare variants in PD were investigated in 67 candidate lysosomal related genes (LRGs), including 15 lysosomal function-related genes and 52 lysosomal storage disorder genes. Results: Compared with the autosomal dominant PD (ADPD) or SEOPD cohorts, a much higher proportion of patients with multiple rare damaging variants of LRGs were found in the autosomal recessive PD (ARPD) cohort. At a gene level, rare damaging variants in GBA and MAN2B1 were enriched in PD, but in SCARB2, MCOLN1, LYST, VPS16, and VPS13C were much less in patients. At an allele level, GBA p. Leu483Pro was found to increase the risk of PD. Genotype-phenotype correlation showed no significance in the clinical features among patients carrying a discrepant number of rare variants in LRGs. Conclusion: Our study suggests rare variants in LRGs might be more important in the pathogenicity of ARPD cases compared with ADPD or SEOPD. We further confirm rare variants in GBA are involve in PD pathogenecity and other genes associated with PD identified in this study should be supported with more evidence.

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