Racial disparities in hospitalization characteristics among Native Hawaiians, Pacific Islanders and Asian American subgroups with Parkinson's disease.

BACKGROUND: Differences among Native Hawaiians/Pacific Islanders (NHPI) and Asian American (AA) subgroups have not been adequately studied in Parkinson's disease (PD). OBJECTIVE: To determine differences in demographics, comorbidities, and healthcare utilization among NHPI, AA subgroups, and White hospitalized PD patients. METHODS: We conducted a retrospective cross-sectional analysis of Hawai'is statewide registry (2016-2020). Patients with PD were identified using ICD10 code G20 and categorized as White, Japanese, Filipino, Chinese, NHPI, or Other. Variables collected included: age, sex, residence (county), primary source of payment, discharge status, length of stay, in-hospital expiration, Charlson Comorbidity Index (CCI) and Deep Brain Stimulation (DBS) utilization. Bivariate analyses were performed: differences in age and CCI were further examined by multivariable linear regression and proportional odds models. RESULTS: Of 229,238 hospitalizations, 2428 had PD (Japanese: 31.3 %, White: 30.4 %, Filipino: 11.3 %, NHPI: 9.6 %, Chinese: 8.0 %). NHPI were younger compared to rest of the subgroups [estimate in years (95 % CI): Whites: 4.4 (3.0-5.8), Filipinos: 4.3 (2.7-5.9), Japanese: 7.7 (6.4-9.1), Chinese: 7.9 (6.1-9.7), p < 0.001)]. NHPI had a higher CCI compared to White, Japanese, and Chinese (p < 0.001). Among AA subgroups, Filipinos were younger and had a higher CCI compared to Japanese and Chinese (p < 0.001). There were no significant differences in DBS utilization among subgroups. CONCLUSIONS: NHPI and Filipinos with PD were hospitalized at a younger age and had a greater comorbidity burden compared to other AAs and Whites. Further research, ideally prospective studies, are needed to understand these racial disparities.

Identification of genetic risk loci and causal insights associated with Parkinson's disease in African and African admixed populations: a genome-wide association study.

BACKGROUND: An understanding of the genetic mechanisms underlying diseases in ancestrally diverse populations is an important step towards development of targeted treatments. Research in African and African admixed populations can enable mapping of complex traits, because of their genetic diversity, extensive population substructure, and distinct linkage disequilibrium patterns. We aimed to do a comprehensive genome-wide assessment in African and African admixed individuals to better understand the genetic architecture of Parkinson's disease in these underserved populations. METHODS: We performed a genome-wide association study (GWAS) in people of African and African admixed ancestry with and without Parkinson's disease. Individuals were included from several cohorts that were available as a part of the Global Parkinson's Genetics Program, the International Parkinson's Disease Genomics Consortium Africa, and 23andMe. A diagnosis of Parkinson's disease was confirmed clinically by a movement disorder specialist for every individual in each cohort, except for 23andMe, in which it was self-reported based on clinical diagnosis. We characterised ancestry-specific risk, differential haplotype structure and admixture, coding and structural genetic variation, and enzymatic activity. FINDINGS: We included 197 918 individuals (1488 cases and 196 430 controls) in our genome-wide analysis. We identified a novel common risk factor for Parkinson's disease (overall meta-analysis odds ratio for risk of Parkinson's disease 1·58 [95% CI 1·37-1·80], p=2·397 × 10-14) and age at onset at the GBA1 locus, rs3115534-G (age at onset ß=-2·00 [SE=0·57], p=0·0005, for African ancestry; and ß=-4·15 [0·58], p=0·015, for African admixed ancestry), which was rare in non-African or non-African admixed populations. Downstream short-read and long-read whole-genome sequencing analyses did not reveal any coding or structural variant underlying the GWAS signal. The identified signal seems to be associated with decreased glucocerebrosidase activity. INTERPRETATION: Our study identified a novel genetic risk factor in GBA1 in people of African ancestry, which has not been seen in European populations, and it could be a major mechanistic basis of Parkinson's disease in African populations. This population-specific variant exerts substantial risk on Parkinson's disease as compared with common variation identified through GWAS and it was found to be present in 39% of the cases assessed in this study. This finding highlights the importance of understanding ancestry-specific genetic risk in complex diseases, a particularly crucial point as the Parkinson's disease field moves towards targeted treatments in clinical trials. The distinctive genetics of African populations highlights the need for equitable inclusion of ancestrally diverse groups in future trials, which will be a valuable step towards gaining insights into novel genetic determinants underlying the causes of Parkinson's disease. This finding opens new avenues towards RNA-based and other therapeutic strategies aimed at reducing lifetime risk of Parkinson's disease. FUNDING: The Global Parkinson's Genetics Program, which is funded by the Aligning Science Across Parkinson's initiative, and The Michael J Fox Foundation for Parkinson's Research.

Moving the Dial Toward Equity in Parkinson's Disease Clinical Research: a Review of Current Literature and Future Directions in Diversifying PD Clinical Trial Participation.

PURPOSE OF REVIEW: Parkinson's disease (PD), the second most common neurodegenerative disease, has a worldwide prevalence projected at 12 million by 2040. While PD has been extensively researched, our understanding of the disease is based on research studies that include mostly participants of European descent. The lack of diversity in clinical trial enrollment has limited the generalizability of scientific discoveries in the field. Here, we discuss contributors to racial and ethnic disparities in PD clinical research enrollment, summarize recently proposed and tested interventions, and propose next steps to increase equity and representation in PD research. RECENT FINDINGS: Enrollment in PD clinical research is vulnerable to upstream disparities and inequities from PD awareness to access to specialized PD centers. While additional research is still needed, recent studies have identified some potential strategies for increasing underrepresented minority (URM) recruitment including increasing the availability of linguistically and culturally diverse research materials and team members, partnering with community organizations, and forming relationships with URM-serving community physicians. To move the dial toward equity in PD research, it will be necessary to implement known successful strategies and further investigate additional contributors to the underrepresentation of URMs in PD clinical research while developing and testing interventions to address these factors.

Does Ethnicity Influence Recruitment into Clinical Trials of Parkinson's Disease?

BACKGROUND: Lack of participation of black and minority ethnic communities (BAME) in registered clinical trials is a concern as data emerging from these studies are used to licence new drugs or other interventions, even though findings made in such selected study populations have limited external validity in the aforesaid ethnic groups. OBJECTIVE: We used Parkinson's disease (PD), the fastest rising neurodegenerative disorder in the world, as an exemplar condition to test our hypothesis that participants from BAME communities are underrepresented in clinical trials. METHODS: A systematic search of clinical trials registered on a Clinicaltrials.gov database which queried for PD with racial distribution data from 2017 to 2021. RESULTS: Out of 266 trials considered, 54 trials were published in peer reviewed journals. Among these, only 23 (42.65%) publications reported data regarding the racial distribution of the participants. Out of these, five studies involved mixed racial participation and two trials included black subjects. CONCLUSION: We found that inclusion of under-represented BAME groups in recently published clinical trials is low, at only 21.57%, and is not even considered in most studies. Out of the reviewed trials, only 5 (21.75%) studies reported detailed demographic categories with black minorities enrolment. This constitutes a severe under-representation when compared to the proportion of Black or African American in the UK population (3%). Results of this study identified the need for better reporting of racial composition in clinical trials. We strongly recommend that future studies should consider ethnicity and other issues around diversity when designing and implementing the clinical trials, not only in the PD field but also beyond.

Mapping the Diverse and Inclusive Future of Parkinson's Disease Genetics and Its Widespread Impact.

Over the last decades, genetics has been the engine that has pushed us along on our voyage to understand the etiology of Parkinson's disease (PD). Although a large number of risk loci and causative mutations for PD have been identified, it is clear that much more needs to be done to solve the missing heritability mystery. Despite remarkable efforts, as a field, we have failed in terms of diversity and inclusivity. The vast majority of genetic studies in PD have focused on individuals of European ancestry, leading to a gap of knowledge on the existing genetic differences across populations and PD as a whole. As we move forward, shedding light on the genetic architecture contributing to PD in non-European populations is essential, and will provide novel insight into the generalized genetic map of the disease. In this review, we discuss how better representation of understudied ancestral groups in PD genetics research requires addressing and resolving all the challenges that hinder the inclusion of these populations. We further provide an overview of PD genetics in the clinics, covering the current challenges and limitations of genetic testing and counseling. Finally, we describe the impact of worldwide collaborative initiatives in the field, shaping the future of the new era of PD genetics as we advance in our understanding of the genetic architecture of PD.

Trends in Mortality From Parkinson Disease in the United States, 1999-2019.

BACKGROUND AND OBJECTIVES: The mortality from Parkinson disease (PD) and its long-term trends in the United States in recent decades remains unknown. This study aimed to describe the trends in PD mortality in the United States from 1999 to 2019. METHODS: We used data from the National Vital Statistics System, a nationwide, population-based death registry, to determine national trends in PD mortality, overall and by age, sex, race/ethnicity, urban-rural classification, and geographic location. Analyses focused on the data from 479,059 deaths due to PD from 1999 to 2019. Joinpoint regression was performed to examine temporal trends in age-adjusted death rates. RESULTS: The age-adjusted mortality from PD increased from 5.4 (95% confidence interval [CI] 5.3-5.5) per 100,000 population in 1999 to 8.8 (95% CI, 8.7-8.9) per 100,000 population in 2019, with an average annual percent change of 2.4% (95% CI, 1.8%-3.0%). From 1999 to 2019, PD mortality increased significantly across all age groups, both sexes, various racial/ethnic groups, and different urban-rural classifications. The US states and District of Columbia with reported death rates all experienced an increase in PD mortality. Significant differences by sex and race/ethnicity were noted. Age-adjusted PD mortality rates were twice as high in men as in women and were greater in White individuals than those from other racial/ethnic groups. DISCUSSION: From 1999 to 2019, the mortality from PD in the United States has increased significantly. The increase was regardless of age, sex, race/ethnicity, urban-rural classification, and geographic location. A comprehensive evaluation of long-term trends in PD mortality is important for health care priority setting.

Racial and Social Disparities in Health and Health Care Delivery among Patients with Parkinson's Disease and Related Disorders in a Multiracial Clinical Setting.

There are racial and socioeconomic disparities in the care of patients with Parkinson's disease (PD). Bellevue Hospital Center (BHC) in New York City is the oldest public hospital in the United States providing care to a multiracial, socioeconomically diverse and medically underserved population. We investigated racial and social disparities in providing care to patients with PD and related disorders at BHC compared to a NYU Langone Health, a Parkinson's Foundation Center of Excellence. Retrospective chart review of patients with diagnosis of PD or PD-related disorders evaluated at BHC or at NYU outpatient clinics from January 2012 to August 2017. 100 patients were enrolled from each site: BHC (55% men); NYU (49% men). The majority of patients at NYU were White (77%), compared to 14% at BHC; Hispanic patients comprised the majority at BHC (56%) (p < 0.001). BHC patients had more clinic visits per year compared to the NYU cohort (2.88 vs. 2.40, p = 0.001). BHC patients were less likely to self-report exercise (p = 0.047) or participation in physical therapy (p = 0.015). There were no clinically significant differences in diagnosis type, time to diagnosis, average Hoehn & Yahr or levodopa equivalent dose. Compared to a Parkinson's Foundation Center of Excellence, PD patients in a public hospital system are more racially diverse, are less likely to be insured, have higher rates of care utilization and are less likely to access necessary interventions such as physical therapy and exercise.

Characterizing the Genetic Architecture of Parkinson's Disease in Latinos.

OBJECTIVE: This work was undertaken in order to identify Parkinson's disease (PD) risk variants in a Latino cohort, to describe the overlap in the genetic architecture of PD in Latinos compared to European-ancestry subjects, and to increase the diversity in PD genome-wide association (GWAS) data. METHODS: We genotyped and imputed 1,497 PD cases and controls recruited from nine clinical sites across South America. We performed a GWAS using logistic mixed models; variants with a p-value <1 × 10-5 were tested in a replication cohort of 1,234 self-reported Latino PD cases and 439,522 Latino controls from 23andMe, Inc. We also performed an admixture mapping analysis where local ancestry blocks were tested for association with PD status. RESULTS: One locus, SNCA, achieved genome-wide significance (p-value <5 × 10-8 ); rs356182 achieved genome-wide significance in both the discovery and the replication cohorts (discovery, G allele: 1.58 OR, 95% CI 1.35-1.86, p-value 2.48 × 10-8 ; 23andMe, G allele: 1.26 OR, 95% CI 1.16-1.37, p-value 4.55 × 10-8 ). In our admixture mapping analysis, a locus on chromosome 14, containing the gene STXBP6, achieved significance in a joint test of ancestries and in the Native American single-ancestry test (p-value <5 × 10-5 ). A second locus on chromosome 6, containing the gene RPS6KA2, achieved significance in the African single-ancestry test (p-value <5 × 10-5 ). INTERPRETATION: This study demonstrated the importance of the SNCA locus for the etiology of PD in Latinos. By leveraging the demographic history of our cohort via admixture mapping, we identified two potential PD risk loci that merit further study. ANN NEUROL 2021;90:353-365.

The impact of COVID-19 on palliative care for people with Parkinson's and response to future pandemics.

Introduction: Although in some countries, palliative care (PC) still remains poorly implemented, its importance throughout the course of Parkinson's disease (PD) is increasingly being acknowledged. With an emergence of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) pandemic, growing emphasis has been placed on the palliative needs of people with Parkinson's (PwP), particularly elderly, frail, and with comorbidities.Areas covered: The ongoing COVID-19 pandemic poses an enormous challenge on aspects of daily living in PwP and might interact negatively with a range of motor and non-motor symptoms (NMS), both directly and indirectly - as a consequence of pandemic-related social and health care restrictions. Here, the authors outline some of the motor and NMS relevant to PC, and propose a pragmatic and rapidly deployable, consensus-based PC approach for PwP during the ongoing COVID-19 pandemic, potentially relevant also for future pandemics.Expert opinion: The ongoing COVID-19 pandemic poses a considerable impact on PwP and their caregivers, ranging from mental health issues to worsening of physical symptoms - both in the short- and long-term, (Long-COVID) and calls for specific, personalized PC strategies relevant in a lockdown setting globally. Validated assessment tools should be applied remotely to flag up particular motor or NMS that require special attention, both in short- and long-term.

Disparities in diagnosis, treatment and survival between Black and White Parkinson patients.

INTRODUCTION: Racial disparities in diagnosis, treatment and survival in Black patients with Parkinson's disease (PD) compared to White patients have not been well studied, largely due to limited number of studies and information on Black patients in healthcare systems. Studying racial disparities and identifying underlying factors in large populations are important to understand PD and improve care. METHODS: We retrospectively identified PD patients on both races from 1/1/2006 to 10/31/2017 and compared demographics, socioeconomic status (educations, incomes and insurances), comorbidities (all categories, including mood, cognition and psychosis), treatment (medications for parkinsonism and major non-motor symptoms, and frequency and locations of healthcare) and survival, and identified factors associated with medication usage and survival. RESULTS: We retrospectively studied 2033 PD patients, of whom 725 were Black. Black patients lacked male predominance, were 4 years older at first diagnosis here, more likely to smoke and live in a low education and income community, and possessed limited insurances compared to White patients. Black patients also had more comorbidities and were more likely to receive care through emergency or inpatient service, but less likely to be on medications for parkinsonism and mood disorders. Race, age, smoking status, insurance type, frequency and locations of healthcare and comorbidities were associated with medication usage. Black race, older age, inpatient admission and malignancy were associated with increased risk of death. CONCLUSION: We revealed racial disparities in diagnosis, treatment and survival, and factors associated with medication usage and survival in the largest reported Black PD cohort from a single center.

Frequency of Parkinsonism and Parkinson Disease in African Americans in the Chicago Community.

BACKGROUND: There is paucity of data about African American (AA) patients with Parkinson's disease (PD) and parkinsonism which may precede PD in older adults. Prior studies suggest that there are lower rates of PD in the AA population, with more cognitive impairment in AA with PD. This study aimed to investigate differences in PD, parkinsonism, and cognition between White and AA populations in 3 longitudinal epidemiologic cohort studies of aging. METHODS: This study examined parkinsonism, PD frequency, and cognition of community-dwelling older individuals in 3 longitudinal epidemiologic cohort studies. Parkinsonism was based on an exam utilizing the modified Unified Parkinson's Disease Rating Scale performed by a nurse. PD was based on self-report, medications used for treatment of PD, and examination findings. Cognition was assessed using 19 performance-based tests that assess 5 cognitive domains. RESULTS: AA participants were less likely to have parkinsonism compared to Whites, even with age and gender differences. Frequency of PD was not significant between groups. AA were more likely to have lower cognitive scores as compared to Whites. AA were less likely to have parkinsonism even with controlling for cognitive differences between groups. CONCLUSIONS: Parkinsonian signs are present among AA in the community at lower rates than in White individuals. Cognitive profiles of AA and Whites with parkinsonism may be different, suggesting differing contributions of pathology to cognitive decline and parkinsonism between groups. Additional research is needed to understand the progression of parkinsonism to PD, as well as to understanding the cognitive differences in AA with parkinsonism.

King's Parkinson's disease pain scale cut-off points for detection of pain severity levels: A reliability and validity study.

BACKGROUND: Pain is one of the most common non-motor symptoms in Parkinson's disease (PD). Using an appropriate and specific measuring tool would be helpful in managing the pain. King's Parkinson's disease Pain Scale (KPPS) is an instrument designed to specifically measure pain in people with PD. PURPOSE: This study aimed to examine the psychometric properties of the Persian version of KPPS (KPPS-P) and its cut-off points for pain severity levels. METHODS: A total of 480 people with PD (with a mean (SD) age of 60.89 (10.98)) were recruited. The acceptability of KPPS-P was calculated. The structural validity and discriminant validity for different levels of pain was explored via the factor analysis, and Receiver Operating Characteristics (ROC) curves, respectively. Internal consistency, test-retest, and inter-rater reliability were estimated by Cronbach's alpha and Interclass Correlation coefficient (ICC). Convergent validity was established between KPPS-P and other scales including Visual Analog Scale-Pain, Douleur Neuropathic 4, Brief Pain Inventory, Short-form McGill Pain Questionnaire-2, and Parkinson's Disease-8. RESULTS: A significant floor effect was observed. The exploratory factor analysis revealed 4 factors. Cronbach's alpha and ICC values were higher than 0.80. The correlation range between KPPS-P and other scales was 0.35-0.76. Cut-off points of 0, 17, and 68 were obtained to discriminate pain severity levels between no pain, mild, moderate, and severe pain, respectively, with sensitivity and specificity above 0.80. CONCLUSION: Our results indicate that the Persian version of KPPS not only has acceptable psychometric properties to assess pain in PD but also has the ability to distinguish between different levels of pain severity.

Clinical Non-Motor Phenotyping of Black and Asian Minority Ethnic Compared to White Individuals with Parkinson's Disease Living in the United Kingdom.

BACKGROUND: Ethnic phenotypic differences in Parkinson's disease (PD) are important to understand the heterogeneity of PD and develop biomarkers and clinical trials. OBJECTIVE: To investigate (i) whether there are non-motor symptoms (NMS)- and comorbidity-based phenotypic differences between Black, Asian and Minority Ethnic (BAME) and White PD patients and (ii) whether clinically available biomarkers may help differentiate and explain the differences between the groups. METHODS: This is a multicentre (four sites, London), real-life, cross-sectional study including PD patients of BAME or White ethnicity. The primary outcome was a detailed NMS assessment; additional measurements included disease and motor stage, comorbidity, sociodemographic parameters and brain MRI imaging. RESULTS: 271 PD patients (54 Asian, 71 Black, and 146 White) were included balanced for age, gender, and disease severity (HY). Black patients had a shorter disease duration compared to White and Asian populations. The SCOPA-Motor activities of daily living scores as well as the NMSS scores were significantly higher in both Black (total score and domain "miscellaneous") and Asian (total score and domains "sleep/fatigue", "mood/apathy" and "perception/hallucinations") than White individuals. Both BAME populations had higher prevalence of arterial hypertension, and the Black population had a higher prevalence of diabetes mellitus. Brain MRI revealed a greater severity of white matter changes in Black compared to the White and Asian cohorts. CONCLUSION: These findings suggest differences in phenotype of PD in BAME populations with greater burden of NMS and motor disability and a higher rate of cardiovascular comorbidities.

Analysis of DNM3 and VAMP4 as genetic modifiers of LRRK2 Parkinson's disease.

The LRRK2 gene has rare (p.G2019S) and common risk variants for Parkinson's disease (PD). DNM3 has previously been reported as a genetic modifier of the age at onset in PD patients carrying the LRRK2 p.G2019S mutation. We analyzed this effect in a new cohort of LRRK2 p.G2019S heterozygotes (n = 724) and meta-analyzed our data with previously published data (n = 754). VAMP4 is in close proximity to DNM3, and was associated with PD in a recent study, so it is possible that variants in this gene may be important. We also analyzed the effect of VAMP4 rs11578699 on LRRK2 penetrance. Our analysis of DNM3 in previously unpublished data does not show an effect on age at onset in LRRK2 p.G2019S carriers; however, the inter-study heterogeneity may indicate ethnic or population-specific effects of DNM3. There was no evidence for linkage disequilibrium between DNM3 and VAMP4. Analysis of sporadic patients stratified by the risk variant LRRK2 rs10878226 indicates a possible interaction between common variation in LRRK2 and VAMP4 in disease risk.

Genome-Scale Expression Pattern of Long Non-Coding RNAs in Chinese Uyghur Patients with Parkinson's Disease.

BACKGROUND Long non-coding RNAs (lncRNAs) are transcripts thought to regulate gene expression at the post-transcriptional level. Some lncRNAs are associated with Parkinson's disease (PD) and participate in pathological processes of PD. The incidence of PD is relatively high in members of the Uyghur minority living in Xingjiang province of China. This study measured the expression of lncRNAs in the peripheral blood cells of Chinese Uyghur individuals with and without PD and analyzed the possible function of these lncRNAs in the development of PD. MATERIAL AND METHODS Peripheral blood samples were collected from 55 Uyghur patients with PD and 55 healthy volunteers. Total RNA was extracted, and the levels of expression of whole-genome lncRNAs and mRNAs in 10 samples (5 PD and 5 controls) were determined by microarray method. The expression levels of lncRNAs in all 100 subjects were determined by qRT-PCR. The lncRNA expression profiles of PD patients were determined based on lncRNA microarray chip analysis, and differentially expressed lncRNAs were identified. The results of chip analysis were confirmed in a large clinical cohort. RESULTS Comparison of subjects with and without PD identified 32 significantly up-regulated and 18 significantly down-regulated lncRNAs in the PD group. GO analysis showed that mRNAs encoding proteins involved in the regulation of biological processes were differentially expressed, with the inflammatory immune response being the most significantly related pathway. CONCLUSIONS The expression of lncRNAs in peripheral blood differed significantly in PD patients and controls. These differentially expressed lncRNAs may play a role in the development of PD.

Parkinson's Disease-Related Motor and Nonmotor Symptoms in the Lancaster Amish.

INTRODUCTION: Previous research has suggested that the Amish may experience a relatively high prevalence of Parkinson's disease (PD) and/or parkinsonian motor signs. METHODS: In a large sample from the Amish community in Lancaster County, Pennsylvania, age ≥18 years, we assessed the prevalence of self-reported PD diagnosis. For those without self-reported PD diagnosis, we assessed the frequency of PD-related motor symptoms using a 9-item questionnaire that was designed by the PD Epidemiology Research Group. Lastly, we queried study participants for the presence of 2 nonmotor symptoms that have been commonly linked to PD: bowel movement frequency and daytime sleepiness. RESULTS: Among 2,025 subjects who answered the PD questionnaire, 430 were older than 60 years. Of 430 participants ≥60 years, 5 (1.2%) reported a PD diagnosis. Of those without a PD diagnosis, 10.5% reported ≥1 and 1.2% ≥ 4 motor symptoms for the 9-item PD screening questionnaire. Of the 3,789 subjects who answered the question about bowel movement frequency, 0.7% reported ≤3 bowel movements per week. Among 1,710 subjects who answered the question about daytime sleepiness, 8.1% of the participants reported "always" sleepy during the day. DISCUSSION: These data neither support a markedly higher PD prevalence in the older Lancaster Amish nor do they show dramatically higher motor and/or selected nonmotor symptoms than the general population. Future studies that employ more rigorous procedures for case identification and PD-specific preclinical symptoms/tests are needed to determine the potential differences and similarities among different Amish populations and between Amish and non-Amish populations.

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

BACKGROUND: Genetic heterogeneity in Parkinson's disease (PD) has been unambiguously reported across different populations. Assuming a higher genetic load, we tested variant burden in PD genes to an early onset PD cohort from India. METHODS: Whole exome sequencing was performed in 250 PD patients recruited following MDS-UPDRS criteria. The number of rare variants in the 20 known PD genes per exome were used to calculate average rare variant burden with the 616 non-PD exomes available in-house as a comparison group. SKAT-O test was used for gene level analysis. RESULTS: 80 patients harboured rare variants in 20 PD genes, of which six had known pathogenic variants accounting for 2.4% of the cohort. Of 80 patients, 12 had homozygous and nine had likely compound heterozygous variants in recessive PD genes and 59 had heterozygous variants in only dominant PD genes. Of the 16 novel variants of as yet unknown significance identified, four homozygous across ATP13A2, PRKN, SYNJ1 and PARK7; and 12 heterozygous among LRRK2, VPS35, EIF4G1 and CHCHD2 were observed. SKAT-O test suggested a higher burden in GBA (punadjusted = 0.002). Aggregate rare variant analysis including 75 more individuals with only heterozygous variants in recessive PD genes (excluding GBA), with an average of 0.85 protein-altering rare variants per PD patient exome versus 0.51 in the non-PD group, revealed a significant enrichment (p < 0.0001). CONCLUSION: This first study in an early onset PD cohort among Indians identified 16 novel variants in known genes and also provides evidence for a high genetic burden in this ethnically distinct population.

Parkinson's Disease Among Immigrant Groups and Swedish-Born Individuals: A Cohort Study of All Adults 50 Years of Age and Older in Sweden.

BACKGROUND: There is a lack of studies of Parkinson's disease (PD) in immigrants. OBJECTIVE: To study the association between country of birth and incident PD in immigrants in Sweden versus Swedish-born individuals. METHODS: Study population included all adults aged 50 years and older in Sweden (n = 2775736). PD was defined as having at least one registered diagnosis of PD in the National Patient Register. The incidence of PD in different first-generation immigrant groups versus Swedish-born individuals was assessed by Cox regression, expressed as hazard ratios (HRs) and 95% confidence intervals (CI). The models were stratified by sex and adjusted for age, geographical residence in Sweden, educational level, marital status, neighbourhood socioeconomic status and co-morbidity. RESULTS: Totally 35833 individuals had an incident diagnosis of PD (20401 men and 15432 women). Incidence rates per 100,000 person-years were for all Swedish-born 95.9 and for all foreign-born 60.1; for all men 112.3 and for all women 73.4, with a male to female ratio of 1.53, with the highest incidence rates for the group 80-84 years of age. After adjusting for potential confounders, the overall relative risk of PD was lower in immigrant men (HR 0.78; 95% CI 0.74-0.82) and women (HR 0.92; 95% CI 0.87-0.98). Among immigrant subgroups, a higher risk of PD was found among women from Finland (HR 1.13; 95% CI 1.05-1.23). CONCLUSION: In general, the risk of PD was lower in first-generation immigrant men and women compared to Swedish-born. The only group with a higher risk of PD was women from Finland.

Whole exome sequencing identified a new compound heterozygous PRKN mutation in a Chinese family with early-onset Parkinson's disease.

Early-onset Parkinson's disease (EOPD) is usually caused by genetic variants and patients with EOPD develop symptoms before the age of 50, accounting for 5% Parkinson's disease (PD). Here we present a Chinese Han pedigree with clinical features of EOPD. To determine the diagnosis and pathogenic mutations of this pedigree, whole exome sequencing, Sanger sequencing and real-time quantitative PCR were performed to detect all the four family members. Our results showed that a new form of compound heterozygous mutation in the PRKN gene, consisting of heterozygous point mutation c.850G > C (p.G284R) along with exon 4 deletion, is the causative genetic factor for EOPD in this pedigree. These discoveries may have implications for genetic counseling, clinical management and developing PRKN target gene therapy strategy.

Age at Onset of Parkinson's Disease Among Ashkenazi Jewish Patients: Contribution of Environmental Factors, LRRK2 p.G2019S and GBA p.N370S Mutations.

BACKGROUND: Both genetic and environmental factors contribute to Parkinson's disease (PD) risk. OBJECTIVE: We investigated the potential association of several relevant variables with PD age at onset (AAO), focusing on LRRK2 p.G2019S and GBA p.N370S mutations. METHODS: Ashkenazi Jewish (AJ) PD patients, screened for LRRK2 and GBA mutations, underwent an interview regarding exposure to the following environmental and lifestyle factors: cigarette smoking, consumption of coffee, tea and alcohol, head injury and rural living. Multivariate linear regression (adjusted for sex) was used to examine the association with AAO, and models included LRRK2 p.G2019S and GBA p.N370S mutation status (carrier/non-carriers), single environmental variable and their interactions terms, as independent variables. RESULTS: 225 Israeli AJ PD patients were enrolled: 65 LRRK2 p.G2019S mutation carriers, 60 GBA p.N370S carriers and 100 non-carries of these mutations. In the dichotomized exposure/non-exposure analyses, positive LRRK2 p.G2019S status was associated with younger AAO in all models, at nominal or near significant levels (p = 0.033-0.082). Smoking was associated with older AAO (p = 0.032), and the interaction between GBA p.N370S and history of head injury was associated with younger AAO (p = 0.049), both at nominal significance. There was no indication of a consistent main effect for GBA p.N370S status or significant LRRK2 p.G2019S-environmental factor interaction. In the dose-dependent analyses, increased coffee and tea consumption levels were associated with older AAO (p = 0.001 and p = 0.002, respectively). CONCLUSIONS: Our results suggest that genetic and environmental factors may affect AAO in PD patients, but validation in additional samples is required.