Lysosomal genes contribute to Parkinson's disease near agriculture with high intensity pesticide use.

Parkinson's disease (PD), the second most common neurodegenerative disorder, develops sporadically, likely through a combination of polygenic and environmental factors. Previous studies associate pesticide exposure and genes involved in lysosomal function with PD risk. We evaluated the frequency of variants in lysosomal function genes among patients from the Parkinson's, Environment, and Genes (PEG) study with ambient pesticide exposure from agricultural sources. 757 PD patients, primarily of White European/non-Hispanic ancestry (75%), were screened for variants in 85 genes using a custom amplicon panel. Variant enrichment was calculated against the Genome Aggregation Database (gnomAD). Enriched exonic variants were prioritized by exposure to a cluster of pesticides used on cotton and severity of disease progression in a subset of 386 patients subdivided by race/ethnicity. Gene enrichment analysis identified 36 variants in 26 genes in PEG PD patients. Twelve of the identified genes (12/26, 46%) had multiple enriched variants and/or a single enriched variant present in multiple individuals, representing 61% (22/36) of the observed variation in the cohort. The majority of enriched variants (26/36, 72%) were found in genes contributing to lysosomal function, particularly autophagy, and were bioinformatically deemed functionally deleterious (31/36, 86%). We conclude that, in this study, variants in genes associated with lysosomal function, notably autophagy, were enriched in PD patients exposed to agricultural pesticides suggesting that altered lysosomal function may generate an underlying susceptibility for developing PD with pesticide exposure. Further study of gene-environment interactions targeting lysosomal function may improve understanding of PD risk in individuals exposed to pesticides.

Higher testosterone and testosterone/estradiol ratio in men are associated with decreased Pheno-/GrimAge and DNA-methylation based PAI1.

Sex hormones are hypothesized to drive sex-specific health disparities. Here, we study the association between sex steroid hormones and DNA methylation-based (DNAm) biomarkers of age and mortality risk including Pheno Age Acceleration (AA), Grim AA, and DNAm-based estimators of Plasminogen Activator Inhibitor 1 (PAI1), and leptin concentrations. We pooled data from three population-based cohorts, the Framingham Heart Study Offspring Cohort, the Baltimore Longitudinal Study of Aging, and the InCHIANTI Study, including 1,062 postmenopausal women without hormone therapy and 1,612 men of European descent. Sex-stratified analyses using a linear mixed regression were performed, with a Benjamini-Hochberg (BH) adjustment for multiple testing. Sex Hormone Binding Globulin (SHBG) was associated with a decrease in DNAm PAI1 among men (per 1 standard deviation (SD): -478 pg/mL; 95%CI: -614 to -343; P:1e-11; BH-P: 1e-10), and women (-434 pg/mL; 95%CI: -589 to -279; P:1e-7; BH-P:2e-6). The testosterone/estradiol (TE) ratio was associated with a decrease in Pheno AA (-0.41 years; 95%CI: -0.70 to -0.12; P:0.01; BH-P: 0.04), and DNAm PAI1 (-351 pg/mL; 95%CI: -486 to -217; P:4e-7; BH-P:3e-6) among men. In men, testosterone was associated with a decrease in DNAm PAI1 (-481 pg/mL; 95%CI: -613 to -349; P:2e-12; BH-P:6e-11). SHBG was associated with lower DNAm PAI1 among men and women. Higher testosterone and testosterone/estradiol ratio were associated with lower DNAm PAI and a younger epigenetic age in men. A decrease in DNAm PAI1 is associated with lower mortality and morbidity risk indicating a potential protective effect of testosterone on lifespan and conceivably cardiovascular health via DNAm PAI1.

Untargeted serum metabolomics reveals novel metabolite associations and disruptions in amino acid and lipid metabolism in Parkinson's disease.

BACKGROUND: Untargeted high-resolution metabolomic profiling provides simultaneous measurement of thousands of metabolites. Metabolic networks based on these data can help uncover disease-related perturbations across interconnected pathways. OBJECTIVE: Identify metabolic disturbances associated with Parkinson's disease (PD) in two population-based studies using untargeted metabolomics. METHODS: We performed a metabolome-wide association study (MWAS) of PD using serum-based untargeted metabolomics data derived from liquid chromatography with high-resolution mass spectrometry (LC-HRMS) using two distinct population-based case-control populations. We also combined our results with a previous publication of 34 metabolites linked to PD in a large-scale, untargeted MWAS to assess external validation. RESULTS: LC-HRMS detected 4,762 metabolites for analysis (HILIC: 2716 metabolites; C18: 2046 metabolites). We identified 296 features associated with PD at FDR<0.05, 134 having a log2 fold change (FC) beyond ±0.5 (228 beyond ±0.25). Of these, 104 were independently associated with PD in both discovery and replication studies at p<0.05 (170 at p<0.10), while 27 were associated with levodopa-equivalent dose among the PD patients. Intriguingly, among the externally validated features were the microbial-related metabolites, p-cresol glucuronide (FC=2.52, 95% CI=1.67, 3.81, FDR=7.8e-04) and p-cresol sulfate. P-cresol glucuronide was also associated with motor symptoms among patients. Additional externally validated metabolites associated with PD include phenylacetyl-L-glutamine, trigonelline, kynurenine, biliverdin, and pantothenic acid. Novel associations include the anti-inflammatory metabolite itaconate (FC=0.79, 95% CI=0.73, 0.86; FDR=2.17E-06) and cysteine-S-sulfate (FC=1.56, 95% CI=1.39, 1.75; FDR=3.43E-11). Seventeen pathways were enriched, including several related to amino acid and lipid metabolism. CONCLUSIONS: Our results revealed PD-associated metabolites, confirming several previous observations, including for p-cresol glucuronide, and newly implicating interesting metabolites, such as itaconate. Our data also suggests metabolic disturbances in amino acid and lipid metabolism and inflammatory processes in PD.

Short sleep and insomnia are associated with accelerated epigenetic age.

OBJECTIVE: Short sleep and insomnia are each associated with greater risk for age-related disease, which suggests that insufficient sleep may accelerate biological aging. We examine whether short sleep and insomnia alone or together relate to epigenetic age among older adults. METHODS: A total of 3,795 men (46.3%) and women aged 56-100 years from the Health and Retirement Study were included. Insomnia was defined as reporting at least one insomnia symptom (difficulty falling asleep, waking up at night, or waking up too early in the morning) and feeling unrested when waking up most of the time. Those reporting <6 hours of bedtime were categorized as short sleepers. Three second- or third-generation epigenetic age acceleration clocks were derived from the 2016 HRS Venous Blood Study. The linear regression analysis was adjusted for age, sex, race/ethnicity, education, and obesity status. RESULTS: Insomnia and short sleep were associated with an 0.49 (95%CI:0.03-0.94; P:0.04) and 1.29 (95%CI:0.52-2.07; P:0.002) years acceleration of GrimAge, respectively, as well as a faster pace of aging (DunedinPACE; 0.018 (95%CI:0.004-0.033; P:0.02); 0.022(95%CI:-0.004-0.048; P:0.11)). Compared to healthy sleepers, individuals with the combination of short sleep and insomnia had an accelerated GrimAge (0.97 years; 95%CI:0.07-1.87; P:0.04) and a greater DunedinPACE (0.032; 95%CI:0.003-0.060; P:0.04). CONCLUSION: Our findings indicate short sleep, insomnia, and the combination of the two, are linked to epigenetic age acceleration, suggesting that these individuals have an older biological age that may contribute to risk for comorbidity and mortality.

Higher testosterone and testosterone/estradiol ratio in men are associated with better epigenetic estimators of mortality risk.

Introduction: Sex hormones are hypothesized to drive sex-specific health disparities. Here, we study the association between sex steroid hormones and DNA methylation-based (DNAm) biomarkers of age and mortality risk including Pheno Age Acceleration (AA), Grim AA, and DNAm-based estimators of Plasminogen Activator Inhibitor 1 (PAI1), and leptin concentrations. Methods: We pooled data from three population-based cohorts, the Framingham Heart Study Offspring Cohort (FHS), the Baltimore Longitudinal Study of Aging (BLSA), and the InCHIANTI Study, including 1,062 postmenopausal women without hormone therapy and 1,612 men of European descent. Sex hormone concentrations were standardized with mean 0 and standard deviation of 1, for each study and sex separately. Sex-stratified analyses using a linear mixed regression were performed, with a Benjamini-Hochberg (BH) adjustment for multiple testing. Sensitivity analysis was performed excluding the previously used training-set for the development of Pheno and Grim age. Results: Sex Hormone Binding Globulin (SHBG) is associated with a decrease in DNAm PAI1 among men (per 1 standard deviation (SD): -478 pg/mL; 95%CI: -614 to -343; P:1e-11; BH-P: 1e-10), and women (-434 pg/mL; 95%CI: -589 to -279; P:1e-7; BH-P:2e-6). The testosterone/estradiol (TE) ratio was associated with a decrease in Pheno AA (-0.41 years; 95%CI: -0.70 to -0.12; P:0.01; BH-P: 0.04), and DNAm PAI1 (-351 pg/mL; 95%CI: -486 to -217; P:4e-7; BH-P:3e-6) among men. In men, 1 SD increase in total testosterone was associated with a decrease in DNAm PAI1 (-481 pg/mL; 95%CI: -613 to -349; P:2e-12; BH-P:6e-11). Conclusion: SHBG was associated with lower DNAm PAI1 among men and women. Higher testosterone and testosterone/estradiol ratio were associated with lower DNAm PAI and a younger epigenetic age in men. A decrease in DNAm PAI1 is associated with lower mortality and morbidity risk indicating a potential protective effect of testosterone on lifespan and conceivably cardiovascular health via DNAm PAI1.

Among men, androgens are associated with a decrease in Alzheimer's disease risk.

INTRODUCTION: Increased levels of sex hormones have been hypothesized to decrease Alzheimer's disease (AD) risk. We assessed the association between sex steroid hormones with AD using a Mendelian randomization (MR) approach. METHODS: An inverse-variance weighting (IVW) MR analysis was performed using effect estimates from external genome-wide association study (GWAS) summary statistics. We included independent variants (linkage disequilibrium R2  < 0.001) and a p-value threshold of 5 × 10-8 . RESULTS: An increase in androgens was associated with a decreased AD risk among men: testosterone (odds ratio [OR]: 0.53; 95% confidence interval [CI]: 0.32-0.88; p-value: 0.01; false discovery rate [FDR] p-value: 0.03); dehydroepiandrosterone sulfate (DHEAS; OR: 0.56; 95% CI: 0.38-0.85; p-value: 0.01; FDR p-value: 0.03); and androsterone sulfate (OR: 0.69; 95% CI: 0.46-1.02; p-value: 0.06; FDR p-value: 0.10). There was no association between sex steroid hormones and AD among women, although analysis for estradiol had limited statistical power. DISCUSSION: A higher concentration of androgens was associated with a decreased risk of AD among men of European ancestry, suggesting that androgens among men might be neuroprotective and could potentially prevent or delay an AD diagnosis. HIGHLIGHTS: Sex hormones are hypothesized to play a role in developing Alzheimer's disease (AD). The effect of sex hormones on AD was assessed using Mendelian randomization (MR) analysis. Among women, genetically determined effects of sex hormones were limited or null. Among men, a higher concentration of androgens decreased AD risk. This study suggests a causal relationship between androgens and AD among men.

Ethnicity and Parkinson's Disease: Motor and Nonmotor Features and Disease Progression in Latino Patients Living in Rural California.

BACKGROUND: Parkinson's disease (PD) is the second most common neurodegenerative disorder among older adults worldwide. Currently, studies of PD progression rely primarily on White non-Latino (WNL) patients. Here, we compare clinical profiles and PD progression in Latino and WNL patients enrolled in a community-based study in rural Central California. METHOD: PD patients within 5 years of diagnosis were identified from 3 counties between 2001 and 2015. During up to 3 visits, participants were examined by movement disorders specialists and interviewed. We analyzed cross-sectional differences in PD clinical features severity at each study visit and used linear mixed models and Cox proportional hazards models to compare motor, nonmotor, and disability progression longitudinally and to assess time to death in Latinos compared to WNL patients. RESULTS: Of 775 patients included, 138 (18%) self-identified as Latino and presented with earlier age at diagnosis (63.6 vs 68.9) and death (78.6 vs 81.5) than WNL. Motor (hazard ratio [HR] = 1.17 [0.71, 1.94]) and nonmotor symptoms did not progress faster in Latino versus WNL patients after accounting for differences in baseline symptom severity. However, Latino patients progressed to disability stages according to Hoehn and Yahr faster than WNL (HR = 1.81 [1.11, 2.96]). Motor and nonmotor symptoms in Latino patients were also medically managed less well than in WNL. CONCLUSIONS: Our PD study with a large proportion of Latino enrollees and progression data reveals disparities in clinical features and progression by ethnicity that may reflect healthcare access and structural socioeconomic disadvantages in Latino patients with PD.

Immune system disruptions implicated in whole blood epigenome-wide association study of depression among Parkinson's disease patients.

Although Parkinson's Disease (PD) is typically described in terms of motor symptoms, depression is a common feature. We explored whether depression influences blood-based genome-wide DNA methylation (DNAm) in 692 subjects from a population-based PD case-control study, using both a history of clinically diagnosed depression and current depressive symptoms measured by the geriatric depression scale (GDS). While PD patients in general had more immune activation and more accelerated epigenetic immune system aging than controls, the patients experiencing current depressive symptoms (GDS≥5) showed even higher levels of both markers than patients without current depressive symptoms (GDS<5). For PD patients with a history of clinical depression compared to those without, we found no differences in immune cell composition. However, a history of clinical depression among patients was associated with differentially methylated CpGs. Epigenome-wide association analysis (EWAS) revealed 35 CpGs associated at an FDR≤0.05 (569 CpGs at FDR≤0.10, 1718 CpGs at FDR≤0.15). Gene set enrichment analysis implicated immune system pathways, including immunoregulatory interactions between lymphoid and non-lymphoid cells (p-adj = 0.003) and cytokine-cytokine receptor interaction (p-adj = 0.004). Based on functional genomics, 25 (71%) of the FDR≤0.05 CpGs were associated with genetic variation at 45 different methylation quantitative trait loci (meQTL). Twenty-six of the meQTLs were also expression QTLs (eQTLs) associated with the abundance of 53 transcripts in blood and 22 transcripts in brain (substantia nigra, putamen basal ganglia, or frontal cortex). Notably, cg15199181 was strongly related to rs823114 (SNP-CpG p-value = 3.27E-310), a SNP identified in a PD meta-GWAS and related to differential expression of PM20D1, RAB29, SLC41A1, and NUCKS1. The entire set of genes detected through functional genomics was most strongly overrepresented for interferon-gamma-mediated signaling pathway (enrichment ratio = 18.8, FDR = 4.4e-03) and T cell receptor signaling pathway (enrichment ratio = 13.2, FDR = 4.4e-03). Overall, the current study provides evidence of immune system involvement in depression among Parkinson's patients.

The Promise of Mendelian Randomization in Parkinson's Disease: Has the Smoke Cleared Yet for Smoking and Parkinson's Disease Risk?

This commentary discusses the strengths and limitations of utilizing the Mendelian randomization (MR) approach in Parkinson's disease (PD) studies. Epidemiologists proposed to employ MR when genetic instruments are available that represent reliable proxies for modifiable lifelong exposures which elude easy measurement in studies of late onset diseases like PD. Here, we are using smoking as an example. The great promise of the MR approach is its resilience to confounding and reverse causation. Nevertheless, the approach has some drawbacks such as being liable to selection- and survival-bias, it makes some strong assumptions about the genetic instruments employed, and requires very large sample sizes. When interpreted carefully and put into the context of other studies that take both genetics and the environment into consideration, MR studies help us to not only ask interesting questions but also can support causal inference and provide novel insights.

Association of Epigenetic Age Acceleration With Incident Mild Cognitive Impairment and Dementia Among Older Women.

BACKGROUND: Epigenetic age acceleration (AgeAccel), which indicates faster biological aging relative to chronological age, has been associated with lower cognitive function. However, the association of AgeAccel with mild cognitive impairment (MCI) or dementia is not well-understood. We examined associations of 4 AgeAccel measures with incident MCI and dementia. METHODS: This prospective analysis included 578 older women from the Women's Health Initiative Memory Study selected for a case-cohort study of coronary heart disease (CHD). Women were free of CHD and cognitive impairment at baseline. Associations of AgeAccel measures (intrinsic AgeAccel [IEAA], extrinsic AgeAccel [EEAA], AgeAccelPheno, and AgeAccelGrim) with risks for incident adjudicated diagnoses of MCI and dementia overall and stratified by incident CHD status were evaluated. RESULTS: IEAA was not significantly associated with MCI (HR, 1.23; 95% CI, 0.99-1.53), dementia (HR, 1.10; 95% CI, 0.88-1.38), or cognitive impairment (HR, 1.18; 95% CI, 0.99-1.40). In stratified analysis by incident CHD status, there was a 39% (HR, 1.39; 95% CI, 1.07-1.81) significantly higher risk of MCI for every 5-year increase in IEAA among women who developed CHD during follow-up. Other AgeAccel measures were not significantly associated with MCI or dementia. CONCLUSIONS: IEAA was not significantly associated with cognitive impairment overall but was associated with impairment among women who developed CHD. Larger studies designed to examine associations of AgeAccel with cognitive impairment are needed, including exploration of whether associations are stronger in the setting of underlying vascular pathologies.

Stochastic Epigenetic Mutations Influence Parkinson's Disease Risk, Progression, and Mortality.

BACKGROUND: Stochastic epigenetic mutations (SEM) reflect a deviation from normal site-specific methylation patterns. Epigenetic mutation load (EML) captures the accumulation of SEMs across an individual's genome and may reflect dysfunction of the epigenetic maintenance system in response to epigenetic challenges. OBJECTIVE: We investigate whether EML is associated with PD risk and time to events (i.e., death and motor symptom decline). METHODS: We employed logistic regression and Cox proportional hazards regression to assess the association between EML and several outcomes. Our analyses are based on 568 PD patients and 238 controls from the Parkinson's disease, Environment and Genes (PEG) study, for whom blood-based methylation data was available. RESULTS: We found an association for PD onset and EML in all genes (OR = 1.90; 95%CI 1.52-2.37) and PD-related genes (OR = 1.87; 95%CI 1.50-2.32). EML was also associated with time to a minimum score of 35 points on the motor UPDRS exam (OR = 1.28; 95%CI 1.06-1.56) and time to death (OR = 1.29, 95%CI 1.11-1.49). An analysis of PD related genes only revealed five intragenic hotspots of high SEM density associated with PD risk. CONCLUSION: Our findings suggest an enrichment of methylation dysregulation in PD patients in general and specifically in five PD related genes. EML may also be associated with time to death and motor symptom progression in PD patients.

Accelerated hematopoietic mitotic aging measured by DNA methylation, blood cell lineage, and Parkinson's disease.

BACKGROUND: Aging and inflammation are important components of Parkinson's disease (PD) pathogenesis and both are associated with changes in hematopoiesis and blood cell composition. DNA methylation (DNAm) presents a mechanism to investigate inflammation, aging, and hematopoiesis in PD, using epigenetic mitotic aging and aging clocks. Here, we aimed to define the influence of blood cell lineage on epigenetic mitotic age and then investigate mitotic age acceleration with PD, while considering epigenetic age acceleration biomarkers. RESULTS: We estimated epigenetic mitotic age using the "epiTOC" epigenetic mitotic clock in 10 different blood cell populations and in a population-based study of PD with whole-blood. Within subject analysis of the flow-sorted purified blood cell types DNAm showed a clear separation of epigenetic mitotic age by cell lineage, with the mitotic age significantly lower in myeloid versus lymphoid cells (p = 2.1e-11). PD status was strongly associated with accelerated epigenetic mitotic aging (AccelEpiTOC) after controlling for cell composition (OR = 2.11, 95 % CI = 1.56, 2.86, p = 1.6e-6). AccelEpiTOC was also positively correlated with extrinsic epigenetic age acceleration, a DNAm aging biomarker related to immune system aging (with cell composition adjustment: R = 0.27, p = 6.5e-14), and both were independently associated with PD. Among PD patients, AccelEpiTOC measured at baseline was also associated with longitudinal motor and cognitive symptom decline. CONCLUSIONS: The current study presents a first look at epigenetic mitotic aging in PD and our findings suggest accelerated hematopoietic cell mitosis, possibly reflecting immune pathway imbalances, in early PD that may also be related to motor and cognitive progression.

Increased Menopausal Age Reduces the Risk of Parkinson's Disease: A Mendelian Randomization Approach.

BACKGROUND: Studies of Parkinson's disease (PD) and the association with age at menarche or menopause have reported inconsistent findings. Mendelian randomization (MR) may address measurement errors because of difficulties accurately reporting the age these life events occur. OBJECTIVE: We used MR to assess the association between age at menopause and age at menarche with PD risk. METHODS: We performed inverse variant-weighted (IVW) MR analysis using external genome-wide association study (GWAS) summary data from the United Kingdom biobank, and the effect estimates between genetic variants and PD among two population-based studies (Parkinson's disease in Denmark (PASIDA) study, Denmark, and Parkinson's Environment and Gene study [PEG], United States) that enrolled 1737 female and 2430 male subjects of European ancestry. We, then, replicated our findings for age at menopause using summary statistics from the PD consortium (19 773 women), followed by a meta-analysis combining all summary statistics. RESULTS: For each year increase in age at menopause, the risk for PD decreased (odds ration [OR], 0.84; 95% confidence interval [CI], 0.73-0.98; P = 0.03) among women in our study, whereas there was no association among men (OR, 0.98; 95% CI, 0.85-1.11; P = 0.71). A replication using summary statistics from the PD consortium estimated an OR of 0.94 (95% CI, 0.90-0.99; P = 0.01), and we calculated a meta-analytic OR of 0.93 (95% CI, 0.89-0.98; P = 0.003). There was no indication for an association between age at menarche and PD (OR, 0.75; 95% CI, 0.44-1.29; P = 0.29). CONCLUSIONS: A later age at menopause was associated with a decreased risk of PD in women, supporting the hypothesis that sex hormones or other factors related to late menopause may be neuroprotective in PD. © 2021 International Parkinson and Movement Disorder Society.

Lack of Association Between GBA Mutations and Motor Complications in European and American Parkinson's Disease Cohorts.

BACKGROUND: Motor complications are a consequence of the chronic dopaminergic treatment of Parkinson's disease (PD) and include levodopa-induced dyskinesia (LIDs) and motor fluctuations (MF). Currently, evidence is on lacking whether patients with GBA-associated PD differ in their risk of developing motor complications compared to the general PD population. OBJECTIVE: To evaluate the association of GBA carrier status with the development of LIDS and MFs from early PD. METHODS: Motor complications were recorded prospectively in 884 patients with PD from four longitudinal cohorts using part IV of the UPDRS or MDS-UPDRS. Subjects were followed for up to 11 years and the associations of GBA mutations with the development of motor complications were assessed using parametric accelerated failure time models. RESULTS: In 439 patients from Europe, GBA mutations were detected in 53 (12.1%) patients and a total of 168 cases of LIDs and 258 cases of MF were observed. GBA carrier status was not associated with the time to develop LIDs (HR 0.78, 95%CI 0.47 to 1.26, p = 0.30) or MF (HR 1.19, 95%CI 0.84 to 1.70, p = 0.33). In the American cohorts, GBA mutations were detected in 36 (8.1%) patients and GBA carrier status was also not associated with the progression to LIDs (HR 1.08, 95%CI 0.55 to 2.14, p = 0.82) or MF (HR 1.22, 95%CI 0.74 to 2.04, p = 0.43). CONCLUSION: This study does not provide evidence that GBA-carrier status is associated with a higher risk of developing motor complications. Publication of studies with null results is vital to develop an accurate summary of the clinical features that impact patients with GBA-associated PD.

Epigenetic mutation load is weakly correlated with epigenetic age acceleration.

DNA methylation (DNAm) age estimators are widely used to study aging-related conditions. It is not yet known whether DNAm age is associated with the accumulation of stochastic epigenetic mutations (SEMs), which reflect dysfunctions of the epigenetic maintenance system. Here, we defined epigenetic mutation load (EML) as the total number of SEMs per individual. We assessed associations between EML and DNAm age acceleration estimators using biweight midcorrelations in four population-based studies (total n = 6,388). EML was not only positively associated with chronological age (meta r = 0.171), but also with four measures of epigenetic age acceleration: the Horvath pan tissue clock, intrinsic epigenetic age acceleration, the Hannum clock, and the GrimAge clock (meta-analysis correlation ranging from r = 0.109 to 0.179). We further conducted pathway enrichment analyses for each participant's SEMs. The enrichment result demonstrated the stochasticity of epigenetic mutations, meanwhile implicated several pathways: signaling, neurogenesis, neurotransmitter, glucocorticoid, and circadian rhythm pathways may contribute to faster DNAm age acceleration. Finally, investigating genomic-region specific EML, we found that EMLs located within regions of transcriptional repression (TSS1500, TSS200, and 1stExon) were associated with faster age acceleration. Overall, our findings suggest a role for the accumulation of epigenetic mutations in the aging process.

Genetic risk scores and hallucinations in patients with Parkinson disease.

OBJECTIVE: We examine the hypothesized overlap of genetic architecture for Alzheimer disease (AD), schizophrenia (SZ), and Parkinson disease (PD) through the use of polygenic risk scores (PRSs) with the occurrence of hallucinations in PD. METHODS: We used 2 population-based studies (ParkWest, Norway, and Parkinson's Environment and Gene, USA) providing us with 399 patients with PD with European ancestry and a PD diagnosis after age 55 years to assess the associations between 4 PRSs and hallucinations after 5 years of mean disease duration. Based on the existing genome-wide association study of other large consortia, 4 PRSs were created: one each using AD, SZ, and PD cohorts and another PRS for height, which served as a negative control. RESULTS: A higher prevalence of hallucinations was observed with each SD increase of the AD-PRS (odds ratio [OR]: 1.37, 95% confidence interval [CI]: 1.03-1.83). This effect was mainly driven by APOE (OR: 1.92, 95% CI: 1.14-3.22). In addition, a suggestive decrease and increase, respectively, in hallucination prevalence were observed with the SZ-PRS and the PD-PRS (OR: 0.77, 95% CI: 0.59-1.01; and OR: 1.29, 95% CI: 0.95-1.76, respectively). No association was observed with the height PRS. CONCLUSIONS: These results suggest that mechanisms for hallucinations in PD may in part be driven by the same genetic architecture that leads to cognitive decline in AD, especially by APOE.

Dopamine receptors and BDNF-haplotypes predict dyskinesia in Parkinson's disease.

OBJECTIVE: Dyskinesia is a known side-effect of the treatment of Parkinson's Disease (PD). We examined the influence of haplotypes in three dopamine receptors (DRD1, DRD2 and DRD3) and the Brain Derived Neurotrophic Factor (BDNF) on dyskinesia. METHODS: Patient data were drawn from a population-based case-control study. We included 418 patients with confirmed diagnoses by movement disorder specialists, using levodopa and a minimum three years disease duration at the time of assessment. Applying Haploview and Phase, we created haploblocks for DRD1-3 and BDNF. Risk scores for DRD2 and DRD3 were generated. We calculated risk ratios using Poisson regression with robust error variance. RESULTS: There was no difference in dyskinesia prevalence among carriers of various haplotypes in DRD1. However, one haplotype in each DRD2 haploblocks was associated with a 29 to 50% increase in dyskinesia risk. For each unit increase in risk score, we observed a 16% increase in dyskinesia risk for DRD2 (95%CI: 1.05-1.29) and a 17% (95%CI: 0.99-1.40) increase for DRD3. The BDNF haploblock was not associated, but the minor allele of the rs6265 SNP was associated with dyskinesia (adjusted RR 1.31 (95%CI: 1.01-1.70)). CONCLUSION: Carriers of DRD2 risk haplotypes and possibly the BDNF variants rs6265 and DRD3 haplotypes, were at increased risk of dyskinesia, suggesting that these genes may be involved in dyskinesia related pathomechanisms. PD patients with these genetic variants might be prime candidates for treatments aiming to prevent or delay the onset of dyskinesia.

Comparative analyses of studies of childhood leukemia and magnetic fields, radon and gamma radiation.

In this paper we compare the findings of epidemiologic studies of childhood leukemia that examined at least two of ELF magnetic fields and/or distance to power lines, and exposure to radon and gamma radiation or distance to nuclear plants. Many of the methodologic aspects are common to studies of non-ionising (i.e. ELF-MF) and ionising radiation. A systematic search and review of studies with more than one exposure under study identified 33 key and 35 supplementary papers from ten countries that have been included in this review. Examining studies that have looked at several radiation exposures, and comparing similarities and differences for the different types of radiation, through the use of directed acyclic graphs, we evaluate to what extent bias, confounding and other methodological issues might be operating in these studies. We found some indication of bias, although results are not clear cut. There is little evidence that confounding has had a substantial influence on results. Influence of the residential mobility on the study conduct and interpretation is complex and can manifest as a selection bias, confounding, increased measurement error or could also be a potential risk factor. Other factors associated with distance to power lines and to nuclear power plants should be investigated. A more complete and consistent reporting of results in the future studies will allow for a more informative comparison across studies and integration of results.