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Contains fulltext : 248871.pdf (Publisher’s version ) (Open Access) BACKGROUND: Previous studies showed that lifestyle behaviors (cigarette smoking, alcohol, coffee) are inversely associated with Parkinson's disease (PD). The prodromal phase of PD raises the possibility that these associations may be explained by reverse causation. OBJECTIVE: To examine associations of lifestyle behaviors with PD using two-sample Mendelian randomisation (MR) and the potential for survival and incidence-prevalence biases. METHODS: We used summary statistics from publicly available studies to estimate the association of genetic polymorphisms with lifestyle behaviors, and from Courage-PD (7,369 cases, 7,018 controls; European ancestry) to estimate the association of these variants with PD. We used the inverse-variance weighted method to compute odds ratios (ORIVW) of PD and 95%confidence intervals (CI). Significance was determined using a Bonferroni-corrected significance threshold (p = 0.017). RESULTS: We found a significant inverse association between smoking initiation and PD (ORIVW per 1-SD increase in the prevalence of ever smoking = 0.74, 95%CI = 0.60-0.93, p = 0.009) without significant directional pleiotropy. Associations in participants ≤67 years old and cases with disease duration ≤7 years were of a similar size. No significant associations were observed for alcohol and coffee drinking. In reverse MR, genetic liability toward PD was not associated with smoking or coffee drinking but was positively associated with alcohol drinking. CONCLUSION: Our findings are in favor of an inverse association between smoking and PD that is not explained by reverse causation, confounding, and survival or incidence-prevalence biases. Genetic liability toward PD was positively associated with alcohol drinking. Conclusions on the association of alcohol and coffee drinking with PD are hampered by insufficient statistical power.

Background: The relationship among neuroticism, smoking, and Parkinson’s disease (PD) is less examined. Objective: To examine the causal associations between neuroticism, smoking initiation, and the risk of PD. Methods: We performed a two-sample Mendelian randomization (MR) design in a network framework. Summary statistics from meta-analyses of genome-wide association studies (GWAS) were based on large cohorts of European ancestry. Study participants were from various cohort studies for neuroticism and smoking initiation, and case-control studies or cohort studies of PD from previously published GWAS meta-analyses. Patients with PD were ascertained from either clinical visit or self-reported. Results: The two-sample MR analysis showed no evidence for a causal association between neuroticism and PD risk (odds ratio [OR] 0.86, 95%confidence intervals [CIs] 0.67 to 1.12). While we did not find a significant association between neuroticism and PD, one SNP, rs58879558 (located in MAPT region), was associated with both neuroticism and PD. We found a significant association of neuroticism on smoking initiation (OR: 1.10, 95%CI: 1.05 to 1.14). Further, our results provided evidence for a protective effect of smoking initiation on the risk of PD (OR: 0.75, 95%CI: 0.62 to 0.91). Conclusion: These findings do not support a causal association of neuroticism on PD risk. However, they provide evidence for a causal relationship between neuroticism and smoking initiation and a strong causal effect of smoking initiation on a reduced risk of PD.

Summary Objective To investigate which cardiometabolic factors underlie clustering of osteoarthritis with cardiovascular disease, and the extent to which these mediate an effect of education. Design Genome-wide association study (GWAS) of osteoarthritis was performed in UK Biobank (60,800 cases and 328,251 controls) to obtain genetic association estimates for osteoarthritis risk. Genetic instruments and association estimates for body mass index (BMI), low-density lipoprotein cholesterol (LDL-C), systolic blood pressure (SBP), smoking and education were obtained from existing GWAS summary data (sample sizes 188,577-866,834 individuals). Two-sample Mendelian randomization (MR) analyses were performed to investigate the effects of exposure traits on osteoarthritis risk. MR mediation analyses were undertaken to investigate whether the cardiometabolic traits mediate any effect of education on osteoarthritis risk. Results MR analyses identified protective effects of higher genetically predicted education (main MR analysis odds ratio [OR] per standard deviation increase 0.59, 95% confidence interval [CI] 0.54-0.64) and LDL-C levels (OR 0.94, 95%CI 0.91-0.98) on osteoarthritis risk, and unfavourable effects of higher genetically predicted BMI (OR 1.82, 95%CI 1.73-1.92) and smoking (OR 2.23, 95%CI 1.85-2.68). There was no strong evidence of an effect of genetically predicted SBP on osteoarthritis risk (OR 0.98, 95% CI 0.90-1.06). The proportion of the effect of genetically predicted education mediated through genetically predicted BMI and smoking was 35% (95%CI 13%-57%). Conclusions These findings highlight education, obesity and smoking as common mechanisms underlying osteoarthritis and cardiovascular disease. These risk factors represent clinical and public health targets for reducing multi-morbidity related to the burden these common conditions.

OBJECTIVE Alterations of the gut microbiome in Parkinson disease (PD) have been repeatedly demonstrated. However, little is known about whether such alterations precede disease onset and how they relate to risk and prodromal markers of PD. We investigated associations of these features with gut microbiome composition. METHODS Established risk and prodromal markers of PD as well as factors related to diet/lifestyle, bowel function, and medication were studied in relation to bacterial α-/β-diversity, enterotypes, and differential abundance in stool samples of 666 elderly TREND (Tubingen Evaluation of Risk Factors for Early Detection of Neurodegeneration) study participants. RESULTS Among risk and prodromal markers, physical inactivity, occupational solvent exposure, and constipation showed associations with α-diversity. Physical inactivity, sex, constipation, possible rapid eye movement sleep behavior disorder (RBD), and smoking were associated with β-diversity. Subthreshold parkinsonism and physical inactivity showed an interaction effect. Among other factors, age and urate-lowering medication were associated with α- and β-diversity. Constipation was highest in individuals with the Firmicutes-enriched enterotype, and physical inactivity was most frequent in the Bacteroides-enriched enterotype. Constipation was lowest and subthreshold parkinsonism least frequent in individuals with the Prevotella-enriched enterotype. Differentially abundant taxa were linked to constipation, physical inactivity, possible RBD, smoking, and subthreshold parkinsonism. Substantia nigra hyperechogenicity, olfactory loss, depression, orthostatic hypotension, urinary/erectile dysfunction, PD family history, and the prodromal PD probability showed no significant microbiome associations. INTERPRETATION Several risk and prodromal markers of PD are associated with gut microbiome composition. However, the impact of the gut microbiome on PD risk and potential microbiome-dependent subtypes in the prodrome of PD need further investigation based on prospective clinical and (multi)omics data in incident PD cases. ANN NEUROL 2021;90:E1-E12.

Recent genome-wide association studies in stroke have enabled the generation of genomic risk scores (GRS) but their predictive power has been modest compared to established stroke risk factors. Here, using a meta-scoring approach, we develop a metaGRS for ischaemic stroke (IS) and analyse this score in the UK Biobank (n = 395,393; 3075 IS events by age 75). The metaGRS hazard ratio for IS (1.26, 95% CI 1.22–1.31 per metaGRS standard deviation) doubles that of a previous GRS, identifying a subset of individuals at monogenic levels of risk: the top 0.25% of metaGRS have three-fold risk of IS. The metaGRS is similarly or more predictive compared to several risk factors, such as family history, blood pressure, body mass index, and smoking. We estimate the reductions needed in modifiable risk factors for individuals with different levels of genomic risk and suggest that, for individuals with high metaGRS, achieving risk factor levels recommended by current guidelines may be insufficient to mitigate risk., Stroke risk is influenced by genetic and lifestyle factors and previously a genomic risk score (GRS) for stroke was proposed, albeit with limited predictive power. Here, Abraham et al. develop a metaGRS that is composed of several stroke-related GRSs and demonstrate improved predictive power compared with individual GRS or classic risk factors.

ObjectiveTo verify the previously reported association between long-term use of β2-adrenoreceptor (β2AR) agonist and antagonist with reduced and increased risk of Parkinson disease (PD), respectively.MethodsWe obtained odds ratios (ORs) associating time of β2AR agonist and antagonist use with PD risk in nationwide Danish health registries.ResultsWe included 2,790 patients with PD and 11,160 controls. Long-term β2AR agonist use was associated with reduced PD risk (OR 0.57, 95% confidence interval [CI] 0.40–0.82) in this cohort. Unexpectedly, short-term β2AR agonist use was equally associated (OR 0.64, 95% CI 0.42–0.98). Because β2AR agonists are prescribed mostly for chronic obstructive pulmonary disease (COPD), often caused by long-term nicotine abuse, we analyzed other markers of smoking. Diagnosis of COPD (OR 0.51, 95% CI 0.37–0.69) and use of inhaled corticosteroids (OR 0.78, 95% CI 0.59–1.02) or inhaled anticholinergics (OR 0.41, 95% CI 0.25–0.67) were also inversely associated with PD. Increased PD risk was not found for all β2AR antagonists but only for propranolol and metoprolol. Associations were markedly stronger for short-term than long-term use.ConclusionWe confirmed β2AR agonist use to be associated with reduced PD risk and β2AR antagonist use with increased PD risk. However, our data indicate the association of β2AR agonists to be indirectly mediated by smoking, which is repeatedly associated with reduced risk of PD. The association of β2AR antagonists indicates reverse causation, with PD symptoms triggering their prescription rather than β2AR antagonists causing PD. Thus, current epidemiologic data do not support a causal link between β2AR agonists and antagonists and PD risk.

Cross-sectional studies suggest a strong association between depression and restless legs syndrome (RLS); however, the temporal relationship between the two disorders remains unknown. We tested whether the presence of clinically relevant depressive symptoms (CRDS) is a risk factor for subsequent RLS in the general population. The relationship between prevalent RLS and incident CRDS was also examined.Two independent, prospective cohort studies with representative, age-stratified random samples, the Dortmund Health Study (DHS; n = 1312/1122 [baseline/follow-up], median follow-up time = 2.1 years) and the Study of Health in Pomerania (SHIP; n = 4308/3300, median follow-up time = 5.0 years) were analyzed. RLS was assessed in both studies according to the RLS minimal criteria, at baseline and at follow-up. CRDS were assessed by the Center for Epidemiologic Studies-Depression scale (a score of ≥16) in DHS only at baseline and by the Munich-Composite International Diagnostic-Screener in SHIP at baseline and at follow-up.Clinically relevant depressive symptoms at baseline were associated new-onset RLS in both studies (DHS: odds ratio [OR] = 1.94, 95% confidence interval [CI] = 1.09-3.44; SHIP: OR = 2.37, 95% CI = 1.65-3.40) after adjustment for age, sex, education, body mass index, smoking, physical activity, and the presence of various comorbidities. RLS at baseline was an independent risk factor of incident CRDS in SHIP (OR = 1.82, 95% CI = 1.10-3.00).The presence of CRDS may be a risk factor for subsequent RLS. The relationship between the two disorders might be bidirectional because RLS also predicts incident depressive symptoms.

Stroke incidence rates have decreased in developed countries over the past 40 years, but trends vary across populations. We investigated whether age-and-sex-specific stroke incidence rates and associated risk factors as well as preventive medication use have changed in Rotterdam in the Netherlands during the last two decades. The study was part of the Rotterdam Study, a large population-based cohort study among elderly people. Participants were 10,994 men and women aged 55-94 years who were stroke-free at baseline. Trends were calculated by comparing the 1990 subcohort (n = 7516; baseline 1990-1993) with the 2000 subcohort (n = 2883; baseline 2000-2001). Poisson regression was used to calculate incidence rates and incidence rate ratios in age-and-sex-specific strata. We further compared the prevalence of stroke risk factors and preventive medication use in the two subcohorts. In the 1990 subcohort 467 strokes occurred during 45,428 person years; in the 2000 subcohort 115 strokes occurred in 18,356 person years. Comparing the subcohorts, incidence rates decreased by 34% in men, but remained unchanged in women. Blood pressure levels increased between 1990 and 2000, whereas the proportion of current cigarette smokers decreased in men, but not in women. There was a strong increase in medication use for treatment of stroke risk factors across all age categories in both sexes. Our findings suggest that in Rotterdam between 1990 and 2008 stroke incidence rates have decreased in men but not in women.

Background Control of modifiable cardiovascular disease (CVD) risk factors has substantially reduced CVD mortality, but risk factor levels in populations may change and need continuous monitoring. This study aims to provide current estimates of the prevalence of these risk factors in Germany according to sex and history of coronary heart disease (CHD) or stroke. Methods The analyses were based on data from the German Health Interview and Examination Survey for Adults (DEGS1; age 40–79 years, n = 5101), which is a cross-sectional population-based examination survey. CVD risk factors were defined according to recommendations in the European Guidelines on Cardiovascular Disease Prevention in Clinical Practice 2012. Results The mean age was 57 years and 52 % were female; 493 participants had prior CHD and 163 participants a prior stroke. The overall prevalence of behavioural risk factors ranged from 17.9 % for high risk alcohol consumption to 90 % for low vegetable intake. Blood pressure ≥ 140/90 mmHg was found in 21 % and 69 % had total cholesterol ≥ 5.0 mmol/l. Only 16 % met the targets for five behavioural factors combined (smoking, physical activity, fruit intake, alcohol intake and obesity), 13 % of those with and 16 % of those without CHD or stroke. The prevalences of most behavioural risk factors were higher among men compared to women. Conclusions There is a high prevention potential from modifiable cardiovascular risk factors in the general population aged 40–79 years in Germany and among those with prior CHD or stroke. Risk factors are often co-occurring, are interrelated and require combined educational, behavioral, medical and policy approaches. Electronic supplementary material The online version of this article (doi:10.1186/s12889-015-1929-5) contains supplementary material, which is available to authorized users.

Rationale: During a smoking quit attempt, a single smoking lapse is highly predictive of future relapse. While several risk factors for a smoking lapse have been identified during clinical trials, a laboratory model of lapse was until recently unavailable and, therefore, it is unclear whether these characteristics also convey risk for lapse in a laboratory environment. Objectives: The primary study goal was to examine whether real-world risk factors of lapse are also predictive of smoking behavior in a laboratory model of smoking lapse. Methods: After overnight abstinence, 77 smokers completed the McKee smoking lapse task, in which they were presented with the choice of smoking or delaying in exchange for monetary reinforcement. Primary outcome measures were the latency to initiate smoking behavior and the number of cigarettes smoked during the lapse. Several baseline measures of smoking behavior, mood, and individual traits were examined as predictive factors. Results: Craving to relieve the discomfort of withdrawal, withdrawal severity, and tension level were negatively predictive of latency to smoke. In contrast, average number of cigarettes smoked per day, withdrawal severity, level of nicotine dependence, craving for the positive effects of smoking, and craving to relieve the discomfort of withdrawal were positively predictive of number of cigarettes smoked. Conclusions: The results suggest that real-world risk factors for smoking lapse are also predictive of smoking behavior in a laboratory model of lapse. Future studies using the McKee lapse task should account for between subject differences in the unique factors that independently predict each outcome measure. © 2014 Springer-Verlag Berlin Heidelberg.

The hippocampus—crucial for memory formation, recall and mood regulation—is involved in the pathophysiology of dementia and depressive disorders. Recent genome-wide association studies (GWAS) have identified five genetic loci associated with hippocampal volume (HV). Previous studies have described psychosocial and clinical factors (for example, smoking, type 2 diabetes and hypertension) to have an impact on HV. However, the interplay between genetic, psychosocial and clinical factors on the HV remains unclear. Still, it is likely that genetic variants and clinical or psychosocial factors jointly act in modifying HV; it might be possible they even interact. Knowledge of these factors might help to quantify ones individual risk of or rather resilience against HV loss. We investigated subjects (N=2463; 55.7% women; mean age 53 years) from the Study of Health in Pomerania (SHIP-2; SHIP-TREND-0) who underwent whole-body magnetic resonance imaging (MRI) and genotyping. HVs were estimated with FreeSurfer. For optimal nonlinear model fitting, we used regression analyses with restricted cubic splines. Genetic variants and associated psychosocial or clinical factors were jointly assessed for potential two-way interactions. We observed associations between HV and gender (P

Background: Leber's hereditary optic neuropathy (LHON) is a mitochondrial disease that typically causes bilateral blindness in young men. Here we describe the clinical and molecular characteristics of 20 patients with disease onset after the age of 50 years (late onset-LHON). Methods: From a cohort of 251 affected and 277 unaffected LHON carriers, we identified 20 patients with onset of visual loss after the age of 50 years. Using structured questionnaires, data including basic demographic details, age of onset, progression of visual loss and severity as well as exposure to possible environmental triggers including alcohol, smoking and illicit drugs were retrospectively collected. Groups were compared using the Mann-Whitney-U-Test for two independent groups of sampled data. Results: The proportion of late onset-LHON in our cohort was 8% (20 patients, 15 males, 5 females). The mtDNA mutations m. 11778G > A and m. 3460G > A were found in 16 and 4 patients, respectively. Among 89 asymptomatic carriers above the age of 50 years (28 males, 61 females), the mtDNA mutations m. 11778G > A, m. 3460G > A and m. 14484 T > C were found in 60, 12 and 17 carriers, respectively. Late onset-LHON patients had significantly higher mean cumulative tobacco and alcohol consumption compared with unaffected carriers. However, there was no significant difference between late onset-and typical LHON patients with regard to daily tobacco and weekly alcohol consumption before disease onset. Conclusion: As already shown for typical LHON, alcohol consumption and smoking are important trigger factors also for the late manifestation. LHON should be considered in the differential diagnosis of subacute blindness even in older patients.

OBJECTIVES: To study the epidemiology of optic nerve hypoplasia. DESIGN AND METHODS: Children with optic nerve hypoplasia and visual impairment were identified through the Swedish Register of Visually Impaired Children. Pre- and perinatal characteristics were obtained from the Medical Birth Registry and by scrutinizing pregnancy and delivery records. Clinical characteristics of children with optic nerve hypoplasia are described. The following risk factors were studied: maternal age, parity, maternal smoking, gestational duration, birth weight, delivery method, Apgar score, maternal disease during pregnancy, drugs used in early pregnancy. RESULTS: Young maternal age, first parity, maternal smoking, preterm birth and factors associated with preterm birth were risk factors for optic nerve hypoplasia. There was an indicated association with the use of fertility drugs and antidepressant drugs. CONCLUSIONS: Optic nerve hypoplasia is apparently associated not only with other anomolies, notably of the central nervous system, but also with signs of general disturbance in fetal development.