Randomisation mendélienne et interactions gène-environnement dans la maladie de Parkinson

Epidemiological studies on the role of environmental factors in Parkinson's disease (PD) have shown several associations, but it is still debated whether they are causal, in particular because of a potential reverse causality bias due to the long prodromal phase of PD. The aim of our work is to provide evidence for the causal role of different exposures (smoking, alcohol, coffee and dairy consumption, body mass index [BMI]) in PD through two-sample Mendelian randomization (MR) analyses in the international Courage-PD consortium. Our results support an inverse causal association for smoking and BMI and a positive one for dairy consumption, with a bidirectional relationship for BMI. These associations were not explained by reverse causation, survival bias or incidence-prevalence bias. No association was found for alcohol and coffee consumption, but these results should be interpreted with caution due to limited statistical power for these exposures. Finally, we showed a significant interaction between smoking and the HLA-DRB1 gene, particularly a valine at position 11, providing further evidence for the role of smoking. This work highlights the interest and difficulties of using complementary causal inference methods for the study of complex diseases. It contributes to open interesting research avenues in the field of exposures involved in PD in order to develop prevention strategies.Les études épidémiologiques sur le rôle de facteurs environnementaux dans la maladie de Parkinson (MP) ont mis en évidence plusieurs associations, mais leur causalité est encore discutée, en particulier en raison d’un biais potentiel de causalité inverse lié à la longue phase prodromale de la MP. Notre travail a pour objectif d’apporter des arguments en faveur du rôle causal de différentes expositions (tabagisme, consommation d’alcool, de café et de produits laitiers, indice de masse corporelle [IMC]) dans la MP au travers d’analyses de randomisation mendélienne (RM) à deux échantillons dans le consortium international Courage-PD. Nos résultats sont en faveur d’une association causale inverse pour la consommation de tabac et l’IMC et positive pour la consommation de produits laitiers, avec une relation bidirectionnelle pour l’IMC. Ces associations ne sont pas expliquées par la causalité inverse ni par un biais de survie ou d’incidence-prévalence. Aucune association n’a été mise en évidence pour la consommation d’alcool et de café, mais ces résultats sont à interpréter avec prudence en raison d’une puissance statistique limitée pour ces expositions. Enfin, nous avons montré une interaction significative entre le tabagisme et le gène HLA-DRB1, et plus particulièrement une valine en position 11, apportant une preuve supplémentaire quant au rôle du tabac. Ce travail souligne l’intérêt d’utiliser des méthodes complémentaires d’inférence causale pour l’étude des maladies complexes et les difficultés rencontrées. Il contribue à ouvrir des pistes de recherche intéressantes dans le domaine des expositions impliquées dans la MP dans le but de développer des stratégies de prévention

Randomisation mendélienne et interactions gène-environnement dans la maladie de Parkinson

Epidemiological studies on the role of environmental factors in Parkinson's disease (PD) have shown several associations, but it is still debated whether they are causal, in particular because of a potential reverse causality bias due to the long prodromal phase of PD. The aim of our work is to provide evidence for the causal role of different exposures (smoking, alcohol, coffee and dairy consumption, body mass index [BMI]) in PD through two-sample Mendelian randomization (MR) analyses in the international Courage-PD consortium. Our results support an inverse causal association for smoking and BMI and a positive one for dairy consumption, with a bidirectional relationship for BMI. These associations were not explained by reverse causation, survival bias or incidence-prevalence bias. No association was found for alcohol and coffee consumption, but these results should be interpreted with caution due to limited statistical power for these exposures. Finally, we showed a significant interaction between smoking and the HLA-DRB1 gene, particularly a valine at position 11, providing further evidence for the role of smoking. This work highlights the interest and difficulties of using complementary causal inference methods for the study of complex diseases. It contributes to open interesting research avenues in the field of exposures involved in PD in order to develop prevention strategies.Les études épidémiologiques sur le rôle de facteurs environnementaux dans la maladie de Parkinson (MP) ont mis en évidence plusieurs associations, mais leur causalité est encore discutée, en particulier en raison d’un biais potentiel de causalité inverse lié à la longue phase prodromale de la MP. Notre travail a pour objectif d’apporter des arguments en faveur du rôle causal de différentes expositions (tabagisme, consommation d’alcool, de café et de produits laitiers, indice de masse corporelle [IMC]) dans la MP au travers d’analyses de randomisation mendélienne (RM) à deux échantillons dans le consortium international Courage-PD. Nos résultats sont en faveur d’une association causale inverse pour la consommation de tabac et l’IMC et positive pour la consommation de produits laitiers, avec une relation bidirectionnelle pour l’IMC. Ces associations ne sont pas expliquées par la causalité inverse ni par un biais de survie ou d’incidence-prévalence. Aucune association n’a été mise en évidence pour la consommation d’alcool et de café, mais ces résultats sont à interpréter avec prudence en raison d’une puissance statistique limitée pour ces expositions. Enfin, nous avons montré une interaction significative entre le tabagisme et le gène HLA-DRB1, et plus particulièrement une valine en position 11, apportant une preuve supplémentaire quant au rôle du tabac. Ce travail souligne l’intérêt d’utiliser des méthodes complémentaires d’inférence causale pour l’étude des maladies complexes et les difficultés rencontrées. Il contribue à ouvrir des pistes de recherche intéressantes dans le domaine des expositions impliquées dans la MP dans le but de développer des stratégies de prévention

Dairy Intake and Parkinson's Disease : A Mendelian Randomization Study

BACKGROUND: Previous prospective studies highlighted dairy intake as a risk factor for Parkinson's disease (PD), particularly in men. It is unclear whether this association is causal or explained by reverse causation or confounding.OBJECTIVE: The aim is to examine the association between genetically predicted dairy intake and PD using two-sample Mendelian randomization (MR).METHODS: We genotyped a well-established instrumental variable for dairy intake located in the lactase gene (rs4988235) within the Courage-PD consortium (23 studies; 9823 patients and 8376 controls of European ancestry).RESULTS: Based on a dominant model, there was an association between genetic predisposition toward higher dairy intake and PD (odds ratio [OR] per one serving per day = 1.70, 95% confidence interval = 1.12-2.60, P = 0.013) that was restricted to men (OR = 2.50 [1.37-4.56], P = 0.003; P-difference with women = 0.029).CONCLUSIONS: Using MR, our findings provide further support for a causal relationship between dairy intake and higher PD risk, not biased by confounding or reverse causation. Further studies are needed to elucidate the underlying mechanisms. © 2022 International Parkinson and Movement Disorder Society

The Interaction between HLA-DRB1 and Smoking in Parkinson's Disease Revisited

BACKGROUND: Two studies that examined the interaction between HLA-DRB1 and smoking in Parkinson's disease (PD) yielded findings in opposite directions.OBJECTIVE: To perform a large-scale independent replication of the HLA-DRB1 × smoking interaction.METHODS: We genotyped 182 single nucleotide polymorphism (SNPs) associated with smoking initiation in 12 424 cases and 9480 controls to perform a Mendelian randomization (MR) analysis in strata defined by HLA-DRB1.RESULTS: At the amino acid level, a valine at position 11 (V11) in HLA-DRB1 displayed the strongest association with PD. MR showed an inverse association between genetically predicted smoking initiation and PD only in absence of V11 (odds ratio, 0.74, 95% confidence interval, 0.59-0.93, PInteraction = 0.028). In silico predictions of the influence of V11 and smoking-induced modifications of α-synuclein on binding affinity showed findings consistent with this interaction pattern.CONCLUSIONS: Despite being one of the most robust findings in PD research, the mechanisms underlying the inverse association between smoking and PD remain unknown. Our findings may help better understand this association. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Replication of a Novel Parkinson's Locus in a European Ancestry Population

International audienceBackground: A recently published East Asian genome-wide association study of Parkinson;s disease (PD) reported 2 novel risk loci, SV2C and WBSCR17.Objectives: The objective of this study were to determine whether recently reported novel SV2C and WBSCR17 loci contribute to the risk of developing PD in European and East Asian ancestry populations.Methods: We report an association analysis of recently reported variants with PD in the COURAGE-PD cohort (9673 PD patients; 8465 controls) comprising individuals of European and East Asian ancestries. In addition, publicly available summary data (41,386 PD patients; 476,428 controls) were pooled.Results: Our findings confirmed the role of the SV2C variant in PD pathogenesis (rs246814, COURAGE-PD PEuropean = 6.64 × 10-4 , pooled PD P = 1.15 × 10-11 ). The WBSCR17 rs9638616 was observed as a significant risk marker in the East Asian pooled population only (P = 1.16 × 10-8 ).Conclusions: Our comprehensive study provides an up-to-date summary of recently detected novel loci in different PD populations and confirmed the role of SV2C locus as a novel risk factor for PD irrespective of the population or ethnic group analyzed. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Mendelian Randomisation Study of Smoking, Alcohol, and Coffee Drinking in Relation to Parkinson's Disease

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