Lack of Causal Associations of Inflammatory Bowel Disease with Parkinson's Disease and Other Neurodegenerative Disorders

Zeng, Ruijie; Wang, Jinghua; Zheng, Chunwen; Jiang, Rui; Tong, Shuangshuang; Wu, Huihuan; Zhuo, Zewei; Yang, Qi; Leung, Felix W.; Sha, Weihong; Chen, Hao

doi:10.1002/mds.29386

Cited by 15 publications

(8 citation statements)

References 36 publications

(60 reference statements)

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“…Interestingly, ATP6V0A1 , a gene that was identified in our NHC analysis, was among the novel pleiotropic loci shared between PD and CD and between PD and UC in that study. However, two recent Mendelian randomization studies, which also used summary statistics from large-scale GWAS of PD and IBD, failed to find a causal relationship between the two conditions [ 92 , 93 ]. These conflicting findings might be attributable to the possibility that common genetic variants contributing to the IBD-PD comorbidity account for only a small fraction of the overall cases [ 50 , 93 ].…”

Section: Discussionmentioning

confidence: 99%

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The landscape of rare genetic variation associated with inflammatory bowel disease and Parkinson’s disease comorbidity

Kars,

Wu,

Stenson

et al. 2024

Genome Med

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Background Inflammatory bowel disease (IBD) and Parkinson’s disease (PD) are chronic disorders that have been suggested to share common pathophysiological processes. LRRK2 has been implicated as playing a role in both diseases. Exploring the genetic basis of the IBD-PD comorbidity through studying high-impact rare genetic variants can facilitate the identification of the novel shared genetic factors underlying this comorbidity. Methods We analyzed whole exomes from the BioMe BioBank and UK Biobank, and whole genomes from a cohort of 67 European patients diagnosed with both IBD and PD to examine the effects of LRRK2 missense variants on IBD, PD and their co-occurrence (IBD-PD). We performed optimized sequence kernel association test (SKAT-O) and network-based heterogeneity clustering (NHC) analyses using high-impact rare variants in the IBD-PD cohort to identify novel candidate genes, which we further prioritized by biological relatedness approaches. We conducted phenome-wide association studies (PheWAS) employing BioMe BioBank and UK Biobank whole exomes to estimate the genetic relevance of the 14 prioritized genes to IBD-PD. Results The analysis of LRRK2 missense variants revealed significant associations of the G2019S and N2081D variants with IBD-PD in addition to several other variants as potential contributors to increased or decreased IBD-PD risk. SKAT-O identified two significant genes, LRRK2 and IL10RA, and NHC identified 6 significant gene clusters that are biologically relevant to IBD-PD. We observed prominent overlaps between the enriched pathways in the known IBD, PD, and candidate IBD-PD gene sets. Additionally, we detected significantly enriched pathways unique to the IBD-PD, including MAPK signaling, LPS/IL-1 mediated inhibition of RXR function, and NAD signaling. Fourteen final candidate IBD-PD genes were prioritized by biological relatedness methods. The biological importance scores estimated by protein–protein interaction networks and pathway and ontology enrichment analyses indicated the involvement of genes related to immunity, inflammation, and autophagy in IBD-PD. Additionally, PheWAS provided support for the associations of candidate genes with IBD and PD. Conclusions Our study confirms and uncovers new LRRK2 associations in IBD-PD. The identification of novel inflammation and autophagy-related genes supports and expands previous findings related to IBD-PD pathogenesis, and underscores the significance of therapeutic interventions for reducing systemic inflammation.

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Section: Discussionmentioning

confidence: 99%

“…Instead, the risks are driven by rarer variants. Other factors, such as chronic low-grade inflammation and environmental factors might cumulatively contribute to the development of PD in some IBD cases [ 6 , 92 ].…”

Section: Discussionmentioning

confidence: 99%

The landscape of rare genetic variation associated with inflammatory bowel disease and Parkinson’s disease comorbidity

Kars,

Wu,

Stenson

et al. 2024

Genome Med

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“…According to the standard protocols of MR study 18,19,29,30 , each instrumental variable (IV) should satisfy three assumptions as shown below: (i) The IV is significantly associated with the exposure; (ii) The IV is independent of all the other IVs and potential confounding factors; (iii) The IV affects the outcome only through the exposure. During the MR analysis, multiple statistical approaches, such as inverse variance weighted (IVW) method and weighted median method, were performed, however, only IVW was selected to be the major method to examine causal associations due to its high statistical power 35,36 . To guarantee the statistical robustness of MR analysis, we conducted comprehensive downstream analyses to evaluate potential biases, which might undermine the reliability of our findings.…”

Section: Methodsmentioning

confidence: 99%

Circulating inflammatory proteins and risk of Parkinson’s disease and other neurodegenerative disorders: a two-sample Mendelian randomization study

Chen,

Li,

Zhou

et al. 2024

Preprint

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Background: Accumulating studies have suggested associations between peripheral inflammation and neurodegenerative disorders, including Parkinson's disease (PD). Objective: To evaluate the causal associations between 91 plasma inflammatory proteins and 4 neurodegenerative disorders. Methods: Two-sample Mendelian randomization studies were performed using summary statistics extracted from genome-wide association studies of 91 plasma inflammatory proteins and 4 neurodegenerative disorders. Results: Genetically proxied tumor necrosis factor receptor superfamily member 9 levels were causally associated with reduced risk of PD (odds ratio [OR] = 0.82, 95% confidence interval [CI] = 0.74-0.92, p = 4.18 x 10-4, Bonferroni-corrected p < 0.05 for 91 proteins). Additionally, we identified potential causal associations between the levels of C-C motif chemokine 20 (OR = 1.14, 95%CI = 1.03-1.25, p = 1.29 x 10-2) and Alzheimer's disease, between levels of leukemia inhibitory factor receptor (OR = 0.91, 95%CI = 0.84-0.98, p = 1.12 x 10-2) and tumor necrosis factor-β (OR = 0.95, 95%CI = 0.93-0.98, p = 1.01 x 10-3) and amyotrophic lateral sclerosis, between levels of adenosine deaminase (OR = 0.81, 95%CI = 0.71-0.94, p = 5.14 x 10-3) and interleukin-18 (OR = 0.81, 95%CI = 0.69-0.96, p = 1.68 x 10-2) and multiple sclerosis. Conclusions: Our study unveils plausible causal associations between circulating inflammatory factors and risk of 4 neurodegenerative disorders. These findings hold promise for promoting risk assessment and prevention of neurodegenerative disorders, meriting further exploration.

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“…In cases where a corresponding outcome had missing SNPs, we substituted them with overlapping proxy SNPs that exhibited complete LD (r 2 = 1). Additionally, we also calculated the F-statistic value for each IVs using the formula (β/SE) 2 [ 26 ]. Meanwhile, the Steiger filtering test was applied, and only those SNPs with a higher explanatory variance in the exposure than the outcome was retained [ 27 ].…”

Section: Methodsmentioning

confidence: 99%

Causal effect of blood osteocalcin on the risk of Alzheimer’s disease and the mediating role of energy metabolism

Guo,

Yang,

Zhou

et al. 2024

Transl Psychiatry

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Growing evidence suggests an association between osteocalcin (OCN), a peptide derived from bone and involved in regulating glucose and lipid metabolism, and the risk of Alzheimer’s disease (AD). However, the causality of these associations and the underlying mechanisms remain uncertain. We utilized a Mendelian randomization (MR) approach to investigate the causal effects of blood OCN levels on AD and to assess the potential involvement of glucose and lipid metabolism. Independent instrumental variables strongly associated (P < 5E-08) with blood OCN levels were obtained from three independent genome-wide association studies (GWAS) on the human blood proteome (N = 3301 to 35,892). Two distinct summary statistics datasets on AD from the International Genomics of Alzheimer’s Project (IGAP, N = 63,926) and a recent study including familial-proxy AD patients (FPAD, N = 472,868) were used. Summary-level data for fasting glucose (FG), 2h-glucose post-challenge, fasting insulin, HbA1c, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, total cholesterol (TC), and triglycerides were incorporated to evaluate the potential role of glucose and lipid metabolism in mediating the impact of OCN on AD risk. Our findings consistently demonstrate a significantly negative correlation between genetically determined blood OCN levels and the risk of AD (IGAP: odds ratio [OR, 95%CI] = 0.83[0.72–0.96], P = 0.013; FPAD: OR = 0.81 [0.70–0.93], P = 0.002). Similar estimates with the same trend direction were obtained using other statistical approaches. Furthermore, employing multivariable MR analysis, we found that the causal relationship between OCN levels and AD was disappeared after adjustment of FG and TC (IGAP: OR = 0.97[0.80–1.17], P = 0.753; FPAD: OR = 0.98 [0.84–1.15], P = 0.831). There were no apparent instances of horizontal pleiotropy, and leave-one-out analysis showed good stability of the estimates. Our study provides evidence supporting a protective effect of blood OCN levels on AD, which is primarily mediated through regulating FG and TC levels. Further studies are warranted to elucidate the underlying physio-pathological mechanisms.

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Lack of Causal Associations of Inflammatory Bowel Disease with Parkinson's Disease and Other Neurodegenerative Disorders

Cited by 15 publications

References 36 publications

The landscape of rare genetic variation associated with inflammatory bowel disease and Parkinson’s disease comorbidity

The landscape of rare genetic variation associated with inflammatory bowel disease and Parkinson’s disease comorbidity

Circulating inflammatory proteins and risk of Parkinson’s disease and other neurodegenerative disorders: a two-sample Mendelian randomization study

Causal effect of blood osteocalcin on the risk of Alzheimer’s disease and the mediating role of energy metabolism

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