Dataset Information

Midnolin is a confirmed genetic risk factor for Parkinson's disease.

ABSTRACT: Objective: Genetic analysis of patients with familial Parkinson's disease (PD) identified many causative genes. However, the majority of PD cases are sporadic, and the mechanisms of onset still remain unclear. Previously, we found that Midnolin (MIDN) is associated with PD in a Yamagata (Japan) cohort study and that MIDN regulates neurite outgrowth and Parkin expression in neuronal cells. In the present study, we aimed to replicate the genetic association between MIDN and PD in a large British population cohort.

Methods: In this replication study, we analyzed the copy number variations and single-nucleotide polymorphisms of the MIDN gene in a large British population on a case-control genome-wide association study dataset including 2,860 controls and 2,168 PD patients.

Results: There was significant copy number loss in the MIDN gene with an odds ratio of 4.35 (P < 2.2 × 10^-16 ). Furthermore, there were many patients in both the British and Yamagata case groups who have a long spanning deletion. The odds ratio dramatically increased to 22.3 (P = 3.59 × 10^-15 ) when a deletion spanning more than 50,000 bp was defined as the copy number loss. There were no significant differences between the controls and study cases for two relatively frequent single-nucleotide polymorphisms (rs3746106 and rs3746107).

Interpretation: We showed the strong genetic association of MIDN with PD development in a British population and in a Japanese population, suggesting MIDN is a confirmed and universal genetic risk factor for PD.

SUBMITTER: Obara Y

PROVIDER: S-EPMC6856597 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Midnolin is a confirmed genetic risk factor for Parkinson's disease.

Obara Yutaro Y Sato Hidenori H Nakayama Takahiro T Kato Takeo T Ishii Kuniaki K

Annals of clinical and translational neurology 20191006 11

<h4>Objective</h4>Genetic analysis of patients with familial Parkinson's disease (PD) identified many causative genes. However, the majority of PD cases are sporadic, and the mechanisms of onset still remain unclear. Previously, we found that Midnolin (MIDN) is associated with PD in a Yamagata (Japan) cohort study and that MIDN regulates neurite outgrowth and Parkin expression in neuronal cells. In the present study, we aimed to replicate the genetic association between MIDN and PD in a large Br ...[more]

PMID: 31588691

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Project description:Growing evidence suggests overlap between Alzheimer's disease (AD) and Parkinson's disease (PD) pathophysiology in a subset of patients. Indeed, 50-80% of autopsy cases with a primary clinicopathological diagnosis of Lewy body disease (LBD)-most commonly manifesting during life as PD-have concomitant amyloid-beta and tau pathology, the defining pathologies of AD. Here we evaluated common genetic variants in genome-wide association with AD as predictors of concomitant AD pathology in the brains of people with a primary clinicopathological diagnosis of PD or Dementia with Lewy Bodies (DLB), diseases both characterized by neuronal Lewy bodies. In the first stage of our study, 127 consecutive autopsy-confirmed cases of PD or DLB from a single center were assessed for AD neuropathological change (ADNC), and these same cases were genotyped at 20 single nucleotide polymorphisms (SNPs) found by genome-wide association study to associate with risk for AD. In these 127 training set individuals, we developed a logistic regression model predicting the presence of ADNC, using backward stepwise regression for model selection and tenfold cross-validation to estimate performance. The best-fit model generated a risk score for ADNC (ADNC-RS) based on age at disease onset and genotype at three SNPs (APOE, BIN1, and SORL1 loci), with an area under the receiver operating curve (AUC) of 0.751 in our training set. In the replication stage of our study, we assessed model performance in a separate test set of the next 81 individuals genotyped in our center. In the test set, the AUC was 0.781, and individuals with ADNC-RS in the top quintile had four-fold increased likelihood of having AD pathology at autopsy compared with those in each of the lowest two quintiles. Finally, in the validation stage of our study, we applied our ADNC-RS model to 70 LBD individuals from 20 Alzheimer's Disease Research Centers (ADRC) whose autopsy and genetic data were available in the National Alzheimer's Coordinating Center (NACC) database. In this validation set, the AUC was 0.754. Thus, in patients with autopsy-confirmed PD or DLB, a simple model incorporating three AD-risk SNPs and age at disease onset substantially enriches for concomitant AD pathology at autopsy, with implications for identifying LBD patients in which targeting amyloid-beta or tau is a therapeutic strategy.

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Dataset Information

Midnolin is a confirmed genetic risk factor for Parkinson's disease.

Publications

Midnolin is a confirmed genetic risk factor for Parkinson's disease.

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