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

Yutaro Obara,Takeo Kato,Takahiro Nakayama,Kuniaki Ishii,Hidenori Sato

doi:10.1002/acn3.50914

Yutaro Obara, Takeo Kato + Show 3 more

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https://doi.org/10.1002/acn3.50914

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Abstract

ObjectiveGenetic 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.MethodsIn 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.ResultsThere 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).InterpretationWe 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.

Highlights

Parkinson’s disease (PD) is the second most common neurodegenerative disease and is characterized by motor impairments including rest tremor, akinesia, and rigidity
It is assumed that only transcripts of multiplication of the entire region of the MIDN gene can be functional, there is no evidence that suggests that this multiplication is associated with PD
The MIDN gene may be disrupted if the segmental multiplication is introduced within the MIDN gene, which is equivalent to the copy number (CN) decrease

Summary

Introduction

Parkinson’s disease (PD) is the second most common neurodegenerative disease and is characterized by motor impairments including rest tremor, akinesia, and rigidity. In Britain, a large-scale molecular epidemiological study related to sporadic PD (sPD) was performed by the Wellcome Trust Case Control Consortium 2 (WTCCC2) (www.wtccc.org.uk). Six previously reported loci and five new loci were identified as genetic risks for PD.[5] 8 of 9387 PD patients and none of the 13,863 controls had a large hemizygous deletion a 2019 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association.

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