MIDN locus structural variants and Parkinson's Disease risk

Abstract

Dear Editor, Based on a candidate gene analysis, Obara and colleagues previously reported an association between Parkinson's disease (PD) and deletion structural variants (SV)s at the MIDN locus in the Japanese population. 1 In their recent study, using genotyping data from a British cohort, Obara and colleagues further suggest MIDN as a confirmed and universal risk factor of PD. 2 To establish the pathogenicity of MIDN, as part of the International Parkinson's Disease Genomics Consortium (IPDGC), we utilized the summary statistics from the most recent PD meta-analysis, which involved 37.7k PD cases, 18.6 U.K. biobank proxy-cases, and 1.4 million controls. Consequently, we did not identify an association with risk of PD at this locus based on common SNP variants ( Fig. S1) 3 . In addition, we analyzed whole genome sequencing data (WGS) from eight cohorts totaling 3868 individuals (2742 PD cases and 1126 controls of European ancestry). SVs were genotyped from the WGS using the highly sensitive detection tool Manta. 4 The only major deletion detected was of a reference Alu retrotransposon (GRCh38 chr19:1247064-1247368, MAF = 0.014); however, further analysis identified no significant association between the Alu deletion and risk for PD (P = 0.74, b = À0.03, SE = 0.22) (Appendix S1). Four additional singleton deletions were detected, including deletions of three reference Alu retrotransposons and a 4822-bp deletion that was detected in a healthy control ( Fig. S2 and Table S1).Further, Obara and colleague reported deletions at the MIDN locus in 1.64% of controls. In view of this, we utilized gnomadSV, a comprehensive public SV database. This resource provides a call set of~445k SVs that were detected in 14,891 genomes, spanning four major global populations. 5 In support of our WGS analysis, as shown in (Fig. S3) no common deletion SVs were detected in the general population.In summary, we did not identify any PD-associated deletions within 100 kb of MIDN in the 3,868 individuals analyzed. SV calling using SNP genotyping data is notoriously difficult and it has been repeatedly reported that this method can result in a high false positive rate. [6][7][8] Due to this factor, SVs require functional validation, which was not presented for the MIDN deletions described in the Obara and colleagues' studies. Therefore, the lack of validation of the reported SVs, supported by the lack of evidence of these events in both the gno-madSV data and our WGS analysis, suggests that the MIDN deletions reported require further study before they can be unequivocally associated with PD.

Structural Variants of <i>Midnolin</i>, a Genetic Risk Factor for Parkinson’s Disease, in a Yamagata Cohort

“…However, Billingsley et al showed that no PDassociated deletions within the MIDN locus were identified by whole genome sequencing and no common deletions were detected in general populations. 11) We assume that discrepancies between our conclusions and those of Billingsley et al reflect the different methodologies used in the studies. 12) We identified no MIDN loss in healthy controls in the Yamagata cohort study, possibly because of Japanese genetic characteristics or because our previous Yamagata cohort study was not large enough to identify MIDN structural variants unlike in the large British population.…”

Insulin Enhances Gene Expression of Midnolin, a Novel Genetic Risk Factor for Parkinson’s Disease, via Extracellular Signal-Regulated Kinase, Phosphoinositide 3-Kinase and Multiple Transcription Factors in SH-SY5Y Cells

“…Although typical DNA-binding or transcription-activating domains have not been identified in the MIDN protein, MIDN affects the transcription levels of a number of genes, including PD-related genes (Obara and Ishii, 2018), indicating that MIDN functions as a transcription modulator. Thus, we believe that MIDN loss is associated with PD although this is controversial (Billingsley et al, 2020;Obara et al, 2020).…”

VolcanoSV enables accurate and robust structural variant calling in diploid genomes from single-molecule long read sequencing

“…Diff olp is the overlapping part of two segments' alignment on the reference and it can not be too large if there exists a real large INS or large DEL. VolcanoSV decides a large INS exits if the following conditions apply Dif f olp < 3000bp Dif f dis ≥ 30bp (6) or a large DEL exits if the following conditions apply…”