Page 107 - GTM-2-3

Global Translational Medicine TEs link to Parkinson’s risk and progression

authorization from the Accelerating Medicines Partnership the PDBP and PPMI cohorts had longitudinal visits with
in PD (AMP-PD) databases (v2.5 release, https://amp-pd. several follow-up visits.
org) upon signing the AMP-PD Data Use Agreement. The
Institutional Review Board of the School of Medicine, Sun 2.2. TEs discovery and annotation
Yat-sen University, approved the current analysis. The WGS CRAM files of 1,931 subjects were generated
To reduce genetic heterogeneity, participants of through the alignment of sequencing reads to the human
Hispanic or Latino heritage were excluded, and only reference genome GRCH38DH using the BWA-MEM
[37]
[38]
subjects from the Caucasian population were included (version 0.7.15) , following the GATK (version 4.0) best
[39]
in subsequent analyses. The majority of subjects initially practices workflow . TEs were called using the Mobile
[40]
recruited in the PPMI, PDBP, and BioIFND cohorts had Element Locator Tool (MELT, version 2.2.2) , which was
PD, although it is possible that some subjects may have specifically designed for detecting TEs in Illumina platform-
received different neurodegenerative disease diagnoses based WGS data. The reliability of the MELT has been
during the follow-up period. For the PD cases, we included validated in projects such as the 1000 Genomes Project
[41]
[42]
only those who were initially diagnosed with PD at baseline (1KGP) and the NyuWa Genome Project . Post-discovery
[43]
and remained exclusively affected by PD throughout the QC was performed using vcftools (version 0.1.16) and
[44]
follow-up period. Regarding healthy controls, we included PLINK (version 1.90b6.22) . In this study, each TE was
subjects who did not exhibit any neurodegenerative assigned a unique ID based on its chromosome position
diseases at both baseline and during the follow-up period. information and TE type, following the ID format: chr_pos_
After quality control (QC), a total of 1,931 PD patients and ALU/LINE1/SVA. A detailed description of TE discovery
healthy controls were included in further analysis (Table 1). and QC is shown in the Sections S2 and S3.
All of them had whole-genome sequencing (WGS) data, The insertion frequency of TEs was calculated
and 1,709 of them also had whole-blood transcriptome using vcftools after QC. The lengths of TEs were
[43]
sequencing (total RNA-seq) data from the baseline visit. extracted from the VCF file using vcftools. The Variant
Detailed information about the QC processes for WGS and Effect Predictor (VEP, version 109) , developed and
[45]
RNA-seq can be found in Section S1. maintained by Ensembl for annotating genomic variation
The clinical information used in this study includes regions, provides comprehensive information on the
sex, age of onset, education level, race, cohort, and PD functional impact of genetic variants. The positions of TEs
diagnosis information, as well as Montreal Cognitive (GRCH38DH) were extracted from the VCF file using
Assessment (MoCA) score, Hoehn-Yahr staging scale vcftools and were used as input for VEP of the Ensembl
(HY), and MDS Unified Parkinson Disease Rating Scale website (https://asia.ensembl.org/info/docs/tools/vep/
(MDS-UPDRS) (Table 1). Notably, patients with PD in index.html) to obtain the annotation results.

Table 1. Clinical characteristics of subjects in the PDBP, PPMI, and BioFIND cohorts at baseline
Group PDBP PPMI BioFIND
PD HC PD HC PD HC
Sample size 748 444 390 190 92 67
Age at baseline (mean years [SD]) 64.7 (11.02) 62.5 (8.96) 61.9 (9.55) 60.9 (10.34) 67.7 (6.22) 66.3 (7.64)
Male (N, %) 477 (73.8%) 197 (45.4%) 253 (74.9%) 125 (67.4%) 59 (64.1%) 36 (65.7%)
Hoehn and Yahr (mean [SD]) 1.28 (1.09) NA 1.56 (0.50) NA 1.93 (0.59) NA
MDS-UPDRS Part I (mean [SD]) 7.62 (5.67) NA 5.63 (4.30) NA 9.43 (6.09) NA
MDS-UPDRS Part II (mean [SD]) 6.90 (7.73) NA 5.96 (4.28) NA 11.04 (6.36) NA
MDS-UPDRS Part III (mean [SD]) 16.15 (14.97) NA 20.99 (8.90) NA 28.26 (14.39) NA
MDS-UPDRS Part IV (mean [SD]) 1.30 (2.94) NA NA a NA 3.17 (2.89) NA
MoCA (mean [SD]) 25.70 (3.25) NA 27.16 (2.28) NA 26.90 (2.51) NA
Legends: Hoehn and Yahr stage: The Hoehn and Yahr stage is a common scale to describe the progression of motor symptoms in PD;
MDS-UPDRS: MDS-Sponsored Revision of the UPDRS is a comprehensive scale for assessing Parkinson’s disease motor and non-motor symptoms.
MDS-UPDRS includes four parts: Part I: Non-motor experiences of daily living; Part II: Motor experiences of daily living; Part III: Motor examination;
Part IV: Motor complications; MOCA: Montreal Cognitive Assessment, an assessment scale for rapid screening for mild cognitive impairment.
a The baseline MDS-UPDRS Part IV: scores were not available for the patients from the PPMI cohort in this study.
Abbreviations: HC: Health control; NA: Not available; PD: Parkinson’s disease; SD: Standard deviation.

Volume 2 Issue 3 (2023) 3 https://doi.org/10.36922/gtm.1583