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An Increased Burden of Highly Active Retrotransposition Competent L1s Is Associated with Parkinson's Disease Risk and Progression in the PPMI Cohort.

ABSTRACT: Long interspersed element-1 (LINE-1/L1s) contributes 17% of the human genome with more than 1 million elements present; however, fewer than 100 of these have evidence for being retrotransposition competent (RC). In addition to those RC-L1s present in the reference genome, there are a small number of known non-reference L1 insertions that are also retrotransposition competent. L1 activity, whether through the potentially detrimental effects of their mRNA or protein expression or somatic retrotransposition events, has been linked to several neurological conditions. The polymorphic nature of both reference and non-reference RC-L1s in terms of their presence or absence will result in individuals harboring a different combination of these elements and it is currently unknown if this type of germline variation contributes to the risk of neurological disease. Here, we utilized whole-genome sequencing data from 178 healthy controls and 372 Parkinson's disease (PD) subjects from the Parkinson's Progression Markers Initiative (PPMI) to investigate the role of RC-L1s in PD. In the PPMI cohort, we identified 22 reference and 50 non-reference polymorphic RC-L1 loci. Focusing on 16 highly active RC-L1 loci, an increased burden of these elements (?9) was associated with PD (OR 1.25, 95% CI 1.03-1.51, p = 0.02). In addition, we identified significant associations of progression markers of PD and the burden of highly active RC-L1s. This study has identified a novel type of genetic element associated with PD risk and disease progression.

SUBMITTER: Pfaff AL

PROVIDER: S-EPMC7554759 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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An Increased Burden of Highly Active Retrotransposition Competent L1s Is Associated with Parkinson's Disease Risk and Progression in the PPMI Cohort.

Pfaff Abigail L AL Bubb Vivien J VJ Quinn John P JP Koks Sulev S

International journal of molecular sciences 20200908 18

Long interspersed element-1 (LINE-1/L1s) contributes 17% of the human genome with more than 1 million elements present; however, fewer than 100 of these have evidence for being retrotransposition competent (RC). In addition to those RC-L1s present in the reference genome, there are a small number of known non-reference L1 insertions that are also retrotransposition competent. L1 activity, whether through the potentially detrimental effects of their mRNA or protein expression or somatic retrotran ...[more]

PMID: 32911699

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Project description:IntroductionGenetic factors play an important role in Parkinson's disease (PD) risk. However, the genetic contribution to progression in Chinese PD patients has rarely been studied. This study investigated genetic associations with progression based on 30 PD risk loci common in a longitudinal cohort of Chinese PD patients and the Parkinson's Progression Markers Initiative (PPMI) cohort.MethodsPD patients from the true world (TW) Chinese PD longitudinal cohort and the PPMI cohort with demographic information and assessment scales were assessed. A panel containing 30 PD risk single nucleotide polymorphisms was tested. Progression rates of each scale were derived from random-effect slope values of mixed-effects regression models. Progression rates of multiple assessments were combined by using principal component analysis (PCA) to derive scores for composite, motor, and nonmotor progression. The association of genetic polymorphism and separate scales or PCA progression was analysed via linear regression.ResultsIn the Chinese PD cohort, MAOB rs1799836 was associated with progression based on the Montreal Cognitive Assessment, the top 3 principal components (PCs) of nonmotor PCA and PC1 of the composite PCA. In the PPMI cohort, both MDS-Unified Parkinson's Disease Rating Scale II and motor PC1 progression were associated with RIT2 rs12456492. The PARK16 haplotype was associated with Geriatric Depression Scale and the State-Trait Anxiety Inventory for Adults progression, and the SNCA haplotype was associated with the Hoehn-Yahr staging progression and motor PC1 progression. Ethnicity-stratified analysis showed that the association between MAOB rs1799836 and PD progression may be specific to Asian or Chinese patients.ConclusionMAOB rs1799836 was associated with the progression of nonmotor symptoms, especially cognitive impairment, and the composite progression of motor and nonmotor symptoms within our Chinese PD cohort. The RIT2 rs12456492 and SNCA haplotypes were associated with motor function decline, and the PARK16 haplotype was associated with progression in mood in the PPMI cohort.

Project description:Long interspersed element-1 (LINE-1/L1) is the only autonomous transposable element in the human genome that currently mobilises in both germline and somatic tissues. Recent studies have identified correlations between altered retrotransposon expression and the fatal neurodegenerative disease amyotrophic lateral sclerosis (ALS) in a subset of patients. The risk of an individual developing ALS is dependent on an interaction of genetic variants and subsequent modifiers during life. These modifiers could include environmental factors, which can lead to epigenetic and genomic changes, such as somatic mutations, occurring in the neuronal cells that degenerate as the disease develops. There are more than 1 million L1 copies in the human genome today, but only 80-100 L1 loci in the reference genome are considered to be retrotransposition-competent (RC) and an even smaller number of these RC-L1s loci are highly active. We hypothesise that RC-L1s could affect normal cellular function through their mutagenic potential conferred by their ability to retrotranspose in neuronal cells and through DNA damage caused by the endonuclease activity of the L1-encoded ORF2 protein. To investigate whether either an increase in the genomic burden of RC-L1s or epigenetic changes to RC-L1s altering their expression, could play a role in disease development, we chose a set of seven well characterised genomic RC-L1 loci that were reported earlier to be highly active in a cellular L1 retrotransposition reporter assay or serve as major source elements for germline and/or somatic retrotransposition events. Analysis of the insertion allele frequency of five polymorphic RC-L1s, out of the set of seven, for their presence or absence, did not identify an increased number individually or when combined in individuals with the disease. However, we did identify reduced levels of methylation of RC-L1s in the motor cortex of those individuals with both familial and sporadic ALS compared to control brains. The changes to the regulation of the loci encompassing these RC-L1s demonstrated tissue specificity and could be related to the disease process.

Project description:BackgroundThe Parkinson's Progression Markers Initiative (PPMI) is an ongoing observational, longitudinal cohort study of participants with Parkinson's disease, healthy controls, and carriers of the most common Parkinson's disease-related genetic mutations, which aims to define biomarkers of Parkinson's disease diagnosis and progression. All participants are assessed annually with a battery of motor and non-motor scales, 123-I Ioflupane dopamine transporter (DAT) imaging, and biological variables. We aimed to examine whether non-manifesting carriers of LRRK2 and GBA mutations have prodromal features of Parkinson's disease that correlate with reduced DAT binding.MethodsThis cross-sectional analysis is based on assessments done at enrolment in the subset of non-manifesting carriers of LRRK2 and GBA mutations enrolled into the PPMI study from 33 participating sites worldwide. The primary objective was to examine baseline clinical and DAT imaging characteristics in non-manifesting carriers with GBA and LRRK2 mutations compared with healthy controls. DAT deficit was defined as less than 65% of putamen striatal binding ratio expected for the individual's age. We used t tests, ?2 tests, and Fisher's exact tests to compare baseline demographics across groups. An inverse probability weighting method was applied to control for potential confounders such as age and sex. To account for multiple comparisons, we applied a family-wise error rate to each set of analyses. This study is registered with ClinicalTrials.gov, number NCT01141023.FindingsBetween Jan 1, 2014, and Jan 1, 2019, the study enrolled 208 LRRK2 (93% G2019S) and 184 GBA (96% N370S) non-manifesting carriers. Both groups were similar with respect to mean age, and about 60% were female. Of the 286 (73%) non-manifesting carriers that had DAT imaging results, 18 (11%) LRRK2 and four (3%) GBA non-manifesting carriers had a DAT deficit. Compared with healthy controls, both LRRK2 and GBA non-manifesting carriers had significantly increased mean scores on the Movement Disorders Society Unified Parkinson's Disease Rating Scale (total score 4·6 [SD 4·4] healthy controls vs 8·4 [7·3] LRRK2 vs 9·5 [9·2] GBA, p<0·0001 for both comparisons) and the Scale for Outcomes for PD - autonomic function (5·8 [3·7] vs 8·1 [5·9] and 8·4 [6·0], p<0·0001 for both comparisons). There was no difference in daytime sleepiness, anxiety, depression, impulsive-compulsive disorders, blood pressure, urate, and rapid eye movement (REM) behaviour disorder scores. Hyposmia was significantly more common only in LRRK2 non-manifesting carriers (69 [36%] of 194 healthy controls vs 114 [55%] of 208 LRRK2 non-manifesting carriers; p=0·0003). Finally, GBA but not LRRK2 non-manifesting carriers showed increased DAT striatal binding ratios compared with healthy controls in the caudate (healthy controls 2·98 [SD 0·63] vs GBA 3·26 [0·63]; p<0·0001), putamen (2·15 [0·56] vs 2·48 [0·52]; p<0·0001), and striatum (2·56 [0·57] vs 2·87 [0·55]; p<0·0001).InterpretationOur data show evidence of subtle motor and non-motor signs of Parkinson's disease in non-manifesting carriers compared with healthy controls that can precede DAT deficit. Longitudinal data will be essential to confirm these findings and define the trajectory and predictors for development of Parkinson's disease.FundingMichael J Fox Foundation for Parkinson's Research.

Dataset Information

An Increased Burden of Highly Active Retrotransposition Competent L1s Is Associated with Parkinson's Disease Risk and Progression in the PPMI Cohort.

Publications

An Increased Burden of Highly Active Retrotransposition Competent L1s Is Associated with Parkinson's Disease Risk and Progression in the PPMI Cohort.

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