Exploring the genetic contribution to idiopathic Parkinson disease

Background: Parkinson disease (PD) is a major cause of death and disability and has a devastating global socioeconomic impact. It affects 1-2% of the population above the age of 65 and its prevalence increases as the population ages. Several biological processes have been implicated in Parkinson disease, including mitochondrial dysfunction, aberrant protein clearance, and neuroinflammation. To which degree these processes are cause, effect or bystander to disease initiation and progression, remains however largely unknown. Having limited understanding of the mechanisms underlying the pathogenesis and pathophysiology of Parkinson disease, we are unable to develop disease-modifying therapies and patients face a future of progressive disability and premature death. There is a clear hereditary component to idiopathic PD, established through both twin studies and genome-wide association studies. However, only a minor fraction of the total estimated heritability can be explained by known associated genetic variability. It has been hypothesized that the cumulative effects of rare, low-impact mutations spread across genes and biological pathways could explain some of this “missing heritability”. Aims: The aim of this work was to explore the genetic contribution to idiopathic PD, focusing on the cumulative effects of rare mutations. Materials and methods: The main study population utilized in all four papers was the ParkWest cohort, a Norwegian population-based cohort of incident PD. In paper I, ParkWest provided both cases and controls, including clinical longitudinal data up to and including 7 years after baseline. All ParkWest cases were whole-exome sequenced and combined with previously sequenced control samples to form the genetic cohort utilized in papers II-IV. Additionally, a whole-exome sequencing cohort from the Parkinson Progression Markers Initiative was used in papers II-IV. Finally, a publicly available chip-genotyped dataset (NeuroX) from the International Parkinson’s Disease Genomics Consortium was used as a replication cohort in paper IV. In paper I, we characterized the familial aggregation of Parkinson disease in the ParkWest cohort and explored the effect of family history on disease progression. Subsequently, we used genetic data from multiple cohorts to assess the impact of rare, protein-altering mutations in mitochondrial biological pathways (paper III) and in genes previously linked to PD (paper II and IV). Results and conclusions: We show that, while familial aggregation is present in our Norwegian cohort, this has a slightly lower effect size compared to previous studies. Through regression analysis we also show that having a family history of PD among first degree relatives is associated with a slightly milder phenotype, which may be due to genetic variability. In paper II, we attempted to replicate the results of a recently published study reporting an association between genetic variation in the TRAP1 gene and Parkinson disease. Our analyses did not replicate this association in our Norwegian cohort. Moreover, using stricter quality control parameters abolished the association in the same dataset used in the original study. Our results do not support the proposed role of TRAP1 in idiopathic PD. In paper III, we sought to investigate the role of rare, amino acid changing variation in molecular pathways related to mitochondrial function. Using the sequence kernel association (SKAT) test, we detected a statistically significant enrichment in the pathway of mitochondrial DNA maintenance. Impaired mitochondrial DNA homeostasis has previously been shown to be present in PD neurons, and our results indicate that this dysfunction could be partly mediated by inherited genetic mutations. In paper IV, we performed a targeted single gene and gene-set association study on genes that had previously been implicated in PD through genome-wide association studies. We identified 303 genes of interest, but did not find statistically significant associations, either in the single gene or gene-set analyses. Our results do not therefore support a major role for rare variant enrichment in genes tagged by GWAS, but cannot rule out effects with small effect sizes.Doktorgradsavhandlin

DNA Methylation Age Acceleration Is Not Associated with Age of Onset in Parkinson's Disease

Background Epigenetic clocks using DNA methylation (DNAm) to estimate biological age have become popular tools in the study of neurodegenerative diseases. Notably, several recent reports have shown a strikingly similar inverse relationship between accelerated biological aging, as measured by DNAm, and the age of onset of several neurodegenerative disorders, including Parkinson's disease (PD). Common to all of these studies is that they were performed without control subjects and using the exact same measure of accelerated aging: DNAm age minus chronological age. Objective We aimed to assess the validity of these findings in PD, using the same dataset as in the original study, blood DNAm data from the Parkinson's Progression Markers Initiative cohort, but also including control samples in the analyses. Methods We replicated the analyses and findings of the previous study and then reanalyzed the dataset incorporating control samples to account for underlying age-related biases. Results Our reanalysis shows that there is no correlation between age of onset and DNAm age acceleration. Conversely, there is a pattern of overestimating DNAm age in younger and underestimating DNAm age in older individuals in the dataset that entirely explains the previously reported association. Conclusions Our findings refute the previously reported inverse relationship between DNAm age acceleration and age of onset in PD. We show that these findings are fully accounted for by an expected over/underestimation of DNAm age in younger/older individuals. Furthermore, this effect is likely to be responsible for nearly identical findings reported in other neurodegenerative diseases. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.publishedVersio

Meta-analysis of whole-exome sequencing data from two independent cohorts finds no evidence for rare variant enrichment in Parkinson disease associated loci

Parkinson disease (PD) is a complex neurodegenerative disorder influenced by both environmental and genetic factors. While genome wide association studies have identified several susceptibility loci, many causal variants and genes underlying these associations remain undetermined. Identifying these is essential in order to gain mechanistic insight and identify biological pathways that may be targeted therapeutically. We hypothesized that gene-based enrichment of rare mutations is likely to be found within susceptibility loci for PD and may help identify causal genes. Whole-exome sequencing data from two independent cohorts were analyzed in tandem and by meta-analysis and a third cohort genotyped using the NeuroX-array was used for replication analysis. We employed collapsing methods (burden and the sequence kernel association test) to detect gene-based enrichment of rare, protein-altering variation within established PD susceptibility loci. Our analyses showed trends for three genes (GALC, PARP9 and SEC23IP), but none of these survived multiple testing correction. Our findings provide no evidence of rare mutation enrichment in genes within PD-associated loci, in our datasets. While not excluding that rare mutations in these genes may influence the risk of idiopathic PD, our results suggest that, if such effects exist, much larger sequencing datasets will be required for their detection.publishedVersio

Meta-analysis of whole-exome sequencing data from two independent cohorts finds no evidence for rare variant enrichment in Parkinson disease associated loci

Parkinson disease (PD) is a complex neurodegenerative disorder influenced by both environmental and genetic factors. While genome wide association studies have identified several susceptibility loci, many causal variants and genes underlying these associations remain undetermined. Identifying these is essential in order to gain mechanistic insight and identify biological pathways that may be targeted therapeutically. We hypothesized that gene-based enrichment of rare mutations is likely to be found within susceptibility loci for PD and may help identify causal genes. Whole-exome sequencing data from two independent cohorts were analyzed in tandem and by meta-analysis and a third cohort genotyped using the NeuroX-array was used for replication analysis. We employed collapsing methods (burden and the sequence kernel association test) to detect gene-based enrichment of rare, protein-altering variation within established PD susceptibility loci. Our analyses showed trends for three genes (GALC, PARP9 and SEC23IP), but none of these survived multiple testing correction. Our findings provide no evidence of rare mutation enrichment in genes within PD-associated loci, in our datasets. While not excluding that rare mutations in these genes may influence the risk of idiopathic PD, our results suggest that, if such effects exist, much larger sequencing datasets will be required for their detection.publishedVersio

The Pre-Raphaelites and Sweden : Reception-historical Analysis of the Pre-Raphaelite Art from a Swedish Point of View

The purpose of this essay is to examine the reception of Pre-Raphaelite art from a Swedish point of view. It is based on comparative and reception-historical analysis and aims to deter-mine how the reception, perception, and views of the Pre-Raphaelites has changed over time. The essay explores how the authors discuss the realism of the Pre-Raphaelites, whether the authors consider the Pre-Raphaelite imagery reactionary or innovative, and the authors' views on the art-historical significance of the Pre-Raphaelites. It examines how Pre-Raphaelite art was described and received by Swedish art historians during the 19th and 20th centuries and the reception of the 2009 Pre-Raphaelite exhibition held at the National Museum of Fine Arts in Stockholm. This was the first exhibition dedicated exclusively to the pre-Raphaelites in Sweden. The purpose of the exhibition was to introduce pre-Raphaelite art to the Northern European audience and included around 200 works of art, such as paintings, textiles, and photography

Students' views on the learning of kanji : A study the views and experiences of students at the Swedish universities concerning the teaching and learning of Chinese characters as used in Japanese

Kanji, the Chinese characters adopted to write the Japanese language, is often mentioned as one of the most difficult aspects of mastering said language. This is especially said about people from outside the Sinosphere i.e. PRC, Taiwan, North and South Korea, Japan and Vietnam. In the following thesis 12 students studying the Japanese language at Swedish universities were interviewed about their experiences when it comes to learning and being taught about kanji. A chapter summarizing some of the research that is relevant to this thesis is also included. Topics touched upon in this and the result chapter include the desire for more structured approach to kanji learning based on breaking down the characters into elemental components, spaced repetition (SRS), mnemonics

The Pre-Raphaelites and Sweden : Reception-historical Analysis of the Pre-Raphaelite Art from a Swedish Point of View

The purpose of this essay is to examine the reception of Pre-Raphaelite art from a Swedish point of view. It is based on comparative and reception-historical analysis and aims to deter-mine how the reception, perception, and views of the Pre-Raphaelites has changed over time. The essay explores how the authors discuss the realism of the Pre-Raphaelites, whether the authors consider the Pre-Raphaelite imagery reactionary or innovative, and the authors' views on the art-historical significance of the Pre-Raphaelites. It examines how Pre-Raphaelite art was described and received by Swedish art historians during the 19th and 20th centuries and the reception of the 2009 Pre-Raphaelite exhibition held at the National Museum of Fine Arts in Stockholm. This was the first exhibition dedicated exclusively to the pre-Raphaelites in Sweden. The purpose of the exhibition was to introduce pre-Raphaelite art to the Northern European audience and included around 200 works of art, such as paintings, textiles, and photography