The promise of genome‐wide SNP genotyping: from population genetics to disease gene identification

Advances in single nucleotide polymorphism (SNP) genotyping technologies have revolutionised our ability to scrutinise the human genome. My PhD research focuses on using these new technologies to catalogue genetic variability in a collection of diverse populations from around the globe, and to determine the role of genetic variants in neurological diseases. First, I present and discuss the analysis of genome‐wide SNP data in individuals from ethnically and geographically diverse human populations uncovering the diversity of genotype, haplotype and copy number variation in these populations. Second, I will describe an autozygosity mapping approach in three Brazilian dystoniaparkinsonism families which lead to the identification of a novel disease‐segregating mutation in the gene PRKRA. Third, I will report on a large genome‐wide association study in Parkinson’s disease, uncovering genetic variability at the SNCA and MAPT loci that are strongly associated with risk for developing disease. Forth, I provide compelling evidence that genetic variants at the SNCA locus are also significantly associated with risk for developing multiple system atrophy. This finding represents the first reproducible risk gene for this devastating disorder, and causally links this condition to the more common neurodegenerative disorder Parkinson’s disease. Finally, I present the results of a comprehensive mutational screening study investigating the frequency and spectrum of sequence and copy number mutations in the parkinsonism genes PRKN and PINK in individuals with early-onset Parkinson’s disease, in multiple system atrophy patients and in normal controls. In summary, the data presented in this thesis emphasise the critical role that genetic variability plays in the pathogenesis of neurological disorders

A genome-wide association study in multiple system atrophy

Objective: To identify genetic variants that play a role in the pathogenesis of multiple system atrophy (MSA), we undertook a genome-wide association study (GWAS). Methods: We performed a GWAS with .5 million genotyped and imputed single nucleotide polymorphisms (SNPs) in 918 patients with MSA of European ancestry and 3,864 controls. MSA cases were collected from North American and European centers, one third of which were neuropathologically confirmed. Results: We found no significant loci after stringent multiple testing correction. A number of regions emerged as potentially interesting for follow-up at p , 1 3 1026, including SNPs in the genes FBXO47, ELOVL7, EDN1, and MAPT. Contrary to previous reports, we found no association of the genes SNCA and COQ2 with MSA. Conclusions: We present a GWAS in MSA.We have identified several potentially interesting gene loci, including the MAPT locus, whose significance will have to be evaluated in a larger sample set. Common genetic variation in SNCA and COQ2 does not seem to be associated with MSA. In the future, additional samples of well-characterized patients with MSA will need to be collected to perform a larger MSA GWAS, but this initial study forms the basis for these next steps

Parkinson's disease age at onset genome-wide association study : Defining heritability, genetic loci, and α-synuclein mechanisms

Background Increasing evidence supports an extensive and complex genetic contribution to PD. Previous genome-wide association studies (GWAS) have shed light on the genetic basis of risk for this disease. However, the genetic determinants of PD age at onset are largely unknown. Objectives To identify the genetic determinants of PD age at onset. Methods Using genetic data of 28,568 PD cases, we performed a genome-wide association study based on PD age at onset. Results We estimated that the heritability of PD age at onset attributed to common genetic variation was similar to 0.11, lower than the overall heritability of risk for PD (similar to 0.27), likely, in part, because of the subjective nature of this measure. We found two genome-wide significant association signals, one at SNCA and the other a protein-coding variant in TMEM175, both of which are known PD risk loci and a Bonferroni-corrected significant effect at other known PD risk loci, GBA, INPP5F/BAG3, FAM47E/SCARB2, and MCCC1. Notably, SNCA, TMEM175, SCARB2, BAG3, and GBA have all been shown to be implicated in alpha-synuclein aggregation pathways. Remarkably, other well-established PD risk loci, such as GCH1 and MAPT, did not show a significant effect on age at onset of PD. Conclusions Overall, we have performed the largest age at onset of PD genome-wide association studies to date, and our results show that not all PD risk loci influence age at onset with significant differences between risk alleles for age at onset. This provides a compelling picture, both within the context of functional characterization of disease-linked genetic variability and in defining differences between risk alleles for age at onset, or frank risk for disease. (c) 2019 International Parkinson and Movement Disorder SocietyPeer reviewe

The promise of genome‐wide SNP genotyping: from population genetics to disease gene identification.

Advances in single nucleotide polymorphism (SNP) genotyping technologies have revolutionised our ability to scrutinise the human genome. My PhD research focuses on using these new technologies to catalogue genetic variability in a collection of diverse populations from around the globe, and to determine the role of genetic variants in neurological diseases. First, I present and discuss the analysis of genome‐wide SNP data in individuals from ethnically and geographically diverse human populations uncovering the diversity of genotype, haplotype and copy number variation in these populations. Second, I will describe an autozygosity mapping approach in three Brazilian dystoniaparkinsonism families which lead to the identification of a novel disease‐segregating mutation in the gene PRKRA. Third, I will report on a large genome‐wide association study in Parkinson’s disease, uncovering genetic variability at the SNCA and MAPT loci that are strongly associated with risk for developing disease. Forth, I provide compelling evidence that genetic variants at the SNCA locus are also significantly associated with risk for developing multiple system atrophy. This finding represents the first reproducible risk gene for this devastating disorder, and causally links this condition to the more common neurodegenerative disorder Parkinson’s disease. Finally, I present the results of a comprehensive mutational screening study investigating the frequency and spectrum of sequence and copy number mutations in the parkinsonism genes PRKN and PINK in individuals with early-onset Parkinson’s disease, in multiple system atrophy patients and in normal controls. In summary, the data presented in this thesis emphasise the critical role that genetic variability plays in the pathogenesis of neurological disorders.

Genome sequencing analysis identifies new loci associated with Lewy body dementia and provides insights into its genetic architecture

The genetic basis of Lewy body dementia (LBD) is not well understood. Here, we performed whole-genome sequencing in large cohorts of LBD cases and neurologically healthy controls to study the genetic architecture of this understudied form of dementia, and to generate a resource for the scientific community. Genome-wide association analysis identified five independent risk loci, whereas genome-wide gene-aggregation tests implicated mutations in the gene GBA. Genetic risk scores demonstrate that LBD shares risk profiles and pathways with Alzheimer’s disease and Parkinson’s disease, providing a deeper molecular understanding of the complex genetic architecture of this age-related neurodegenerative condition. © 2021, This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply

A comprehensive screening of copy number variability in dementia with Lewy bodies

The role of genetic variability in dementia with Lewy bodies (DLB) is now indisputable; however, data regarding copy number variation (CNV) in this disease has been lacking. Here, we used whole-genome genotyping of 1454 DLB cases and 1525 controls to assess copy number variability. We used 2 algorithms to confidently detect CNVs, performed a case-control association analysis, screened for candidate CNVs previously associated with DLB-related diseases, and performed a candidate gene approach to fully explore the data. We identified 5 CNV regions with a significant genome-wide association to DLB; 2 of these were only present in cases and absent from publicly available databases: one of the regions overlapped LAPTM4B, a known lysosomal protein, whereas the other overlapped the NME1 locus and SPAG9. We also identified DLB cases presenting rare CNVs in genes previously associated with DLB or related neurodegenerative diseases, such as SNCA, APP, and MAPT. To our knowledge, this is the first study reporting genome-wide CNVs in a large DLB cohort. These results provide preliminary evidence for the contribution of CNVs in DLB risk.Celia Kun-Rodrigues ... Tamas Revesz ... Jose Bra

Heritability and genetic variance of dementia with Lewy bodies

Recent large-scale genetic studies have allowed for the first glimpse of the effects of common genetic variability in dementia with Lewy bodies (DLB), identifying risk variants with appreciable effect sizes. However, it is currently well established that a substantial portion of the genetic heritable component of complex traits is not captured by genome-wide significant SNPs. To overcome this issue, we have estimated the proportion of phenotypic variance explained by genetic variability (SNP heritability) in DLB using a method that is unbiased by allele frequency or linkage disequilibrium properties of the underlying variants. This shows that the heritability of DLB is nearly twice as high as previous estimates based on common variants only (31% vs 59.9%). We also determine the amount of phenotypic variance in DLB that can be explained by recent polygenic risk scores from either Parkinson's disease (PD) or Alzheimer's disease (AD), and show that, despite being highly significant, they explain a low amount of variance. Additionally, to identify pleiotropic events that might improve our understanding of the disease, we performed genetic correlation analyses of DLB with over 200 diseases and biomedically relevant traits. Our data shows that DLB has a positive correlation with education phenotypes, which is opposite to what occurs in AD. Overall, our data suggests that novel genetic risk factors for DLB should be identified by larger GWAS and these are likely to be independent from known AD and PD risk variants.Rita Guerreiro ... Tamas Revesz ... Jose Bra

"But I'm not going to be a mental health nurse": nursing students' perceptions of the influence of experts by experience on their attitudes to mental health nursing

Published online 18 October 2019Background: Mental health nursing skills and knowledge are vital for the provision of high-quality healthcare across all settings. Negative attitudes of nurses, towards both mental illness and mental health nursing as a profession, limit recognition of the value of these skills and knowledge. Experts by Experience have a significant role in enhancing mental health nursing education. The impact of this involvement on attitudes to mental health nursing has not been well researched. Aim: To explore the impact of Expert by Experience-led teaching on students' perceptions of mental health nursing. Methods: Qualitative exploratory study involving focus groups with nursing students from five European countries and Australia. Results: Following Expert by Experience-led teaching, participants described more positive views towards mental health nursing skills and knowledge in three main ways: learning that mental health is everywhere, becoming better practitioners, and better appreciation of mental health nursing. Conclusions: Experts by experience contribute to promoting positive attitudinal change in nursing students towards mental health nursing skills and knowledge. Attitudinal change is essential for the provision of high-quality mental health care in specialist mental health services and throughout the healthcare sector.Brenda Happell ... Brett Scholz ... et al

On the optimal number of scale points in graded paired comparisons

In market research, it is common practice to measure individuals’ brand or product preference through graded paired comparisons (GPCs). One important decision concerns the (odd) number of scale points (e.g., five, seven, nine, or eleven) that has to be assigned to either brands or products in each pair. Using data from an experiment with 122 students, we assessed the extent to which GPCs with a higher number of scale points (requiring more cognitive effort) really outperform GPCs with a smaller number of scale points (requiring less cognitive effort). Our data analyses have shown that one may reduce the (odd) number of scale points from eleven to nine or seven, depending on what minor compromises one is willing to make. The detailed psychometric results presented in this paper are useful to applied researchers as they help them in making well-informed decisions on the number of scale points in a GPC task