Sleep disorders among Aboriginal Australians with Machado-Joseph Disease: Quantitative results from a multiple methods study to assess the experience of people living with the disease and their caregivers

Objective: To investigate frequency and characteristics of sleep disorders and their association with health-related quality of life and psychosocial wellbeing for Aboriginal Australians living with MJD. Methods: A convenience sample of MJD participants n = 24 participated in a semi-attended, ambulatory diagnostic sleep study to capture polysomnography, actigraphy and sleep diary data. Self-report measures collected were the Pittsburgh Sleep Quality Index (PSQI), STOP-BANG Questionnaire for Obstructive Sleep Apnoea (OSA), International Restless Legs Syndrome Study Group rating scale (IRLS), Kessler-5 (K5) and EuroQoL-5 Dimension (EQ5D). Caregivers (n = 22) reported EQ-5D, K5 and bed partners’ sleep behaviour (Mayo Sleep Questionnaire-Informant). Environmental factors were measured. Results: We observed Nocturia, Sleep Related Leg Cramps, OSA, REM Behaviour Disorder, and RLS, respectively in 100%, 71%, 47%, 43%, and 33% of participants with a significant positive correlation between Body mass index (BMI) and Apnoea hypopnea index (AHI). The majority of sleep was spent in non-rapid eye movement sleep (NREM)-N2 stage (77.8% (67.7, 81.6)). Overcrowding (92%) and overnight care needs (42%) interrupted sleep. MJD participants and caregivers reported high psychological distress (K5 median 12.5 IQR 7, 16.5 & 8 IQR 6, 12 respectively). Conclusion: Poor sleep quality and sleep disturbances are prevalent among this cohort. Disease manifestations and environmental factors are driving factors. Larger sample sizes are required to predict risk factors and confirm observed associations

Genome-wide association study of multisite chronic pain in UK Biobank

Chronic pain is highly prevalent worldwide and represents a significant socioeconomic and public health burden. Several aspects of chronic pain, for example back pain and a severity-related phenotype ‘chronic pain grade’, have been shown previously to be complex heritable traits with a polygenic component. Additional pain-related phenotypes capturing aspects of an individual’s overall sensitivity to experiencing and reporting chronic pain have also been suggested as a focus for investigation. We made use of a measure of the number of sites of chronic pain in individuals within the UK general population. This measure, termed Multisite Chronic Pain (MCP), is a complex trait and its genetic architecture has not previously been investigated. To address this, we carried out a large-scale genome-wide association study (GWAS) of MCP in ~380,000 UK Biobank participants. Our findings were consistent with MCP having a significant polygenic component, with a Single Nucleotide Polymorphism (SNP) heritability of 10.2%. In total 76 independent lead SNPs at 39 risk loci were associated with MCP. Additional gene-level association analyses identified neurogenesis, synaptic plasticity, nervous system development, cell-cycle progression and apoptosis genes as enriched for genetic association with MCP. Genetic correlations were observed between MCP and a range of psychiatric, autoimmune and anthropometric traits, including major depressive disorder (MDD), asthma and Body Mass Index (BMI). Furthermore, in Mendelian randomisation (MR) analyses a causal effect of MCP on MDD was observed. Additionally, a polygenic risk score (PRS) for MCP was found to significantly predict chronic widespread pain (pain all over the body), indicating the existence of genetic variants contributing to both of these pain phenotypes. Overall, our findings support the proposition that chronic pain involves a strong nervous system component with implications for our understanding of the physiology of chronic pain. These discoveries may also inform the future development of novel treatment approaches

The genetics and pathophysiology of cluster headache and associated disorders

Cluster headache (CH) is described as one of the most painful conditions known to humans. It effects approximately 60,000 individuals in the UK and carries significant morbidity. It exhibits hereditability evident by reports of familial aggregation and is categorised as a trigeminal autonomic cephalalgia (TAC). Despite this, the exact pathophysiological and genetic drivers of this condition remain elusive. The purpose of this thesis is to examine the clinical and genetic determinants of CH, and thus gain insights into the underlying neurobiological mechanisms. This work consists of two components. In the first section, I conduct clinical observational studies to further delineate the CH phenotype. I address the postulated association between pituitary adenomas and CH and question the utility of dedicated pituitary imagining in this patient group. I also describe the largest series of Post-Traumatic Headache of Cluster Headache (PTH-CH) and demonstrate its distinct features and increased intractability to treatment. Finally, through meta-analysis, I estimate the prevalence of familial CH to be 6.27% and demonstrate an overlap with concurrent short-Lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) in familial cases. The second section explores the genetics architecture underlying CH. I perform a Genome-Wide Association Study (GWAS) to identify replicable susceptibility loci and conduct a downstream analysis. Subsequent genetic correlation analysis showed an overlap with migraine, depression, bipolar and sleep disturbance implying the possibility of a common genetic driver for these conditions, which frequently present concurrently. I then carry out linkage analysis in CH families and replicate a linked region suggestive of significance on chromosome 2 that also overlaps a genome wide significant locus. Finally, I execute whole exome sequencing and utilise rare variant association tests and segregation analysis to identify causal variants for familial CH

Genetic analysis of multiple system atrophy and related movement disorders

The understanding of the pathophysiology of most neurodegenerative movement disorders has been elusive. Such is the case of multiple system atrophy (MSA) and primary familial brain calcification (PFBC). In this thesis I used a range of genetic techonologies and functional strategies to unravel the genetic basis of MSA and PFBC. First, I describe the work performed in MSA and related atypical movement disorders initially by investigating candidate genes. My key findings were: i) begative results when attempting to replicate the association between COQ2 and the risk of MSA, by Sanger sequencing the largest pathologically confirmed MSA cohort the largest pathologically confirmed MSA cohort; ii) reduced levels of Coenzyme Q10 (CoQ10) in the cerebellum of MSA patients with a cerebellar or mixed MSA subtypes when compared to normal controls and other neurodegenerative movement disorders, when I measured the levels in post-mortem brain tissue of MSA and other patients and controls by high performance liquid chromatography (HPLC); iii) identification of three C9orf72 repeat expansions and one intermediate expansion in patients presenting with a corticobasal and progressive supranuclear palsy syndrome, and confirmation of the absence of the expansion in pathologically proven MSA, corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP); iv) identification of a LRRK2 protective variant in MSA by case control analysis of genotyping of LRRK2 candidate variants. Second, I detail my work applying next generation sequencing techonologies (i.e. whole exome sequencing (WES)) to the study of genetic risk factors in MSA: i) Initially I analysed a definite MSA family and ii) later I performed the largest WES study so far in sporadic MSA. This study included 450 cases out of which 298 were pathologically confirmed. These data were first investigated for candidate genes linked to MSA, other synucleinopathies and related neurodegenerative disorders, and later by peforming a case control association study for common and rare variants. The results of this work where not able to replicate previous findings that linked MSA to COQ2 or SNCA, notwidstanding it revealed interesting candidates that require follow up. Third, I studied genetically patients with PFBC. My key findings were: i) a pathogenic SLC20A2 mutation segregating with the disease in an interesting family, found by investigating recently discovered candidate genes I identified by Sanger sequencing; ii) I detail how I studied two independent primary brain calcification consanguineous families by means of homozygosity mapping and WES. I was able to identify a homozygous nonsense mutation segregating with the disease in both families in JAM2, a gene encoding the Junction adhesion molecule 2, a tight junction protein. This is a novel gene previously unreported as a cause of human disease. Through collaborations with other scientists, I showed the absence of the expression of the JAM2 protein in a fibroblast cell line of a homozygous patient compared to a heterozygous carrier and 2 independent controls. Aditionally we studied a knock out JAM-b (ortolog of human JAM2) mouse model and showed gait abnormalities and abnormal brain histopathology. In conclusion, by applying genetic technologies and related methods, I generated important insights into the CoQ10 pathway in MSA, I generated the largest dataset of WES in MSA and I discovered a new gene for PFBC. My findings are discussed inlight of the recent literature and future directions of research into each subject

The evolving genetic and pathophysiological spectrum of migraine

The research in this thesis was aimed at identifying and characterizing novel migraine gene mutations and pathways. Several FHM and non-FHM genes were investigated in patients with monogenic familial hemiplegic migraine or other monogenic disorders in which migraine can be prevalent. Functional consequences of these mutations and the clinical phenotypes associated with them were investigated. Common migraine with a complex genetic background was studied using a genome-wide association analysis in an isolated population and with a meta-analysis study. Furthermore, FHM1 mice were used to study expression profiles in brain tissues that are relevant for the induction of cortical spreading depression ___ underlying the migraine aura - (i.e., the occipital cortex) and cerebellar ataxia (i.e., the cerebellum). These studies will further our insight in the molecular pathophysiology of migraine.J.E. Jurriaanse Stichting Nederlandse Hoofdpijn Vereniging Menarini Farma Nederland AllerganUBL - phd migration 201

Migreenin sairastuvuuteen vaikuttavien geneettisten tekijöiden tunnistaminen

Migraine is the common cause of chronic episodic headache, affecting 12%-15% of the Caucasian population (41 million Europeans and some half a million Finns), and causes considerable loss of quality of life to its sufferers, as well as being linked to increased risk for a wide range of conditions, from depression to stroke. Migraine is the 19th most severe disease in terms of disability-adjusted life years, and 9th among women. It is characterized by attacks of headache accompanied by sensitivity to external stimuli lasting 4-72 hours, and in a third of cases by neurological aura symptoms, such as loss of vision, speech or muscle function. The underlying pathophysiology, including what triggers migraine attacks and why they occur in the first place, is largely unknown. The aim of this study was to identify genetic factors associated with the hereditary susceptibility to migraine, in order to gain a better understanding of migraine mechanisms. In this thesis, we report the results of genetic linkage and association analyses on a Finnish migraine patient collection as well as migraineurs from Australia, Denmark, Germany, Iceland and the Netherlands. Altogether we studied genetic information of nearly 7,000 migraine patients and over 50,000 population-matched controls. We also developed a new migraine analysis method called the trait component analysis, which is based on individual patient responses instead of the clinical diagnosis. Using this method, we detected a number of new genetic loci for migraine, including on chromosome 17p13 (HLOD 4.65) and 10q22-q23 (female-specific HLOD 7.68) with significant evidence of linkage, along with five other loci (2p12, 8q12, 4q28-q31, 18q12-q22, and Xp22) detected with suggestive evidence of linkage. The 10q22-q23 locus was the first genetic finding in migraine to show linkage to the same locus and markers in multiple populations, with consistent detection in six different scans. Traditionally, ion channels have been thought to play a role in migraine susceptibility, but we were able to exclude any significant role for common variants in a candidate gene study of 155 ion transport genes. This was followed up by the first genome-wide association study in migraine, conducted on 2,748 migraine patients and 10,747 matched controls followed by a replication in 3,209 patients and 40,062 controls. In this study, we found interesting results with genome-wide significance, providing targets for future genetic and functional studies. Overall, we found several promising genetic loci for migraine providing a promising base for future studies in migraine.Migreeni on yleisin kroonisen kohtauksellisen päänsäryn syy ja siitä kärsii 12-15% väestöstä. Monitekijäisten kansantautien - kuten migreenin, diabeteksen ja masennuksen - tautimekanismien ymmärtäminen on yksi nykylääketieteen ja -genetiikan vaikeimmista haasteista. Nämä taudit ovat osa päivittäistä elämää niin lääkärin vastaanotolla kuin kotonakin, ja niiden tutkimuksella ja edistysaskeleilla on mahdollisuus parantaa potilaiden elämänlaatua. Nykykäsityksen mukaan kansantautien perinnöllinen alttius perustuu ympäristötekijöiden ohella lukuisten eri perimänvaihteluiden yhteisvaikutukseen ja siksi vaihteluiden tunnistaminen vaatii suuria potilasaineistoja. Tämä väitöskirjatutkimus perustuu laajaan kansainväliseen yhteistyöhön, jonka tuloksena pystyimme tutkimaan migreenille altistavia perimän alueita lähes 7 000 migreenipotilaasta uusimmilla geenitutkimuksen menetelmillä. Migreeni on 19. vakavin elämänlaadun laskija maailmassa ja yhdeksänneksi pahin naisten keskuudessa. Euroopassa migreenikkoja on 41 miljoonaa (Suomessa 441 000) ja tauti on eniten kustannuksia ja elämänlaadun laskua aiheuttava neurologinen tauti. Jopa puolet migreenipotilaista joutuu käymään sairaalapäivystyksessä kerran vuodessa migreenin vuoksi ja 15% migreeniä sairastavista tarvitsi viisi terveyskeskuskäyntikertaa tai enemmän vuodessa. Migreenillä on kaksi päätyyppiä: esioireellinen (aurallinen) ja esioireeton (auraton) migreeni, jossa edellisessä kohtaukseen liittyy kivun lisäksi erilaisia neurologisia oireita, kuten näkö- ja puhevaikeuksia. Molemmat muodot kuuluvat edellä mainittuihin monitekijäisiin tauteihin, eikä yhtään yleiseen migreenialttiuteen vaikuttavaa geneettistä tekijää ole ennen tätä tutkimusta varmuudella tunnistettu. Tässä väitöskirjatutkimuksessa esittelemme uudenlaisen lähestymistavan, oirekomponenttianalyysin, migreenin luokitteluun sekä sovellamme sitä uusien geneettisten alttiusalueiden tunnistamiseen suomalaisissa ja kansainvälisissä potilasaineistoissa. Sitä käyttämällä tunnistimme kaksi uutta migreenille altistavaa geenialuetta sekä kykenimme vahvistamaan useita aikaisemmin havaittuja. Migreenin perinnöllisen alttiuden taustalla on pitkään ajateltu olevan muutoksia solun ionikanavissa, mutta pystyimme tutkimuksessamme poissulkemaan niiden osuuden migreenin alttiustekijänä. Suoritimme ensimmäisen migreenin kokogenomiassosiaatiotutkimuksen (käsittäen n. 5 700 potilasta ja 50 000 populaatioverrokkia) jossa tunnistimme genominlaajuisesti merkittäviä variantteja, jotka muodostavat vahvan pohjan geneettisille ja funktionaalisille jatkotutkimuksille

Využití kognitivích testů u Huntingtonovy nemoci v klinické praxi

Úvod: Huntingtonova nemoc (HN) je dědičné neurodegenerativní onemocnění projevující se poruchami hybnosti, chování a kognitivním deficitem s fatálními následky. Cíle: Cílem této studie bylo ověřit psychometrické vlastnosti standardní kognitivní baterie používané u HN a stanovit jazykově specifické normativní hodnoty. Soubor a metodika: V první studii byl porovnáván kognitivní výkon u 106 pacientů v různých stádiích HN a u 100 zdravých kontrol párovaných podle věku, pohlaví a vzdělání. Neuropsychologická baterie zahrnovala Test modalit čísel a symbolů (SDMT), Stroopův test, Test cesty, kategoriální a fonemickou verbální fluenci. U pacientů byl navíc komplexně hodnocen motorický a funkční stav. Ve druhé studii byl hodnocen kognitivní výkon 3 267 zdravých osob. Práce byla zaměřena na stratifikaci kognitivního výkonu v souvislosti s věkem, pohlavím, rodným jazykem a vzděláním. Dalším cílem bylo na základě získaných dat vytvořit normativní kalukátor pro hodnocení míry kognitivního deficitu v různých jazycích (angličtina, němčina, španělština, italština, polština, francouzština, nizozemština, dánština). Výsledky: V první studii analýza rozptylu ukázala, že zdravé kontroly dosahovaly významně lepších výsledků než pacienti. Kognitivní výkon koreloval s motorickým a funkčním postižením (p < 0,001) nezávisle na věku...Introduction: Huntington disease (HD) is an autosomal dominant neurodegenerative disorder manifested by motor, behavioural and cognitive deficits with fatal consequences. Aims: This study aims to validate the psychometric properties of a standard cognitive battery used in HD and establish language-specific normative values. Methods: In the first study, cognitive performance was compared in 106 patients at different stages of HD and 100 healthy controls matched for age, sex, and education. The neuropsychological battery included the Symbol Digit Modalities Test, Stroop Word Reading Test, Stroop Colour Naming Test, Stroop Interference Test, Trail Making Test-A and B, Category and Letter Verbal Fluency. In addition, patients were comprehensively assessed for motor and functional status. In the second study, the cognitive performance of 3,267 healthy subjects was assessed. The work focused on the stratification of cognitive performance concerning age, gender, language and level of education. Another aim was to establish the language-specific normative values and implement a web-based normative calculator to assess the degree of cognitive deficit in different languages (English, German, Spanish, Italian, Polish, French, Dutch, Danish). Results: In the first study, analysis of variance showed that healthy...Neurologická klinika 1. LF UK a VFNDepartment of Neurology First Faculty of Medicine Charles University and General University Hospital in Prague1. lékařská fakultaFirst Faculty of Medicin

Genetic Investigations of Sporadic Inclusion Body Myositis and Myopathies with Structural Abnormalities and Protein Aggregates in Muscle

The application of whole-exome sequencing (WES) has not only dramatically accelerated the discovery of pathogenic genes of Mendelian diseases, but has also shown promising findings in complex diseases. This thesis focuses on exploring genetic risk factors for a large series of sporadic inclusion body myositis (sIBM) cases, and identifying disease-causing genes for several groups of patients with abnormal structure and/or protein aggregates in muscle. Both conventional and advanced techniques were applied. Based on the International IBM Genetics Consortium (IIBMGC), the largest sIBM cohort of blood and muscle tissue for DNA analysis was collected as the initial part of this thesis. Candidate gene studies were carried out and revealed a disease modifying effect of an intronic polymorphism in TOMM40, enhanced by the APOE ε3/ε3 genotype. Rare variants in SQSTM1 and VCP genes were identified in seven of 181 patients, indicating a mutational overlap with neurodegenerative diseases. Subsequently, a first whole-exome association study was performed on 181 sIBM patients and 510 controls. This reported statistical significance of several common variants located on chromosome 6p21, a region encompassing genes related to inflammation/infection. WES was performed on a group of 35 cases with tubular aggregates/cylindrical spirals, and detected rare variants in known/candidate genes. Disease-causing genes were identified in four families with protein aggregates in muscle also by WES. In one family identified with a novel homozygous deletion in SBF1 with a rare autosomal-recessive neuromuscular condition, functional analysis was carried out indicating a loss-of-function mechanism underlying the pathogenesis of the disease. The collection of a large series of sIBM patients through the IIBMGC has been shown here to reveal important genetic findings and will be a valuable resource for the future. WES proved to be important in sIBM and also to be an efficient method to investigate the genetics basis of rare complex muscle disorders

Investigating causal relationships between major depression and chronic pain using UK general-population datasets with whole-genome genotyping

Chronic pain, considered here to be pain lasting 3 months or longer, imparts significant socioeconomic and public health burden around the globe. Chronic pain is associated with a wide range of conditions, illnesses, or injuries, and is categorised and investigated in many ways. Treatment and management of chronic pain is complicated by this heterogeneity, and by lack of full understanding of factors (including genetic) that influence vulnerability to developing chronic pain and biological mechanisms of chronic pain development. Major depression is commonly comorbid with chronic pain, and results of studies into potential causal direction between the two conditions are mixed. Due to symptom overlap and common comorbidity, it may be that cases of chronic pain are misclassified as major depression and vice versa. Understanding genetic factors that contribute to chronic pain vulnerability and development has the potential to improve treatment of both conditions, in addition to allowing for investigation of potential causal relationships and clinical heterogeneity. Recently, the International Association for the Study of Pain released an updated definition of chronic pain and advocated for the study of chronic pain as a disease entity. Studying the genetics of chronic pain through genome wide association study of broad chronic pain traits, in line with this updated pain definition, may present a more tractable way to uncover common genetic variation associated with vulnerability to and mechanisms of development of chronic pain. This mode of study can also provide genome wide association study summary statistics for use in analyses that aim to investigate causality, genetic correlation and pleiotropy, and clinical heterogeneity in chronic pain and major depression. The overall aim of this PhD project is therefore to explore causal relationships between chronic pain and MDD in large UK general-population cohorts with whole-genome genotyping data using a wide range of statistical genetic methods. Data were obtained from two large UK cohorts with whole-genome genotyping. One, UK Biobank, is a cohort of 0.5 million participants recruited in middle age (40-79) with information on an extensive list of physical, behavioural and health related traits. Generation Scotland is a smaller (N ~ 22,000) Scottish cohort of participants recruited mainly through general practitioners in a family-based manner, again with information of physical, health, and behavioural traits. Summary statistic data were also obtained from a 23andMe-Pfizer genome wide association study of chronic pain grade. As part of this PhD the largest genome wide association study of any chronic pain trait to date was carried out in UK Biobank. Validation of the trait (multisite chronic pain) was carried out through polygenic risk score analysis in Generation Scotland, examining the relationship between this novel chronic pain trait and chronic pain grade. Genetic correlation analyses were used to explore the genetic overlap of multisite chronic pain and a range of traits of interest, including other chronic pain phenotypes such as chronic widespread pain and chronic pain grade, in addition to major depression. Gene-level analyses were carried out to investigate genes of interest associated with chronic pain and potentially relevant to mechanisms of chronic pain development. BUHMBOX analyses were performed to test for clinical heterogeneity in chronic pain with respect to major depression and vice versa in UK Biobank. Conditional false discovery rate analyses using 23andMe-Pfizer data were also used to explore pleiotropy in chronic pain grade and major depression and to highlight pleiotropic loci of interest. Mendelian randomisation analyses, including recent mendelian randomisation methods explicitly designed to account for extensive horizontal pleiotropy, were carried out to assess potential causal relationships between major depression and chronic pain grade, and between major depression and multisite chronic pain. Results indicated multisite chronic pain was a polygenic, moderately heritable trait. Associated genes of interest implicated a strong central nervous system component, in addition to immune related genes. Conditional false discovery rate analysis highlighted loci of interest mapped to LRFN5, a gene involved in neuroinflammation, and that were associated with regulation of gene expression at this locus. Polygenic risk scoring analysis showed multisite chronic pain to be significantly associated with both chronic pain grade and chronic widespread pain, in addition to a multisite chronic pain-like trait in Generation Scotland, validating multisite chronic pain as a trait and indicating strong genetic overlap between widespread and non-widespread pain. Genetic correlation analysis showed significant genetic overlap between multisite chronic pain and mental health traits, markedly major depressive disorder, and depressive symptoms, but a lower degree of genetic correlation with conditions associated with significant chronic pain such as rheumatoid arthritis, and no significant genetic correlation with inflammatory bowel diseases. BUHMBOX analyses showed no evidence of clinical heterogeneity in chronic pain with respect to major depression in UK Biobank or vice versa. Mendelian randomisation analyses showed no causal relationship between chronic pain grade and major depressive disorder, but a significant causal effect of multisite chronic pain on major depressive disorder. In conclusion, I have shown that broad chronic pain traits such as multisite chronic pain present a powerful and tractable way to study mechanisms of, and factors contributing to vulnerability to, chronic pain development. Output from well-powered genome wide association studies can also be used to validate phenotypes, explore genetic overlap with traits of interest, and conduct causal analyses