Large-scale pathway specific polygenic risk and transcriptomic community network analysis identifies novel functional pathways in Parkinson disease.

Polygenic inheritance plays a central role in Parkinson disease (PD). A priority in elucidating PD etiology lies in defining the biological basis of genetic risk. Unraveling how risk leads to disruption will yield disease-modifying therapeutic targets that may be effective. Here, we utilized a high-throughput and hypothesis-free approach to determine biological processes underlying PD using the largest currently available cohorts of genetic and gene expression data from International Parkinson's Disease Genetics Consortium (IPDGC) and the Accelerating Medicines Partnership-Parkinson's disease initiative (AMP-PD), among other sources. We applied large-scale gene-set specific polygenic risk score (PRS) analyses to assess the role of common variation on PD risk focusing on publicly annotated gene sets representative of curated pathways. We nominated specific molecular sub-processes underlying protein misfolding and aggregation, post-translational protein modification, immune response, membrane and intracellular trafficking, lipid and vitamin metabolism, synaptic transmission, endosomal-lysosomal dysfunction, chromatin remodeling and apoptosis mediated by caspases among the main contributors to PD etiology. We assessed the impact of rare variation on PD risk in an independent cohort of whole-genome sequencing data and found evidence for a burden of rare damaging alleles in a range of processes, including neuronal transmission-related pathways and immune response. We explored enrichment linked to expression cell specificity patterns using single-cell gene expression data and demonstrated a significant risk pattern for dopaminergic neurons, serotonergic neurons, hypothalamic GABAergic neurons, and neural progenitors. Subsequently, we created a novel way of building de novo pathways by constructing a network expression community map using transcriptomic data derived from the blood of PD patients, which revealed functional enrichment in inflammatory signaling pathways, cell death machinery related processes, and dysregulation of mitochondrial homeostasis. Our analyses highlight several specific promising pathways and genes for functional prioritization and provide a cellular context in which such work should be done.

A text message intervention to support women's physical and mental health after breast cancer treatments (EMPOWER-SMS): a randomised controlled trial protocol.

BACKGROUND: Breast cancer is the most common cancer diagnosed in women worldwide. In developed countries, 80-90% of women will survive five years after diagnosis but the transition from hospital-based care to health self-management and self-efficacy can be difficult. Text messaging programs offer a simple and proven way to provide support to people with chronic diseases. This study aims to test the effectiveness of a text message support program at improving women's health self-efficacy, and physical and mental health outcomes after breast cancer treatments compared to usual care at 6-months and to understand the barriers and enablers to widespread implementation. METHODS: Single-blind randomised control trial (RCT; N = 160) comparing a text message support intervention to usual care in women with breast cancer (recruited from a large tertiary referral hospital in Sydney, Australia). The intervention group will receive a six-month text message support program, which consists of semi-personalised, supportive, lifestyle-focused text messages (4 messages/week) in addition to usual care. The control group will receive usual care without the text message program. Outcomes will be assessed at 6-months. The primary outcome is change in self-efficacy for managing chronic disease. Secondary outcomes include change in clinical outcomes (body mass index), lifestyle outcomes (physical activity levels, dietary behaviours), mood (depression and anxiety scales), quality of life, satisfaction with, and usefulness of the intervention. Analyses will be performed on the principle of intention-to-treat to examine differences between intervention and control groups. DISCUSSION: This study will test if a scalable and cost-effective text-messaging intervention is effective at improving women's health self-efficacy, as well as physical and mental health outcomes. Moreover, this study will provide essential preliminary data to bolster a large multicentre RCT to helpsupport breast cancer survivors throughout recovery and beyond. TRIAL REGISTRATION: Australia New Zealand Clinical Trials Registry (ANZCTR) number ACTRN12618002020268 , 17 December 2018.

Genetic risk factors in Parkinson's disease.

Over the last two decades, we have witnessed a revolution in the field of Parkinson's disease (PD) genetics. Great advances have been made in identifying many loci that confer a risk for PD, which has subsequently led to an improved understanding of the molecular pathways involved in disease pathogenesis. Despite this success, it is predicted that only a relatively small proportion of the phenotypic variability has been explained by genetics. Therefore, it is clear that common heritable components of disease are still to be identified. Dissecting the genetic architecture of PD constitutes a critical effort in identifying therapeutic targets and although such substantial progress has helped us to better understand disease mechanism, the route to PD disease-modifying drugs is a lengthy one. In this review, we give an overview of the known genetic risk factors in PD, focusing not on individual variants but the larger networks that have been implicated following comprehensive pathway analysis. We outline the challenges faced in the translation of risk loci to pathobiological relevance and illustrate the need for integrating big-data by noting success in recent work which adopts a broad-scale screening approach. Lastly, with PD genetics now progressing from identifying risk to predicting disease, we review how these models will likely have a significant impact in the future.

Whole-exome sequencing of the BDR cohort: evidence to support the role of the PILRA gene in Alzheimer's disease.

AIM: Late-onset Alzheimer's disease (LOAD) accounts for 95% of all Alzheimer's cases and is genetically complex in nature. Overlapping clinical and neuropathological features between AD, FTD and Parkinson's disease highlight the potential role of genetic pleiotropy across diseases. Recent genome-wide association studies (GWASs) have uncovered 20 new loci for AD risk; however, these exhibit small effect sizes. Using NGS, here we perform association analyses using exome-wide and candidate-gene-driven approaches. METHODS: Whole-exome sequencing was performed on 132 AD cases and 53 control samples. Exome-wide single-variant association and gene burden tests were performed for 76 640 nonsingleton variants. Samples were also screened for known causative mutations in familial genes in AD and other dementias. Single-variant association and burden analysis was also carried out on variants in known AD and other neurological dementia genes. RESULTS: Tentative single-variant and burden associations were seen in several genes with kinase and protease activity. Exome-wide burden analysis also revealed significant burden of variants in PILRA (P = 3.4 × 10-5 ), which has previously been linked to AD via GWAS, hit ZCWPW1. Screening for causative mutations in familial AD and other dementia genes revealed no pathogenic variants. Variants identified in ABCA7, SLC24A4, CD33 and LRRK2 were nominally associated with disease (P < 0.05) but did not withstand correction for multiple testing. APOE (P = 0.02) and CLU (P = 0.04) variants showed significant burden on AD. CONCLUSIONS: In addition, polygenic risk scores (PRS) were able to distinguish between cases and controls with 83.8% accuracy using 3268 variants, sex, age at death and APOE ε4 and ε2 status as predictors.

Genetics of Hereditary Ataxia in Scottish Terriers.

BACKGROUND: Scottish Terriers have a high incidence of juvenile onset hereditary ataxia primarily affecting the Purkinje neuron of the cerebellar cortex and causing slowly progressive cerebellar dysfunction. OBJECTIVE: To identify chromosomal regions associated with hereditary ataxia in Scottish Terriers. ANIMALS: One hundred and fifty-three Scottish Terriers were recruited through the Scottish Terrier Club of America. MATERIALS AND METHODS: Prospective study. Dogs were classified as affected if they had slowly progressive cerebellar signs. When possible, magnetic resonance imaging and histopathological evaluation of the brain were completed as diagnostic aids. To identify genomic regions connected with the disease, genome-wide mapping was performed using both linkage- and association-based approaches. Pedigree evaluation and homozygosity mapping were also performed to examine mode of inheritance and to investigate the region of interest, respectively. RESULTS: Linkage and genome-wide association studies in a cohort of Scottish Terriers both identified a region on CFA X strongly associated with the disease trait. Homozygosity mapping revealed a 4 Mb region of interest. Pedigree evaluation failed to identify the possible mode of inheritance due to the lack of complete litter information. CONCLUSION AND CLINICAL IMPORTANCE: This finding suggests that further genetic investigation of the potential region of interest on CFA X should be considered in order to identify the causal mutation as well as develop a genetic test to eliminate the disease from this breed.

Rare variants analysis of cutaneous malignant melanoma genes in Parkinson's disease.

A shared genetic susceptibility between cutaneous malignant melanoma (CMM) and Parkinson's disease (PD) has been suggested. We investigated this by assessing the contribution of rare variants in genes involved in CMM to PD risk. We studied rare variation across 29 CMM risk genes using high-quality genotype data in 6875 PD cases and 6065 controls and sought to replicate findings using whole-exome sequencing data from a second independent cohort totaling 1255 PD cases and 473 controls. No statistically significant enrichment of rare variants across all genes, per gene, or for any individual variant was detected in either cohort. There were nonsignificant trends toward different carrier frequencies between PD cases and controls, under different inheritance models, in the following CMM risk genes: BAP1, DCC, ERBB4, KIT, MAPK2, MITF, PTEN, and TP53. The very rare TYR p.V275F variant, which is a pathogenic allele for recessive albinism, was more common in PD cases than controls in 3 independent cohorts. Tyrosinase, encoded by TYR, is the rate-limiting enzyme for the production of neuromelanin, and has a role in the production of dopamine. These results suggest a possible role for another gene in the dopamine-biosynthetic pathway in susceptibility to neurodegenerative Parkinsonism, but further studies in larger PD cohorts are needed to accurately determine the role of these genes/variants in disease pathogenesis.

Role of students' context in predicting academic performance at a medical school: a retrospective cohort study.

OBJECTIVES: This study examines associations between medical students' background characteristics (postcode-based measures of disadvantage, high school attended, sociodemographic characteristics), and academic achievement at a Russell Group University. DESIGN: Retrospective cohort analysis. SETTING: Applicants accepted at the University of Liverpool medical school between 2004 and 2006, finalising their studies between 2010 and 2011. PARTICIPANTS: 571 students (with an English home postcode) registered on the full-time Medicine and Surgery programme, who successfully completed their medical degree. MAIN OUTCOME MEASURES: Final average at year 4 of the medical programme (represented as a percentage). RESULTS: Entry grades were positively associated with final attainment (p<0.001). Students from high-performing schools entered university with higher qualifications than students from low-performing schools (p<0.001), though these differences did not persist at university. Comprehensive school students entered university with higher grades than independent school students (p<0.01), and attained higher averages at university, though differences were not significant after controlling for multiple effects. Associations between school type and achievement differed between sexes. Females attained higher averages than males at university. Significant academic differences were observed between ethnic groups at entry level and university. Neither of the postcode-based measures of disadvantage predicted significant differences in attainment at school or university. CONCLUSIONS: The findings of this study suggest that educational attainment at school is a good, albeit imperfect, predictor of academic attainment at medical school. Most attainment differences observed between students either decreased or disappeared during university. Unlike previous studies, independent school students did not enter university with the highest grades, but achieved the lowest attainment at university. Such variations depict how patterns may differ between subjects and higher-education institutions. Findings advocate for further evidence to help guide the implementation of changes in admissions processes and widen participation at medical schools fairly.

Delta-9-tetrahydrocannabinol (THC) affects forelimb motor map expression but has little effect on skilled and unskilled behavior.

It has previously been shown in rats that acute administration of delta-9-tetrahydrocannabinol (THC) exerts a dose-dependent effect on simple locomotor activity, with low doses of THC causing hyper-locomotion and high doses causing hypo-locomotion. However the effect of acute THC administration on cortical movement representations (motor maps) and skilled learned movements is completely unknown. It is important to determine the effects of THC on motor maps and skilled learned behaviors because behaviors like driving place people at a heightened risk. Three doses of THC were used in the current study: 0.2mg/kg, 1.0mg/kg and 2.5mg/kg representing the approximate range of the low to high levels of available THC one would consume from recreational use of cannabis. Acute peripheral administration of THC to drug naïve rats resulted in dose-dependent alterations in motor map expression using high resolution short duration intracortical microstimulation (SD-ICMS). THC at 0.2mg/kg decreased movement thresholds and increased motor map size, while 1.0mg/kg had the opposite effect, and 2.5mg/kg had an even more dramatic effect. Deriving complex movement maps using long duration (LD)-ICMS at 1.0mg/kg resulted in fewer complex movements. Dosages of 1.0mg/kg and 2.5mg/kg THC reduced the number of reach attempts but did not affect percentage of success or the kinetics of reaching on the single pellet skilled reaching task. Rats that received 2.5mg/kg THC did show an increase in latency of forelimb removal on the bar task, while dose-dependent effects of THC on unskilled locomotor activity using the rotorod and horizontal ladder tasks were not observed. Rats may be employing compensatory strategies after receiving THC, which may account for the robust changes in motor map expression but moderate effects on behavior.

Genome-wide estimate of the heritability of Multiple System Atrophy.

INTRODUCTION: Multiple System Atrophy (MSA) is a neurodegenerative disease which presents heterogeneously with symptoms and signs of parkinsonism, ataxia and autonomic dysfunction. Although MSA typically occurs sporadically, rare pathology-proven MSA families following either autosomal recessive or autosomal dominant patterns have been described, indicating a heritable contribution to the pathogenesis. METHODS: We used Genome-Wide Complex Trait Analysis (GCTA) to estimate the heritable component of MSA due to common coding variability in imputed genotype data of 907 MSA cases and 3866 population-matched controls. GCTA only assesses the effect of putative causal variants in linkage disequilibrium (LD) with all common SNPs on the genotyping platform. RESULTS: We estimate the heritability among common variants of MSA in pooled cases at 2.09-6.65%, with a wider range of values in geographic and diagnostic subgroups. Meta-analysis of our geographic cohorts reveals high between-group heterogeneity. Contributions of single chromosomes are generally negligible. We suggest that all calculated MSA heritability among common variants could be explained by the presence of misdiagnosed cases in the clinical subgroup based on a Bayesian estimate using literature-derived rates of misdiagnosis. DISCUSSION: MSA is a challenging disease to study due to high rates of misdiagnosis and low prevalence. Given our low estimates of heritability, common genetic variation appears to play a less prominent role in risk for MSA than in other complex neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, and Amyotrophic Lateral Sclerosis. The success of future gene discovery efforts rests on large pathologically-confirmed case series and an interrogation of both common and rare genetic variants.

Gene transcripts associated with muscle strength: a CHARGE meta-analysis of 7,781 persons.

Lower muscle strength in midlife predicts disability and mortality in later life. Blood-borne factors, including growth differentiation factor 11 (GDF11), have been linked to muscle regeneration in animal models. We aimed to identify gene transcripts associated with muscle strength in adults. Meta-analysis of whole blood gene expression (overall 17,534 unique genes measured by microarray) and hand-grip strength in four independent cohorts (n = 7,781, ages: 20-104 yr, weighted mean = 56), adjusted for age, sex, height, weight, and leukocyte subtypes. Separate analyses were performed in subsets (older/younger than 60, men/women). Expression levels of 221 genes were associated with strength after adjustment for cofactors and for multiple statistical testing, including ALAS2 (rate-limiting enzyme in heme synthesis), PRF1 (perforin, a cytotoxic protein associated with inflammation), IGF1R, and IGF2BP2 (both insulin like growth factor related). We identified statistical enrichment for hemoglobin biosynthesis, innate immune activation, and the stress response. Ten genes were associated only in younger individuals, four in men only and one in women only. For example, PIK3R2 (a negative regulator of PI3K/AKT growth pathway) was negatively associated with muscle strength in younger (<60 yr) individuals but not older (≥ 60 yr). We also show that 115 genes (52%) have not previously been linked to muscle in NCBI PubMed abstracts. This first large-scale transcriptome study of muscle strength in human adults confirmed associations with known pathways and provides new evidence for over half of the genes identified. There may be age- and sex-specific gene expression signatures in blood for muscle strength.

Genetic overlap between Alzheimer's disease and Parkinson's disease at the MAPT locus.

We investigated the genetic overlap between Alzheimer's disease (AD) and Parkinson's disease (PD). Using summary statistics (P-values) from large recent genome-wide association studies (GWAS) (total n=89 904 individuals), we sought to identify single nucleotide polymorphisms (SNPs) associating with both AD and PD. We found and replicated association of both AD and PD with the A allele of rs393152 within the extended MAPT region on chromosome 17 (meta analysis P-value across five independent AD cohorts=1.65 × 10(-7)). In independent datasets, we found a dose-dependent effect of the A allele of rs393152 on intra-cerebral MAPT transcript levels and volume loss within the entorhinal cortex and hippocampus. Our findings identify the tau-associated MAPT locus as a site of genetic overlap between AD and PD, and extending prior work, we show that the MAPT region increases risk of Alzheimer's neurodegeneration.

FTO genotype and aging: pleiotropic longitudinal effects on adiposity, brain function, impulsivity and diet.

Although overweight and obesity are associated with poor health outcomes in the elderly, the biological bases of obesity-related behaviors during aging are poorly understood. Common variants in the FTO gene are associated with adiposity in children and younger adults as well as with adverse mental health in older individuals. However, it is unclear whether FTO influences longitudinal trajectories of adiposity and other intermediate phenotypes relevant to mental health during aging. We examined whether a commonly carried obesity-risk variant in the FTO gene (rs1421085 single-nucleotide polymorphism) influences adiposity and is associated with changes in brain function in participants within the Baltimore Longitudinal Study of Aging, one of the longest-running longitudinal aging studies in the United States. Our results show that obesity-related risk allele carriers of FTO gene show dose-dependent increments in body mass index during aging. Moreover, the obesity-related risk allele is associated with reduced medial prefrontal cortical function during aging. Consistent with reduced brain function in regions intrinsic to impulse control and taste responsiveness, risk allele carriers of FTO exhibit dose-dependent increments in both impulsivity and intake of fatty foods. We propose that a common neural mechanism may underlie obesity-associated impulsivity and increased consumption of high-calorie foods during aging.

Common genetic variation near the connexin-43 gene is associated with resting heart rate in African Americans: a genome-wide association study of 13,372 participants.

BACKGROUND: Genome-wide association studies have identified several genetic loci associated with variation in resting heart rate in European and Asian populations. No study has evaluated genetic variants associated with heart rate in African Americans. OBJECTIVE: To identify novel genetic variants associated with resting heart rate in African Americans. METHODS: Ten cohort studies participating in the Candidate-gene Association Resource and Continental Origins and Genetic Epidemiology Network consortia performed genome-wide genotyping of single nucleotide polymorphisms (SNPs) and imputed 2,954,965 SNPs using HapMap YRI and CEU panels in 13,372 participants of African ancestry. Each study measured the RR interval (ms) from 10-second resting 12-lead electrocardiograms and estimated RR-SNP associations using covariate-adjusted linear regression. Random-effects meta-analysis was used to combine cohort-specific measures of association and identify genome-wide significant loci (P≤2.5×10(-8)). RESULTS: Fourteen SNPs on chromosome 6q22 exceeded the genome-wide significance threshold. The most significant association was for rs9320841 (+13 ms per minor allele; P = 4.98×10(-15)). This SNP was approximately 350 kb downstream of GJA1, a locus previously identified as harboring SNPs associated with heart rate in Europeans. Adjustment for rs9320841 also attenuated the association between the remaining 13 SNPs in this region and heart rate. In addition, SNPs in MYH6, which have been identified in European genome-wide association study, were associated with similar changes in the resting heart rate as this population of African Americans. CONCLUSIONS: An intergenic region downstream of GJA1 (the gene encoding connexin 43, the major protein of the human myocardial gap junction) and an intragenic region within MYH6 are associated with variation in resting heart rate in African Americans as well as in populations of European and Asian origin.

Exome sequencing: an efficient diagnostic tool for complex neurodegenerative disorders.

BACKGROUND AND PURPOSE: Autosomal recessive cerebellar ataxia (ARCA) comprises a large and heterogeneous group of neurodegenerative disorders. We studied three families diagnosed with ARCA. METHODS: To determine the gene lesions responsible for their disorders, we performed high-density single-nucleotide polymorphism genotyping and exome sequencing. RESULTS: We identified a new mutation in the SACS gene and a known mutation in SPG11. Notably, we also identified a homozygous variant in APOB, a gene previously associated with ataxia. CONCLUSIONS: These findings demonstrate that exome sequencing is an efficient and direct diagnostic tool for identifying the causes of complex and genetically heterogeneous neurodegenerative diseases, early-stage disease or cases with limited clinical data.

Lewy-like aggregation of α-synuclein reduces protein phosphatase 2A activity in vitro and in vivo.

α-synuclein (α-Syn) is a chaperone-like protein that is highly implicated in Parkinson's disease (PD) as well as in dementia with Lewy bodies (DLB). Rare forms of PD occur in individuals with mutations of α-Syn or triplication of wild type α-Syn, and in both PD and DLB the intraneuronal inclusions known as Lewy bodies contain aggregated α-Syn that is highly phosphorylated on serine 129. In neuronal cells and in the brains of α-Syn overexpressing transgenic mice, soluble α-Syn stimulates the activity of protein phosphatase 2A (PP2A), a major serine/threonine phosphatase. Serine 129 phosphorylation of α-Syn attenuates its stimulatory effects on PP2A and also accelerates α-Syn aggregation; however, it is unknown if aggregation of α-Syn into Lewy bodies impairs PP2A activity. To assess for this, we measured the impact of α-Syn aggregation on PP2A activity in vitro and in vivo. In cell-free assays, aggregated α-Syn had ∼50% less PP2A stimulatory effects than soluble recombinant α-Syn. Similarly in DLB and α-Syn triplication brains, which contain robust α-Syn aggregation with high levels of serine 129 phosphorylation, PP2A activity was also ∼50% attenuated. As α-Syn normally stimulates PP2A activity, our data suggest that overexpression of α-Syn or sequestration of α-Syn into Lewy bodies has the potential to alter the phosphorylation state of key PP2A substrates; raising the possibility that all forms of synucleinopathy will benefit from treatments aimed at optimizing PP2A activity.

Exome sequencing in Parkinson's disease.

Exome sequencing is rapidly becoming a fundamental tool for genetics and functional genomics laboratories. This methodology has enabled the discovery of novel pathogenic mutations causing mendelian diseases that had, until now, remained elusive. In this review, we discuss not only how we envisage exome sequencing being applied to a complex disease, such as Parkinson's disease, but also what are the known caveats of this approach.

Clinical features of patients with blepharospasm: a report of 240 patients.

BACKGROUND AND PURPOSE: To characterize patients with benign essential blepharospasm (BEB) by diagnosis, environmental risk factors, and family history. METHODS: Two hundred and forty patients with BEB were evaluated through a clinical examination and questionnaire. The questionnaire reviewed personal medical history, demographic factors, risk factors for the development of blepharospasm and family history of dystonia and other neurological conditions. RESULTS: Benign essential blepharospasm was more commonly found in women (2.8:1) and 93% of the patients were Caucasian. Fifty percent had pure BEB, 31% had BEB/Meige's syndrome, and 4% had BEB and eyelid opening apraxia (+/- Meige's syndrome). A minority of patients reported preceding photophobia (25%) or other eye conditions (22%). The majority were non-smokers, had no exposure to anti-emetic or antipsychotic agents, had a normal birth history, and had no history of head trauma. Seventy-two percent did report a stressful event immediately prior to the development of symptoms. Treatments reported included botulinum toxin (BoNT), oral medications, surgical procedures, and acupuncture. Thirty-two percent of patients reported a family history of focal dystonia, and BEB was the most commonly reported. CONCLUSION: This study confirms previous reports of usual age, sex, caffeine and tobacco use, and family history in patients with blepharospasm. New findings include a report on occupation, lower reports of preceding eye conditions and photophobia, and higher reported stressful events. Further, this study shows a change in treatment with an increase in BoNT use and decrease in surgical procedures.