Genome sequence analyses identify novel risk loci for multiple system atrophy.

Multiple system atrophy (MSA) is an adult-onset, sporadic synucleinopathy characterized by parkinsonism, cerebellar ataxia, and dysautonomia. The genetic architecture of MSA is poorly understood, and treatments are limited to supportive measures. Here, we performed a comprehensive analysis of whole genome sequence data from 888 European-ancestry MSA cases and 7,128 controls to systematically investigate the genetic underpinnings of this understudied neurodegenerative disease. We identified four significantly associated risk loci using a genome-wide association study approach. Transcriptome-wide association analyses prioritized USP38-DT, KCTD7, and lnc-KCTD7-2 as novel susceptibility genes for MSA within these loci, and single-nucleus RNA sequence analysis found that the associated variants acted as cis-expression quantitative trait loci for multiple genes across neuronal and glial cell types. In conclusion, this study highlights the role of genetic determinants in the pathogenesis of MSA, and the publicly available data from this study represent a valuable resource for investigating synucleinopathies.

A genetic and transcriptomic assessment of the KTN1 gene in Parkinson's disease risk.

Parkinson's disease (PD) is a progressive neurological disorder caused by both genetic and environmental factors. An association has been described between KTN1 genetic variants and changes in its expression in the putamen and substantia nigra brain regions and an increased risk for PD. Here, we examine the link between PD susceptibility and KTN1 using individual-level genotyping data and summary statistics from the most recent genome-wide association studies (GWAS) for PD risk and age at onset from the International Parkinson's Disease Genomics Consortium (IPDGC), as well as whole-genome sequencing data from the Accelerating Medicines Partnership Parkinson's disease (AMP-PD) initiative. To investigate the potential effect of changes in KTN1 expression on PD compared to unaffected individuals, we further assess publicly available expression quantitative trait loci (eQTL) results from GTEx v8 and BRAINEAC and transcriptomics data from AMP-PD. Overall, we found no genetic associations between KTN1 and PD in our cohorts but found potential evidence of differences in mRNA expression, which needs to be further explored.

Association Between Insulin-Like Growth Factor-1 and Social Cognition in Huntington's Disease.

Background: Insulin-like growth factor 1 (IGF-1) seems to be involved in the neural circuits associated with social cognition and brain structure. Objectives: To investigate the association of IGF-1 levels with social cognition and brain structure in Huntington's disease (HD). Methods: We evaluated social cognition using the Ekman test in 22 HD patients and 19 matched controls. Brain structure was assessed using standard volume-based voxel-based morphometry and surface-based cortical thickness pipeline. We analyzed the association of IGF-1 levels with social cognition and brain structure using adjusted regression analysis. Results: Social cognition was worse in HD patients (P < 0.001), on antidopaminergic drugs (P = 0.02), and with lower IGF-1 levels (P = 0.04). In neuroimaging analyses, lower IGF-1 levels were associated with social cognition impairment and atrophy mainly in frontotemporal regions (P < 0.05 corrected). Conclusions: In HD, abnormal IGF-1 function seems to be associated with brain atrophy leading to clinical deficits in social cognition.

Mendelian Randomisation Confirms the Role of Y-Chromosome Loss in Alzheimer's Disease Aetiopathogenesis in Men.

Mosaic loss of chromosome Y (mLOY) is a common ageing-related somatic event and has been previously associated with Alzheimer's disease (AD). However, mLOY estimation from genotype microarray data only reflects the mLOY degree of subjects at the moment of DNA sampling. Therefore, mLOY phenotype associations with AD can be severely age-confounded in the context of genome-wide association studies. Here, we applied Mendelian randomisation to construct an age-independent mLOY polygenic risk score (mloy-PRS) using 114 autosomal variants. The mloy-PRS instrument was associated with an 80% increase in mLOY risk per standard deviation unit (p = 4.22 × 10-20) and was orthogonal with age. We found that a higher genetic risk for mLOY was associated with faster progression to AD in men with mild cognitive impairment (hazard ratio (HR) = 1.23, p = 0.01). Importantly, mloy-PRS had no effect on AD conversion or risk in the female group, suggesting that these associations are caused by the inherent loss of the Y chromosome. Additionally, the blood mLOY phenotype in men was associated with increased cerebrospinal fluid levels of total tau and phosphorylated tau181 in subjects with mild cognitive impairment and dementia. Our results strongly suggest that mLOY is involved in AD pathogenesis.

Polymorphisms in the oxytocin receptor and their association with apathy and impaired social cognition in Huntington's disease.

BACKGROUND: Huntington's disease (HD) is a neurodegenerative disorder characterized by cognitive, motor, and neuropsychiatric manifestations. Oxytocin is a neuropeptide studied for its role as a neuromodulator regulating multiple behaviors linked to social cognition. Genetic variation of oxytocin receptor (OXTR) might interact in the etiology and development of several impaired social behaviors. Our aim was to study OXTR polymorphisms and their relationship with apathy and social cognition in HD. METHODS: OXTR was sequenced in 21 cases and 22 controls. We assessed apathy, anxiety, depression, and irritability (Hospital Anxiety and Depression Scale-Snaith Irritability scale, HADS-SIS) and social cognition (Ekman 60 faces test), motor symptoms and functionality with the total functional capacity (TFC), and the Unified HD rating Scale (UHDRS). RESULTS: We identified ten variants in OXTR. Three variants were classified as possibly damaging (p.Arg40Gly) or probably damaging (p.Leu46Pro, p.Thr102Asn). Subjects carrying the wild-type genotype of the synonymous variant p.Val45 showed a significantly lower score in the HADS-SIS scale, related to lower irritability (p = 0.013). The only subject carrying the heterozygous genotype of the synonymous variant p.Leu62 showed a significantly higher score on Ekman scale, compared to wild-type (p = 0.049); however, this finding was not confirmed after bootstrapping. CONCLUSION: Variations in OXTR could have a relevant role in the correct development of social and cognitive functions. Future approaches will include the molecular study of p.Arg40Gly, p.Leu46Pro, and p.Thr102Asn to confirm their pathogenicity, as well as the validation of the influence of p.Val45 and p.Leu62 variants for their involvement in irritability and social cognition in HD.

Vitamin D Receptor and Binding Protein Gene Variants in Patients with Essential Tremor.

Several studies have shown an association between some variants in the vitamin D receptor (VDR) and the GC vitamin D binding protein (GC) genes with the risk for Parkinson's disease or other neurological disorders. VDR rs2228570 has shown an association with essential tremor (ET) in a previous study. The aim of this study is to look for the association between several common variants in these genes and the risk for ET. We genotyped 272 patients diagnosed with familial ET and 272 age-matched controls using specific TaqMan assays for VDR rs2228570, VDR rs731236, VDR rs7975232, VDR rs739837, VDR rs78783628, GC rs7041, and GC rs4588 single nucleotide variants (SNVs). We found an association between GC rs7041 SNV and ET using recessive, codominant, and allelic models. Despite our results did not find an association between VDR rs2228570 and ET, the pooled data with those by a previous report suggest this association under recessive, codominant, and allelic models. None of the SNVs studied was related to the age at onset of tremor in ET patients. Data from the current study suggest an association between GC rs7041 and VDR rs2228570 SNVs and ET risk.

Serum Trace Elements Concentrations in Patients with Restless Legs Syndrome.

Increased brain and serum zinc levels in patients with idiopathic restless legs syndrome (idiopathic RLS or iRLS) were described when compared with controls, suggesting a possible role of zinc in the pathogenesis of this disease. However, serum magnesium, calcium, manganese, iron, and copper levels of RLS patients were similar to controls, suggesting a specific impairment of zinc-dependent metabolism in RLS. The aim of this study is to assess the serum concentrations of trace elements involved in oxidative stress or causing peripheral nerve toxicity in a large series of patients with iRLS and controls. We determined serum levels of iron, copper, manganese, zinc, magnesium, selenium, calcium, aluminium, lead, cadmium, arsenic and mercury in 100 patients diagnosed with iRLS and in 110 age- and sex-matched controls using Inductively Coupled Plasma Mass Spectrometry. Serum copper, magnesium, selenium, and calcium concentrations were significantly higher in RLS patients than in controls. These differences were observed both in men and women. There were no major correlations between serum trace metal concentrations and age at onset of RLS or RLS severity, nor was there any association with a family history of RLS or drug response. This study shows an association between increased serum concentrations of copper, magnesium, selenium, and calcium with RLS in a Spanish Caucasian population and does not confirm the previously reported increase in serum zinc concentrations in patients suffering from this disease, suggesting that the different accuracy of the analytical methods used could have influenced the inconsistent results found in the literature.

Association of Essential Tremor With Novel Risk Loci: A Genome-Wide Association Study and Meta-analysis.

Importance: Essential tremor (ET) is one of the most common movement disorders, affecting 5% of the general population older than 65 years. Common variants are thought to contribute toward susceptibility to ET, but no variants have been robustly identified. Objective: To identify common genetic factors associated with risk of ET. Design, Setting, and Participants: Case-control genome-wide association study. Inverse-variance meta-analysis was used to combine cohorts. Multicenter samples collected from European populations were collected from January 2010 to September 2019 as part of an ongoing study. Included patients were clinically diagnosed with or reported having ET. Control individuals were not diagnosed with or reported to have ET. Of 485 250 individuals, data for 483 054 passed data quality control and were used. Main Outcomes and Measures: Genotypes of common variants associated with risk of ET. Results: Of the 483 054 individuals included, there were 7177 with ET (3693 [51.46%] female; mean [SD] age, 62.66 [15.12] years), and 475 877 control individuals (253 785 [53.33%] female; mean [SD] age, 56.40 [17.6] years). Five independent genome-wide significant loci and were identified and were associated with approximately 18% of ET heritability. Functional analyses found significant enrichment in the cerebellar hemisphere, cerebellum, and axonogenesis pathways. Genetic correlation (r), which measures the degree of genetic overlap, revealed significant common variant overlap with Parkinson disease (r, 0.28; P = 2.38 × 10-8) and depression (r, 0.12; P = 9.78 × 10-4). A separate fine-mapping of transcriptome-wide association hits identified genes such as BACE2, LRRN2, DHRS13, and LINC00323 in disease-relevant brain regions, such as the cerebellum. Conclusions and Relevance: The results of this genome-wide association study suggest that a portion of ET heritability can be explained by common genetic variation and can help identify new common genetic risk factors for ET.

Genomic Characterization of Host Factors Related to SARS-CoV-2 Infection in People with Dementia and Control Populations: The GR@ACE/DEGESCO Study.

Emerging studies have suggested several chromosomal regions as potential host genetic factors involved in the susceptibility to SARS-CoV-2 infection and disease outcome. We nested a COVID-19 genome-wide association study using the GR@ACE/DEGESCO study, searching for susceptibility factors associated with COVID-19 disease. To this end, we compared 221 COVID-19 confirmed cases with 17,035 individuals in whom the COVID-19 disease status was unknown. Then, we performed a meta-analysis with the publicly available data from the COVID-19 Host Genetics Initiative. Because the APOE locus has been suggested as a potential modifier of COVID-19 disease, we added sensitivity analyses stratifying by dementia status or by disease severity. We confirmed the existence of the 3p21.31 region (LZTFL1, SLC6A20) implicated in the susceptibility to SARS-CoV-2 infection and TYK2 gene might be involved in COVID-19 severity. Nevertheless, no statistically significant association was observed in the COVID-19 fatal outcome or in the stratified analyses (dementia-only and non-dementia strata) for the APOE locus not supporting its involvement in SARS-CoV-2 pathobiology or COVID-19 prognosis.

The Genetic Landscape of Parkinsonism-Related Dystonias and Atypical Parkinsonism-Related Syndromes.

In recent decades, genetic research has nominated promising pathways and biological insights contributing to the etiological landscape of parkinsonism-related dystonias and atypical parkinsonism-related syndromes. Several disease-causing mutations and genetic risk factors have been unraveled, providing a deeper molecular understanding of the complex genetic architecture underlying these conditions. These disorders are difficult to accurately diagnose and categorize, thus making genetics research challenging. On one hand, dystonia is an umbrella term linked to clinically heterogeneous forms of disease including dopa-responsive dystonia, myoclonus-dystonia, rapid-onset dystonia-parkinsonism and dystonia-parkinsonism, often viewed as a precursor to Parkinson's disease. On the other hand, atypical parkinsonism disorders, such as progressive supranuclear palsy, multiple system atrophy and corticobasal degeneration, are rare in nature and represent a wide range of diverse and overlapping phenotypic variabilities, with genetic research limited by sample size availability. The current review summarizes the plethora of available genetic information for these diseases, outlining limits and future directions.

Common variants in Alzheimer's disease and risk stratification by polygenic risk scores.

Genetic discoveries of Alzheimer's disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer's disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer's disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer's disease.

Common Endothelial Nitric Oxide Synthase Single Nucleotide Polymorphisms are not Related With the Risk for Restless Legs Syndrome.

Because nitric oxide and endothelial dysfunction could play a role in the pathogenesis of idiopathic restless legs syndrome (RLS), as was suggested by some preliminary data, we investigated the possible association between the rs2070744 variants in the endothelial nitric oxide synthase (eNOS or NOS3) gene (chromosome 7q36.1) and the risk for RLS in a Caucasian Spanish population. We assessed the frequencies of NOS3 single nucleotide polymorphisms (SNPs) rs2070744, rs1799983, and rs79467411 genotypes and allelic variants in 273 patients with idiopathic RLS and 325 healthy controls using a TaqMan-based qPCR assay. We also analyzed the possible influence of genotype frequency on age at onset of RLS symptoms, gender, family history of RLS, and response to drugs commonly used in the treatment of RLS such as dopaminergic drugs, clonazepam, and GABAergic drugs. The frequencies of genotypes and allelic variants were not associated with the risk for RLS and were not influenced by gender, age, and positive family history of RLS. We identified weak statistical associations of the SNP rs1799983 with the response to dopamine agonists (Pc = 0.018 for the rs1799983 G/T genotype) and of the SNP rs79467411 with the response to clonazepam (Pc = 0.018 for the rs79467411 G allele), although these findings should be cautiously interpreted and require further confirmation. These associations aside, our findings suggest that common NOS3 SNPs are not associated with the risk for idiopathic RLS in Caucasian Spanish people.

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.

Assessment of LIN28A variants in Parkinson's disease in large European cohorts.

Parkinson's disease (PD) is a complex neurodegenerative disease with a strong genetic component. To date, several genes have been associated with monogenic forms of the disease, but these only explain a small fraction of the observed familial aggregation in PD. Recently, a heterozygous loss-of-function variant in LIN28A was associated with PD pathogenesis in the Asian population. Here, we comprehensively investigate the role of LIN28A variants in PD patients of European ancestry and assess susceptibility using individual-level genotyping data from 14,671 PD cases and 17,667 controls, as well as whole-genome sequencing data from 1647 patients with PD and 1050 controls. In addition, we further assess the summary statistics from the most recent genome-wide association studies meta-analyses to date for PD risk and age at onset. After evaluating these data, we did not find evidence to support a role for LIN28A as a major causal gene for PD. However, additional large-scale familial and case-control studies in non-European ancestry populations are necessary to further evaluate the role of LIN28A in PD etiology.

Genetic variation in APOE, GRN, and TP53 are phenotype modifiers in frontotemporal dementia.

Frontotemporal dementia (FTD) is a clinical, genetic, and pathologic heterogeneous group of neurodegenerative diseases. In this study, we investigated the role of APOƐ4, rs5848 in GRN, and rs1042522 in TP53 gene as disease risk factors and/or phenotype modifiers in 440 FTD patients, including 175 C9orf72 expansion carriers. We found that the C9orf72 expansion carriers showing an earlier age at onset (p < 0.001). Among the clinical groups, the FTD-MND (motoneuron disease) showed the lowest survival (hazard ratio [HR] = 4.12), and the progressive nonfluent aphasia group showed the highest onset age (p = 0.03). In our cohort, the rs1042522 in TP53 was associated with disease onset (p = 0.02) and survival (HR = 1.73) and rs5848 GRN with a significantly shorter survival in CC homozygous patients (HR = 1.98). The frequency of APOƐ4 carriers was significantly increased in the C9orf72 noncarriers (p = 0.022). Although validation of our findings is necessary, our results suggest that TP53, GRN, and APOE genes may act as phenotype modifiers in FTD and should be considered in future clinical trials.

Added value of cerebrospinal fluid multimarker analysis in diagnosis and progression of dementia.

BACKGROUND AND PURPOSE: Recently, some emerging cerebrospinal fluid (CSF) markers have been proposed as diagnostic tools for Alzheimer disease (AD) that can have an effect on disease progression. We analyze the accuracy of these CSF markers for diagnosis of AD in reference to brain amyloid positron emission tomography (PET). We also investigated whether they help in differentiating AD from other dementias and examined their influence in tracing the progression to dementia. METHODS: Amyloid-ß (Aß) 1-42, total tau (t-tau), phosphorylated tau, Aß40 , Aß38 , beta-site amyloid precursor protein cleaving enzyme 1 (BACE-1), neurogranin (ng), phosphorylated neurofilament heavy-chain, and α-synuclein (α-syn) CSF levels were analyzed in 319 subjects, among whom 57 also underwent an amyloid PET scan. We also analyzed longitudinal clinical data from 239 subjects. RESULTS: Emerging CSF markers, especially ng/BACE-1 ratio (area under the curve = 0.77) and their combinations with core AD CSF markers (all AUCs >0.85), showed high accuracy to discriminate amyloid PET positivity. Subjects with AD had higher CSF BACE-1, ng, and α-syn levels than those with non-AD dementia. CSF t-tau/α-syn ratio was higher in subjects with dementia with Lewy bodies than in those with frontotemporal dementia. Most emerging/core AD ratios predicted a faster conversion from mild cognitive impairment (MCI) stage to AD and appeared to be helpful when core AD CSF markers were discordant. In addition, the rate of cognitive decline was associated with all CSF core AD markers, several emerging/core AD two-marker ratios, and CSF ng levels. CONCLUSIONS: These results suggest that emerging biomarkers in conjunction with core AD markers improve diagnosis of AD, are associated with the conversion from MCI into AD, and predict a faster progression of dementia.

Serum vitamin D, vitamin D receptor and binding protein genes polymorphisms in restless legs syndrome.

BACKGROUND/OBJECTIVES: Several studies showed lower serum 25-hydroxyvitamin D levels in patients with idiopathic restless legs syndrome (RLS) compared with matched controls, and a single study showed an association between the rs731236 single nucleotide polymorphism (SNP) in the vitamin D receptor (VDR) gene and the risk for RLS. We aimed to study the relationship between the serum 25-hydroxyvitamin D levels and to confirm previous findings related to SNPs in the VDR and the GC vitamin D binding protein (GC) gene, with the risk for RLS in the Spanish Caucasian population. METHODS: We genotyped 285 idiopathic RLS patients and 325 age and sex-matched controls for VDRrs2228750, VDRrs7975232, VDRrs739837, VDRrs78783628, GCrs7041 and GCrs4588 SNPs using TaqMan assays, and determined serum 25-hydroxyvitamin D levels in 111 idiopathic RLS patients and 167 controls using an ELISA commercial kit. RESULTS: Serum 25-hydroxyvitamin D levels were significantly higher in RLS patients than in controls but were unrelated with the 7 SNPs studied. None of the 7 SNPs analyzed was associated with the risk for idiopathic RLS or with a positive family history of RLS. However, RLS patients carrying the rs7975232CC genotype or the rs7975232C allele, had a higher frequency of response to GABAergic drugs. Associations between the age at onset and the severity of RLS with SNPs were inconsistent. CONCLUSIONS: This study shows an association between increased serum concentrations of 25-hydroxyvitamin D and a lack of association between 7 SNPs in the VDR and in the GC genes with RLS in the Spanish Caucasian population.

Exome-wide rare variant analysis in familial essential tremor.

INTRODUCTION: Essential tremor (ET) is one of the most common movement disorders. Despite its high prevalence and heritability, its genetic etiology remains elusive with only a few susceptibility genes identified and poorly replicated. Our aim was to find novel candidate genes involved in ET predisposition through whole exome sequencing. METHODS: We studied eight multigenerational families (N = 40 individuals) with an autosomal-dominant inheritance using a comprehensive strategy combining whole exome sequencing followed by case-control association testing of prioritized variants in a separate cohort comprising 521 ET cases and 596 controls. We further performed gene-based burden analyses in an additional dataset comprising 789 ET patients and 770 healthy individuals to investigate whether there was an enrichment of rare deleterious variants within our candidate genes. RESULTS: Fifteen variants co-segregated with disease status in at least one of the families, among which rs749875462 in CCDC183, rs535864157 in MMP10 and rs114285050 in GPR151 showed a nominal association with ET. However, we found no significant enrichment of rare variants within these genes in cases compared with controls. Interestingly, MMP10 protein is involved in the inflammatory response to neuronal damage and has been previously associated with other neurological disorders. CONCLUSIONS: We prioritized a set of promising genes, especially MMP10, for further genetic and functional studies in ET. Our study suggests that rare deleterious coding variants that markedly increase susceptibility to ET are likely to be found in many genes. Future studies are needed to replicate and further infer biological mechanisms and potential disease causality for our identified genes.