Neuromics and Neurological Disease

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ArticleNeuromics and Neurological DiseaseApril 2008JAMA Neurology 65(3):307-8DOI:10.1001/archneur.65.3.307SourcePubMedAuthors: Roger N RosenbergRoger N RosenbergThis person is not on ResearchGate, or hasn t claimed this research yet. Request full-text PDFTo read the full-text of this research, you can request a copy directly from the author.Request full-textDownload citation Copy link Link copied Request full-text Download citation Copy link Link copiedTo read the full-text of this research, you can request a copy directly from the author.Citations (2)References (13)AbstractNeuromics, the analysis of genomic DNA for risk association with a neurological disease, has achieved considerable success recently. An increased risk for amyotrophic lateral sclerosis (ALS), Alzheimer disease (AD), restless leg syndrome (RLS), and multiple sclerosis has been associated with polymorphisms in specific genes. These observations are truly significant advances in the appreciation of the causation of inherited, complex polygenetic, multifactorial neurological diseases. They have been made possible by the publication of the human genome and haplotype studies (HapMap analyses). Neurome-wide association studies will increase in the future and we plan on devoting an increased interest in them, as they provide a new detailed level of analyses to achieve a clearer understanding of multigene interactions responsible for neurological disease. For the time being, most of these neurome-wide analyses will not have direct clinical relevance and will not directly affect patient care. Eventually, and perhaps quite soon, they will at least provide a risk assessment to monitor specific patients in large pedigrees for their risk of disease presentation. Pharmacogenomics, or more specifically, pharmaconeuromics, will be an early positive result by initiating the design of specific drug therapies for a patient s neurological disease based on his or her neuromic risk.¹ Discover the world s research20+ million members135+ million publications700k+ research projectsJoin for freeNo full-text available To read the full-text of this research, you can request a copy directly from the author.Request full-text PDFCitations (2)References (13)... Our results highlight the variety of data that can be obtained from these different analytic approaches. Previous GWASs in AD using a categorical approach have not been able to consistently identify risk genes in AD other than APOE [62]. To further evaluate our finding of no interaction with diagnosis and APOE we performed a QT analysis removing APOE–related SNPs. ...Hippocampal Atrophy as a Quantitative Trait in a Genome-Wide Association Study Identifying Novel Susceptibility Genes for Alzheimer s DiseaseArticleFull-text availableFeb 2009PLOS ONE Steven G Potkin Guia Guffanti A. Lakatos Fabio MacciardiWith the exception of APOE epsilon4 allele, the common genetic risk factors for sporadic Alzheimer s Disease (AD) are unknown.We completed a genome-wide association study on 381 participants in the ADNI (Alzheimer s Disease Neuroimaging Initiative) study. Samples were genotyped using the Illumina Human610-Quad BeadChip. 516,645 unique Single Nucleotide Polymorphisms (SNPs) were included in the analysis following quality control measures. The genotype data and raw genetic data are freely available for download (LONI, http://www.loni.ucla.edu/ADNI/Data/). Two analyses were completed: a standard case-control analysis, and a novel approach using hippocampal atrophy measured on MRI as an objectively defined, quantitative phenotype. A General Linear Model was applied to identify SNPs for which there was an interaction between the genotype and diagnosis on the quantitative trait. The case-control analysis identified APOE and a new risk gene, TOMM40 (translocase of outer mitochondrial membrane 40), at a genome-wide significance level of or =10(-6) (10(-11) for a haplotype). TOMM40 risk alleles were approximately twice as frequent in AD subjects as controls. The quantitative trait analysis identified 21 genes or chromosomal areas with at least one SNP with a p-value or =10(-6), which can be considered potential new candidate loci to explore in the etiology of sporadic AD. These candidates included EFNA5, CAND1, MAGI2, ARSB, and PRUNE2, genes involved in the regulation of protein degradation, apoptosis, neuronal loss and neurodevelopment. Thus, we identified common genetic variants associated with the increased risk of developing AD in the ADNI cohort, and present publicly available genome-wide data. Supportive evidence based on case-control studies and biological plausibility by gene annotation is provided. Currently no available sample with both imaging and genetic data is available for replication.Using hippocampal atrophy as a quantitative phenotype in a genome-wide scan, we have identified candidate risk genes for sporadic Alzheimer s disease that merit further investigation.ViewShow abstractConsciousness, Coma, and Brain Death—2009ArticleApr 2009J Am Med AssocRoger N. RosenbergThis landmark classic article was the first to quantitatively define the clinical and laboratory criteria used to measure the presence of brain death. The study included \"only those comatose individuals who have no discernible central nervous system activity.” Criteria to establish the presence of irreversible coma included (1) unreceptivity and unresponsitivity; (2) no movements or breathing; (3) no reflexes (brain stem); and (4) flat electroencephalogram. These criteria are still considered to be reliable and acceptable by the medical community and have become established into law, which states that brain death is equivalent to death and that all artificial support systems sustaining heart, respiratory, and metabolic functions can be legally stopped.See PDF for full text of the original JAMA article.ViewShow abstractEvidence for novel susceptibility genes for late-onset Alzheimer s disease from a genome-wide association study of putative functional variantsArticleFull-text availableApr 2007HUM MOL GENETAndrew GrupeRichard AbrahamYonghong Li Julie WilliamsThis study sets out to identify novel susceptibility genes for late-onset Alzheimer s disease (LOAD) in a powerful set ofsamples from the UK and USA (1808 LOAD cases and 2062 controls). Allele frequencies of 17 343 gene-based putative functionalsingle nucleotide polymorphisms (SNPs) were tested for association with LOAD in a discovery case–control sample from the UK.A tiered strategy was used to follow-up significant variants from the discovery sample in four independent sample sets. Here,we report the identification of several candidate SNPs that show significant association with LOAD. Three of the identifiedmarkers are located on chromosome 19 (meta-analysis: full sample P = 6.94E − 81 to 0.0001), close to the APOE gene and exhibit linkage disequilibrium (LD) with the APOEε4 and ε2/3 variants (0.09 D′ 1). Two of the three SNPs can be regarded as study-wide significant (expected number of false positives reaching the observedsignificance level less than 0.05 per study). Sixteen additional SNPs show evidence for association with LOAD [P = 0.0010-0.00006; odds ratio (OR) = 1.07–1.45], several of which map to known linkage regions, biological candidate genesand novel genes. Four SNPs not in LD with APOE show a false positive rate of less than 2 per study, one of which shows study-widesuggestive evidence taking account of 17 343 tests. This is a missense mutation in the galanin-like peptide precursor gene(P = 0.00005, OR = 1.2, false positive rate = 0.87).ViewShow abstractA High-Density Whole-Genome Association Study Reveals That APOE Is the Major Susceptibility Gene for Sporadic Late-Onset Alzheimer s DiseaseArticleFull-text availableMay 2007J Clin PsychiatrKeith D Coon Amanda J Myers David CraigDietrich A StephanWhile the apolipoprotein E (APOE) epsilon allele is a well-established risk factor for late-onset Alzheimer s disease (AD), initial genome scans using microsatellite markers in late-onset AD failed to identify this locus on chromosome 19. Recently developed methods for the simultaneous assessment of hundreds of thousands of single nucleotide polymorphisms (SNPs) promise to help more precisely identify loci that contribute to the risk of AD and other common multigenic conditions. We sought here to demonstrate that more precise identification of loci that are associated with complex, multi-genic genetic disorders can be achieved using ultra-high-density whole-genome associations by demonstrating their ability to identify the APOE locus as a major susceptibility gene for late-onset AD, despite the absence of SNPs within the APOE locus itself, as well as to refine odds ratios (ORs) based on gold-standard phenotyping of the study population.An individualized genome-wide association study using 502,627 SNPs was performed in 1086 his-topathologically verified AD cases and controls to determine the OR associated with genes predisposing to Alzheimer s disease.As predicted, ultra-high-density SNP genotyping, in contrast to traditional microsatellite-based genome screening approaches, precisely identified the APOE locus as having a significant association with late-onset AD. SNP rs4420638 on chromosome 19, located 14 kilobase pairs distal to the APOE epsilon variant, significantly distinguished between AD cases and controls (Bonferroni corrected p value = 5.30 x 10(-34), OR = 4.01) and was far more strongly associated with the risk of AD than any other SNP of the 502,627 tested.This study provides empirical support for the suggestion that the APOE locus is the major susceptibility gene for late-onset AD in the human genome, with an OR significantly greater than any other locus in the human genome. It also supports the feasibility of the ultra-high-density whole-genome association approach to the study of AD and other heritable phenotypes. These whole-genome association studies show great promise to identify additional genes that contribute to the risk of AD.ViewShow abstractA Genetic Risk Factor for Periodic Limb Movements in SleepArticleFull-text availableSep 2007New Engl J Med Hreinn Stefansson David Rye Andrew A. HicksKari StefanssonThe restless legs syndrome (RLS) is a common neurologic disorder characterized by an irresistible urge to move the legs. It is a major cause of sleep disruption. Periodic limb movements in sleep are detectable in most patients with RLS and represent an objective physiological metric.To search for sequence variants contributing to RLS, we performed a genomewide association study and two replication studies. To minimize phenotypic heterogeneity, we focused on patients with RLS who had objectively documented periodic limb movements in sleep. We measured serum ferritin levels, since iron depletion has been associated with the pathogenesis of RLS.In an Icelandic discovery sample of patients with RLS and periodic limb movements in sleep, we observed a genomewide significant association with a common variant in an intron of BTBD9 on chromosome 6p21.2 (odds ratio, 1.8; P=2x10(-9)). This association was replicated in a second Icelandic sample (odds ratio, 1.8; P=4x10(-4)) and a U.S. sample (odds ratio, 1.5; P=4x10(-3)). With this variant, the population attributable risk of RLS with periodic limb movements was approximately 50%. An association between the variant and periodic limb movements in sleep without RLS (and the absence of such an association for RLS without periodic limb movements) suggests that we have identified a genetic determinant of periodic limb movements in sleep (odds ratio, 1.9; P=1x10(-17)). Serum ferritin levels were decreased by 13% per allele of the at-risk variant (95% confidence interval, 5 to 20; P=0.002).We have discovered a variant associated with susceptibility to periodic limb movements in sleep. The inverse correlation of the variant with iron stores is consistent with the suspected involvement of iron depletion in the pathogenesis of the disease.ViewShow abstractInterleukin 7 receptor chain (IL7R) shows allelic and functional association with multiple sclerosisArticleFull-text availableOct 2007Nat. Genet. Simon G Gregory Silke SchmidtPuneet Seth Jonathan l. HainesMultiple sclerosis is a demyelinating neurodegenerative disease with a strong genetic component. Previous genetic risk studies have failed to identify consistently linked regions or genes outside of the major histocompatibility complex on chromosome 6p. We describe allelic association of a polymorphism in the gene encoding the interleukin 7 receptor alpha chain (IL7R) as a significant risk factor for multiple sclerosis in four independent family-based or case-control data sets (overall P = 2.9 x 10(-7)). Further, the likely causal SNP, rs6897932, located within the alternatively spliced exon 6 of IL7R, has a functional effect on gene expression. The SNP influences the amount of soluble and membrane-bound isoforms of the protein by putatively disrupting an exonic splicing silencer.ViewShow abstractWhole-Genome Analysis of Sporadic Amyotrophic Lateral SclerosisArticleFull-text availableAug 2007New Engl J Med Travis Dunckley Matthew J Huentelman David CraigDietrich A StephanApproximately 90% of persons with amyotrophic lateral sclerosis (ALS) have the sporadic form, which may be caused by the interaction of multiple environmental factors and previously unknown genes.We performed a genomewide association analysis using 766,955 single-nucleotide polymorphisms (SNPs) found in 386 white patients with sporadic ALS and 542 neurologically normal white controls (the discovery series). Associations of SNPs with sporadic ALS were confirmed in two independent replication populations: replication series 1, with 766 case patients with the disease and 750 neurologically normal controls, and replication series 2, with 135 case patients and 275 controls.We identified 10 genetic loci that are significantly associated (P 0.05) with sporadic ALS in three independent series of case patients and controls and an additional 41 loci that had significant associations in two of the three series. The most significant association with disease in white case patients as compared with controls was found for a SNP near an uncharacterized gene known as FLJ10986 (P=3.0x10(-4); odds ratio for having the genotype in patients vs. controls, 1.35; 95% confidence interval, 1.13 to 1.62). The FLJ10986 protein was found to be expressed in the spinal cord and cerebrospinal fluid of patients and of controls. Specific SNPs seem to be associated with sex, age at onset, and site of onset of sporadic ALS.Variants of FLJ10986 may confer susceptibility to sporadic ALS. FLJ10986 and 50 other candidate loci warrant further investigation for their potential role in conferring susceptibility to the disease.ViewShow abstractGenome-Wide Pharmacogenomic Analysis of the Response to Interferon Beta Therapy in Multiple SclerosisArticleFull-text availableApr 2008ARCH NEUROL-CHICAGOEsther H. Byun Stacy J Caillier Xavier MontalbanJorge R OksenbergTo identify promising candidate genes linked to interindividual differences in the efficacy of interferon beta therapy. Recombinant interferon beta therapy is widely used to reduce disease activity in multiple sclerosis (MS). However, up to 50% of patients continue to have relapses and worsening disability despite therapy.We used a genome-wide pharmacogenomic approach to identify single-nucleotide polymorphism (SNP) allelic differences associated with interferon beta therapy response.Four collaborating centers in the Mediterranean Basin. Data Coordination Center at the University of California, San Francisco.A cohort of 206 patients with relapsing-remitting MS followed up prospectively for 2 years after initiation of treatment.DNA was pooled and hybridized to Affymetrix 100K GeneChips. Pooling schemes were designed to minimize confounding batch effects and increase confidence by technical replication.Single-nucleotide polymorphism detection. Comparison of allelic frequencies between good responders and nonresponders to interferon beta therapy.A multianalytical approach detected significant associations between several SNPs and treatment response, which were validated by individual DNA genotyping on an independent platform. After the validation stage was complete, 81 additional individuals were added to the analysis to increase power. We found that responders and nonresponders had significantly different genotype frequencies for SNPs located in many genes, including glypican 5, collagen type XXV alpha1, hyaluronan proteoglycan link protein, calpastatin, and neuronal PAS domain protein 3.The reported results address the question of genetic heterogeneity in MS and the response to immunotherapy by analysis of the correlation between different genotypes and clinical response to interferon beta therapy. Many of the detected differences between responders and nonresponders were genes associated with ion channels and signal transduction pathways. The study also suggests that genetic variants in heparan sulfate proteoglycan genes may be of clinical interest in MS as predictors of the response to therapy. In addition to new insights into the mechanistic biology of interferon beta, these results help define the molecular basis of interferon beta therapy response heterogeneity.ViewShow abstractPublishing Genomewide Association StudiesArticleAug 2007NEW ENGL J MEDJeffrey M. DrazenElizabeth G. PhimisterOn July 18, 2007, two original research articles appeared on the Journal s Web site (and will be published in this and later print issues) conveying the results of \"genomewide association studies.” We anticipate that we will publish a number of such articles during the coming months and years. These articles are a major fruit of the human genome and HapMap projects, and they report variants of specific genes, or narrow genomic regions, that are associated with the presence or severity of specific clinical conditions. Because the publishing of the results of such studies is a new endeavor for the . . .ViewShow abstractGAB2 alleles modify Alzheimer s risk in APOE e4 carriersArticleJul 2007NEURONEric M. ReimanJennifer A Webster Amanda J MyersDietrich A StephanThe apolipoprotein E (APOE) epsilon4 allele is the best established genetic risk factor for late-onset Alzheimer s disease (LOAD). We conducted genome-wide surveys of 502,627 single-nucleotide polymorphisms (SNPs) to characterize and confirm other LOAD susceptibility genes. In epsilon4 carriers from neuropathologically verified discovery, neuropathologically verified replication, and clinically characterized replication cohorts of 1411 cases and controls, LOAD was associated with six SNPs from the GRB-associated binding protein 2 (GAB2) gene and a common haplotype encompassing the entire GAB2 gene. SNP rs2373115 (p = 9 x 10(-11)) was associated with an odds ratio of 4.06 (confidence interval 2.81-14.69), which interacts with APOE epsilon4 to further modify risk. GAB2 was overexpressed in pathologically vulnerable neurons; the Gab2 protein was detected in neurons, tangle-bearing neurons, and dystrophic neuritis; and interference with GAB2 gene expression increased tau phosphorylation. Our findings suggest that GAB2 modifies LOAD risk in APOE epsilon4 carriers and influences Alzheimer s neuropathology.ViewShow abstractA Genomewide Screen for Late-Onset Alzheimer Disease in a Genetically Isolated Dutch PopulationArticleAug 2007AM J HUM GENET Fan Liu Alejandro Arias-VásquezKristel SleegersCornelia M van DuijnAlzheimer disease (AD) is the most common cause of dementia. We conducted a genome screen of 103 patients with late-onset AD who were ascertained as part of the Genetic Research in Isolated Populations (GRIP) program that is conducted in a recently isolated population from the southwestern area of The Netherlands. All patients and their 170 closely related relatives were genotyped using 402 microsatellite markers. Extensive genealogy information was collected, which resulted in an extremely large and complex pedigree of 4,645 members. The pedigree was split into 35 subpedigrees, to reduce the computational burden of linkage analysis. Simulations aiming to evaluate the effect of pedigree splitting on false-positive probabilities showed that a LOD score of 3.64 corresponds to 5% genomewide type I error. Multipoint analysis revealed four significant and one suggestive linkage peaks. The strongest evidence of linkage was found for chromosome 1q21 (heterogeneity LOD [HLOD]=5.20 at marker D1S498). Approximately 30 cM upstream of this locus, we found another peak at 1q25 (HLOD=4.0 at marker D1S218). These two loci are in a previously established linkage region. We also confirmed the AD locus at 10q22-24 (HLOD=4.15 at marker D10S185). There was significant evidence of linkage of AD to chromosome 3q22-24 (HLOD=4.44 at marker D3S1569). For chromosome 11q24-25, there was suggestive evidence of linkage (HLOD=3.29 at marker D11S1320). We next tested for association between cognitive function and 4,173 single-nucleotide polymorphisms in the linked regions in an independent sample consisting of 197 individuals from the GRIP region. After adjusting for multiple testing, we were able to detect significant associations for cognitive function in four of five AD-linked regions, including the new region on chromosome 3q22-24 and regions 1q25, 10q22-24, and 11q25. With use of cognitive function as an endophenotype of AD, our study indicates the that the RGSL2, RALGPS2, and C1orf49 genes are the potential disease-causing genes at 1q25. Our analysis of chromosome 10q22-24 points to the HTR7, MPHOSPH1, and CYP2C cluster. This is the first genomewide screen that showed significant linkage to chromosome 3q23 markers. For this region, our analysis identified the NMNAT3 and CLSTN2 genes. Our findings confirm linkage to chromosome 11q25. We were unable to confirm SORL1; instead, our analysis points to the OPCML and HNT genes.ViewShow abstractGenome-wide association study of restless legs syndrome identifies common variants in three genomic regionsArticleSep 2007Nat. Genet.Juliane Winkelmann Barbara SchormairPeter Lichtner Thomas MeitingerRestless legs syndrome (RLS) is a frequent neurological disorder characterized by an imperative urge to move the legs during night, unpleasant sensation in the lower limbs, disturbed sleep and increased cardiovascular morbidity. In a genome-wide association study we found highly significant associations between RLS and intronic variants in the homeobox gene MEIS1, the BTBD9 gene encoding a BTB(POZ) domain as well as variants in a third locus containing the genes encoding mitogen-activated protein kinase MAP2K5 and the transcription factor LBXCOR1 on chromosomes 2p, 6p and 15q, respectively. Two independent replications confirmed these association signals. Each genetic variant was associated with a more than 50% increase in risk for RLS, with the combined allelic variants conferring more than half of the risk. MEIS1 has been implicated in limb development, raising the possibility that RLS has components of a developmental disorder.ViewShow abstractRisk Alleles for Multiple Sclerosis Identified by a Genomewide StudyArticleAug 2007New Engl J Med David A HaflerAlastair CompstonStephen SawcerStephen L HauserMultiple sclerosis has a clinically significant heritable component. We conducted a genomewide association study to identify alleles associated with the risk of multiple sclerosis.We used DNA microarray technology to identify common DNA sequence variants in 931 family trios (consisting of an affected child and both parents) and tested them for association. For replication, we genotyped another 609 family trios, 2322 case subjects, and 789 control subjects and used genotyping data from two external control data sets. A joint analysis of data from 12,360 subjects was performed to estimate the overall significance and effect size of associations between alleles and the risk of multiple sclerosis.A transmission disequilibrium test of 334,923 single-nucleotide polymorphisms (SNPs) in 931 family trios revealed 49 SNPs having an association with multiple sclerosis (P 1x10(-4)); of these SNPs, 38 were selected for the second-stage analysis. A comparison between the 931 case subjects from the family trios and 2431 control subjects identified an additional nonoverlapping 32 SNPs (P 0.001). An additional 40 SNPs with less stringent P values ( 0.01) were also selected, for a total of 110 SNPs for the second-stage analysis. Of these SNPs, two within the interleukin-2 receptor alpha gene (IL2RA) were strongly associated with multiple sclerosis (P=2.96x10(-8)), as were a nonsynonymous SNP in the interleukin-7 receptor alpha gene (IL7RA) (P=2.94x10(-7)) and multiple SNPs in the HLA-DRA locus (P=8.94x10(-81)).Alleles of IL2RA and IL7RA and those in the HLA locus are identified as heritable risk factors for multiple sclerosis.ViewShow abstractCandidate Single-Nucleotide Polymorphisms From a Genomewide Association Study of Alzheimer DiseaseArticleJan 2008ARCH NEUROL-CHICAGOHao LiSally Wetten Li Gao Allen RosesTo identify single-nucleotide polymorphisms (SNPs) associated with risk and age at onset of Alzheimer disease (AD) in a genomewide association study of 469 438 SNPs.Case-control study with replication.Memory referral clinics in Canada and the United Kingdom.The hypothesis-generating data set consisted of 753 individuals with AD by National Institute of Neurological and Communicative Diseases and Stroke/Alzheimer s Disease and Related Disorders Association criteria recruited from 9 memory referral clinics in Canada and 736 ethnically matched control subjects; control subjects were recruited from nonbiological relatives, friends, or spouses of the patients and did not exhibit cognitive impairment by history or cognitive testing. The follow-up data set consisted of 418 AD cases and 249 nondemented control cases from the United Kingdom Medical Research Council Genetic Resource for Late-Onset AD recruited from clinics at Cardiff University, Cardiff, Wales, and King s College London, London, England.Odds ratios and 95% confidence intervals for association of SNPs with AD by logistic regression adjusted for age, sex, education, study site, and French Canadian ancestry (for the Canadian data set). Hazard ratios and 95% confidence intervals from Cox proportional hazards regression for age at onset with similar covariate adjustments.Unadjusted, SNP RS4420638 within APOC1 was strongly associated with AD due entirely to linkage disequilibrium with APOE. In the multivariable adjusted analyses, 3 SNPs within the top 120 by P value in the logistic analysis and 1 in the Cox analysis of the Canadian data set provided additional evidence for association at P .05 within the United Kingdom Medical Research Council data set: RS7019241 (GOLPH2), RS10868366 (GOLPH2), RS9886784 (chromosome 9), and RS10519262 (intergenic between ATP8B4 and SLC27A2).Our genomewide association analysis again identified the APOE linkage disequilibrium region as the strongest genetic risk factor for AD. This could be a consequence of the coevolution of more than 1 susceptibility allele, such as APOC1, in this region. We also provide new evidence for additional candidate genetic risk factors for AD that can be tested in further studies.ViewShow abstractGenome-Wide Association Studies in Alzheimer DiseaseArticleApr 2008ARCH NEUROL-CHICAGO Steve WaringRoger N. RosenbergThe genetics of Alzheimer disease (AD) to date support an age-dependent dichotomous model whereby earlier age of disease onset ( 60 years) is explained by 3 fully penetrant genes (APP [NCBI Entrez gene 351], PSEN1 [NCBI Entrez gene 5663], and PSEN2 [NCBI Entrez gene 5664]), whereas later age of disease onset ( or = 65 years) representing most cases of AD has yet to be explained by a purely genetic model. The APOE gene (NCBI Entrez gene 348) is the strongest genetic risk factor for later onset, although it is neither sufficient nor necessary to explain all occurrences of disease. Numerous putative genetic risk alleles and genetic variants have been reported. Although all have relevance to biological mechanisms that may be associated with AD pathogenesis, they await replication in large representative populations. Genome-wide association studies have emerged as an increasingly effective tool for identifying genetic contributions to complex diseases and represent the next frontier for furthering our understanding of the underlying etiologic, biological, and pathologic mechanisms associated with chronic complex disorders. There have already been success stories for diseases such as macular degeneration and diabetes mellitus. Whether this will hold true for a genetically complex and heterogeneous disease such as AD is not known, although early reports are encouraging. This review considers recent publications from studies that have successfully applied genome-wide association methods to investigations of AD by taking advantage of the currently available high-throughput arrays, bioinformatics, and software advances. The inherent strengths, limitations, and challenges associated with study design issues in the context of AD are presented herein.ViewShow abstractRecommended publicationsDiscover moreArticleExcessive daytime sleepiness in Chinese patients with sporadic amyotrophic lateral sclerosis and its...July 2018 · Journal of Neurology Neurosurgery PsychiatryShuangwu LiuYan HuangHongfei Tai[...] Lili CuiObjectiveTo examine the frequency and clinical features of excessive daytime sleepiness (EDS) and its association with cognitive and behavioural impairments in patients with amyotrophic lateral sclerosis (ALS).MethodsWe conducted a cross-sectional investigation to explore the frequency and clinical features of EDS in a group of 121 Chinese patients with ALS compared with 121 age-matched and ... [Show full abstract] sex-matched healthy subjects. EDS was diagnosed using the Epworth Sleepiness Scale (ESS). Other characteristics of patients with ALS including sleep quality, REM sleep behaviour disorder (RBD), restless legs syndrome (RLS), cognition, behaviour, depression and anxiety were also evaluated.ResultsEDS was significantly more frequent in patients with ALS than in controls (26.4% vs 8.3%; p 0.05). Patients with ALS with EDS scored lower scores on the revised ALS Functional Rating Scale (ALSFRS-R), Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA) and MMSE and MoCA delayed memory subitems and higher on the Frontal Behavioural Inventory (FBI) than patients with ALS without EDS. ESS scores correlated with global ALSFRS-R, FBI, MMSE and MoCA scores and MMSE and MoCA delayed memory scores. RLS and global ALSFRS-R scores were independently associated with EDS in patients with ALS.ConclusionsWe identified a high frequency of EDS symptoms in Chinese patients with ALS, and these patients might have more serious physical, cognitive and frontal behaviour impairment. Patients with ALS might improve quality of life from the timely recognition and optimised management of EDS symptoms. Our results further suggest that ALS is a heterogeneous disease that might exhibit abnormal sleep-wake patterns.Read moreArticleGenetics in restless legs syndromeJune 2004 · Sleep Medicine Giorgio Casari Luigi Ferini-Strambi Maria Teresa Bonati[...]Alessandro OldaniSeveral studies on Restless legs syndrome (RLS) have suggested a substantial genetic contribution in the etiology of this sleep disorder. Clinical surveys of idiopathic RLS patients have shown that up to 60% report a positive family history. Investigations of single families with RLS have suggested an autosomal dominant mode of inheritance with variable expressivity, and some families show ... [Show full abstract] possible anticipation. At present, only one twin study is available, showing a high concordance rate (83.3%) between identical twins. Despite several reports suggesting a genetic contribution to the etiology of idiopathic RLS, few molecular genetic studies have been carried out attempting to identify genes that can predispose to this disorder. In particular, genes encoding for the GABA A receptor subunits, the gene for the alpha1 subunit of the glycine receptor, and genes involved in dopaminergic transmission and metabolism have been analyzed, but no significant findings have been reported. Genome-wide studies have been conducted to map genes that play a role in vulnerability to RLS. In a single French-Canadian family significant linkage was established on chromosome 12q. The susceptibility locus on chromosome 12q was not confirmed in two South Tyrolean families, or in our two Italian families. However, the efforts toward the identification of RLS genes must continue in order to obtain a better characterization of the syndrome and to identify new therapeutic strategies.Read moreArticleAssociation of restless legs syndrome, chronic motor tic disorder and migraine with aura: A case of...February 2010 · Journal of Neurology Sonja Tartarotti Ulf Kallweit Claudio BassettiRead moreArticleGenome-wide association studies in neurologyMarch 2013 · Annals of Translational Medicine Meng-Shan TanTeng JiangLan TanJin-Tai YuGenome-wide association studies (GWAS) are a powerful tool for understanding the genetic underpinnings of human disease. In this article, we briefly review the role and findings of GWAS in common neurological diseases, including Stroke, Alzheimer’s disease, Parkinson’s disease, epilepsy, multiple sclerosis, migraine, amyotrophic lateral sclerosis, frontotemporal lobar degeneration, restless legs ... [Show full abstract] syndrome, intracranial aneurysm, human prion diseases and moyamoya disease. We then discuss the present and future implications of these findings with regards to disease prediction, uncovering basic biology, and the development of potential therapeutic agents.Read moreArticlePrevalence of restless legs syndrome and REM sleep behavior disorder in multiple sclerosisAugust 2007 · Multiple Sclerosis Manuel Gomez-ChocoA. Iranzo Yolanda Blanco[...]A SaizA total of 135 consecutive, unrelated, multiple sclerosis (MS) patients were interviewed for symptoms suggestive of restless legs syndrome (RLS) and REM sleep behavior disorder (RBD), using semi-structured questionnaires. Some 118 unrelated healthy controls of similar sex and age distribution were included for comparison. Patients and controls with equivocal symptoms were re-evaluated by a sleep ... [Show full abstract] disorders specialist and video-polisomnography in those who fulfilled the criteria for RBD. We did not find significant differences in frequency (13.3 versus 9.3%), proportion of females (66.7 versus 58.5%), and mean age (42.1+/-12.6 versus 43+/-7.8 years) among MS patients and controls with RLS. RBD was found in three patients (1.4%), one associated with antidepressant intake, but in none of the controls. Our study shows that RLS in MS is not more frequent than in the general population, and that RBD, although uncommon, may occur in the setting of this neurological disease.Read moreArticleMode of Inheritance and Susceptibility Locus for Restless Legs Syndrome, on Chromosome 12qAugust 2002 · The American Journal of Human GeneticsNorman Kock Biljana CuljkovicSusanna Maniak[...]Patricia KramerRead moreArticleFull-text availableSleep disturbance and neurological diseaseJune 2011 · Clinical medicine (London, England) Kirstie N AndersonView full-textArticleFull-text availablePharmacotherapy of Restless Legs Syndrome with PramipexoleApril 2010 · Clinical Medicine Insights: Therapeutics Giovanni MerlinoSimone LorenzutMartina Sommaro[...] Mariarosaria ValenteRestless Legs Syndrome (RLS) is one of the most common neurological diseases characterized by an urge to move the legs, often associated with unpleasant sensations relieved by movement. It is engendered by rest, and is worse in the evening or at night. Patients affected by severe RLS should be treated pharmacologically. Dopamine-agonists represent the first-line treatment for RLS symptoms. ... [Show full abstract] Pramipexole is a non-ergot derived dopamine agonist with a high selectivity for D2 and D3 receptors. At doses comprised between 0.125 and 0.75 mg, pramipexole improves subjective symptoms and objective signs of primary RLS even after the first administration. In addition, pramipexole seems to be safe and well tolerated. However, physicians should be aware that augmentation and compulsive behaviours might occur in their RLS patients treated with pramipexole. Further studies are needed to confirm the efficacy of pramipexole in uremic RLS and in children affected by the sleep disorder. © the author(s), publisher and licensee Libertas Academica Ltd.View full-textArticleRestless Legs Syndrome, the Pitfall: Hardly Diagnosed and Rarely Treated Neurological DiseaseJuly 2017 Snehal PatelRead moreArticleGenomewide association studies in multiple sclerosis, amyotrophic lateral sclerosis and restless leg...August 2007 · Journal of Neurology Michael StruppRead moreArticleA TRAPPC6B splicing variant associates to restless legs syndromeAugust 2016 · Parkinsonism Related DisordersPaolo AridonMaurizio De FuscoJuliane W Winkelmann[...] Giorgio CasariIntroduction: RLS is a common movement disorders with a strong genetic component in its pathophysiology, but, up to now, no causative mutation has been reported.Methods: We re-evaluated the previously described RLS2 family by exome sequencing.Results: We identified fifteen variations in the 14q critical region. The c.485G A transition of the TRAPPC6B gene segregates with the RLS2 ... [Show full abstract] haplotype, is absent in 200 local controls and is extremely rare in 12988 exomes from the Exome Variant Server (EVS). This variant alters a splicing site and hampers the normal transcript processing by promoting exon 3-skipping as demonstrated by minigene transfection and by patient transcripts.Conclusions: We identified a TRAPPC6B gene mutation associated to the RLS locus on chromosome 14.Read moreArticleVariable Expressivity in Familial Restless Legs SyndromeDecember 1990 · JAMA NeurologyArthur S WaltersDaniel L PicchiettiWayne HeningA LazzariniA 62-year-old man with a 20-year history of excessive daytime somnolence and kicking during sleep was an obligate carrier of the restless legs syndrome gene because his paternal grandfather, father, and all three of his children had symptoms of restless legs syndrome. The patient himself, however, denied motor restlessness after a careful and exhaustive medical history and he was originally ... [Show full abstract] believed to have periodic movements in sleep without restless legs. Close clinical observation did reveal nighttime motor restlessness, although the patient continued to deny its importance. Polysomnography showed frequent periodic movements in sleep. We conclude that there can be variable expressivity of the clinical features in familial restless legs syndrome and that there are probably some relatively nonrestless patients with prominent periodic movements in sleep who are carriers of the restless legs syndrome gene. Some sleep-disordered patients who are believed to have only periodic movements in sleep may have a forme fruste of autosomal dominant restless legs syndrome. If one does not examine these patients carefully at night and take an adequate family history, one may miss the diagnosis of restless legs syndrome.Read moreDiscover the world s researchJoin ResearchGate to find the people and research you need to help your work.Join for free ResearchGate iOS AppGet it from the App Store now.InstallKeep up with your stats and moreAccess scientific knowledge from anywhere orDiscover by subject areaRecruit researchersJoin for freeLoginEmail Tip: Most researchers use their institutional email address as their ResearchGate loginPasswordForgot password? Keep me logged inLog inorContinue with GoogleWelcome back! Please log in.Email · HintTip: Most researchers use their institutional email address as their ResearchGate loginPasswordForgot password? Keep me logged inLog inorContinue with GoogleNo account? Sign upCompanyAbout usNewsCareersSupportHelp CenterBusiness solutionsAdvertisingRecruiting© 2008-2021 ResearchGate GmbH. 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