scholarly journals Towards genomic database of Alexander disease to identify variations modifying disease phenotype

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Rei Yasuda ◽  
Masakazu Nakano ◽  
Tomokatsu Yoshida ◽  
Ryuichi Sato ◽  
Hiroko Adachi ◽  
...  
Keyword(s):  
Neurodegenerative Disorder ◽  
Late Onset ◽  
Phenotypic Diversity ◽  
Association Studies ◽  
Age At Onset ◽  
The Elderly ◽  
Alexander Disease ◽  
Candidate Gene Approach ◽  
Intermediate Form ◽  
Independent Population

Abstract Alexander disease (AxD) is an extremely rare neurodegenerative disorder caused by glial fibrillary acidic protein (GFAP) gene mutations. Compared with the cerebral type, which is characterized by infantile onset, the bulbospinal type and intermediate form are associated with a late onset, spanning from juveniles to the elderly, and more diverse clinical spectrum, suggesting the existence of factors contributing to phenotypic diversity. To build a foundation for future genetic studies of this rare disease, we obtained genomic data by whole exome-sequencing (WES) and DNA microarray derived from thirty-one AxD patients with the bulbospinal type and intermediate form. Using this data, we aimed to identify genetic variations determining the age at onset (AAO) of AxD. As a result, WES- or microarray-based association studies between younger (<45 years; n = 13)- and older (≥45 years; n = 18)-onset patients considering the predicted GFAP-mutation pathogenicity identified no genome-wide significant variant. The candidate gene approach identified several variants likely correlated with AAO (p < 0.05): GAN, SLC1A2, CASP3, HDACs, and PI3K. Although we need to replicate the results using an independent population, this is the first step towards constructing a database, which may serve as an important tool to advance our understanding of AxD.

scholarly journals Gene4PD: A Comprehensive Genetic Database of Parkinson’s Disease

2021 ◽  
Vol 15 ◽  
Author(s):  
Bin Li ◽  
Guihu Zhao ◽  
Qiao Zhou ◽  
Yali Xie ◽  
Zheng Wang ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neurodegenerative Disorder ◽  
Late Onset ◽  
Association Studies ◽  
Age At Onset ◽  
Genetic Data ◽  
Genome Wide Association Studies ◽  
Onset Age ◽  
Loss Of Function

Parkinson’s disease (PD) is a complex neurodegenerative disorder with a strong genetic component. A growing number of variants and genes have been reported to be associated with PD; however, there is no database that integrate different type of genetic data, and support analyzing of PD-associated genes (PAGs). By systematic review and curation of multiple lines of public studies, we integrate multiple layers of genetic data (rare variants and copy-number variants identified from patients with PD, associated variants identified from genome-wide association studies, differentially expressed genes, and differential DNA methylation genes) and age at onset in PD. We integrated five layers of genetic data (8302 terms) with different levels of evidences from more than 3,000 studies and prioritized 124 PAGs with strong or suggestive evidences. These PAGs were identified to be significantly interacted with each other and formed an interconnected functional network enriched in several functional pathways involved in PD, suggesting these genes may contribute to the pathogenesis of PD. Furthermore, we identified 10 genes were associated with a juvenile-onset (age ≤ 30 years), 11 genes were associated with an early-onset (age of 30–50 years), whereas another 10 genes were associated with a late-onset (age &gt; 50 years). Notably, the AAOs of patients with loss of function variants in five genes were significantly lower than that of patients with deleterious missense variants, while patients with VPS13C (P = 0.01) was opposite. Finally, we developed an online database named Gene4PD (http://genemed.tech/gene4pd) which integrated published genetic data in PD, the PAGs, and 63 popular genomic data sources, as well as an online pipeline for prioritize risk variants in PD. In conclusion, Gene4PD provides researchers and clinicians comprehensive genetic knowledge and analytic platform for PD, and would also improve the understanding of pathogenesis in PD.

scholarly journals What do elderly problem drinkers aim for? Choice of goal for treatment among elderly treatment-seeking alcohol-dependent patients

2019 ◽  
Vol 36 (6) ◽  
pp. 511-521 ◽  
Author(s):  
Jakob Emiliussen ◽  
Kjeld Andersen ◽  
Anette Søgaard Nielsen ◽  
Barbara Braun ◽  
Randi Bilberg
Keyword(s):  
Alcohol Use ◽  
Alcohol Use Disorder ◽  
Late Onset ◽  
Age At Onset ◽  
The Elderly ◽  
Treatment Goal ◽  
Treatment Goals ◽  
Logistics Regression ◽  
Choice Of Treatment ◽  
General Individuals

Objective: The patient’s free choice of treatment goals for alcohol use disorder (AUD) is predictive for treatment outcome. Presently there is limited knowledge of whether the age at onset of AUD influences the choice of goal for treatment. The present study investigates whether there are differences in choice of treatment goal between patients with very late onset alcohol use disorder (VLO AUD ≥ 60 years) and those having early or mid-age onset of AUD (EMO AUD < 60 years). Method: Participants were 341 persons, voluntarily enrolled in the Elderly Study, who were seeking treatment for AUD in outpatient centres for alcohol treatment in Denmark. Data regarding thoughts about abstinence, alcohol use in the last 90 days, motivation for treatment and psychiatric diagnosis were collected via questionnaires. A logistics regression was used to analyse the data. Results: 32.1% of the participants with VLO AUD chose temporary abstinence goals, compared to 18.2% of the patients with earlier-onset AUD ( p = 0.024). Further, 10.7% of participants with VLO AUD chose total abstinence goals compared to 31.3% of participants with early or mid-age onset AUD ( p = 0.002). Conclusion: There are significant differences in choice of goal between participants with very late onset AUD and early or mid-age onset AUD. Individuals with very late onset alcohol use disorder tend to choose temporary abstinence over any other treatment goal whereas, in general, individuals with early onset alcohol use disorder choose permanent abstinence over other treatment goals.

scholarly journals Investigation of five polymorphic DNA markers associated with late onset Alzheimer disease

Genetika ◽  
2013 ◽  
Vol 45 (2) ◽  
pp. 503-514 ◽  
Author(s):  
Jalal Gharesouran ◽  
Maryam Rezazadeh ◽  
Mohaddes Mojtaba
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Dna Markers ◽  
Neurodegenerative Disorder ◽  
Late Onset ◽  
The Elderly ◽  
Healthy Controls ◽  
Genotype Frequencies ◽  
Significant Difference ◽  
And Control

Alzheimer's disease is a complex neurodegenerative disorder characterized by memory and cognitive impairment and is the leading cause of dementia in the elderly. The aim of our study was to examine the polymorphic DNA markers CCR2 (+190 G/A), CCR5?32, TNF-? (-308 G/A), TNF-? (-863 C/A) and CALHM1 (+394 C/T) to determine the relationship between these polymorphisms and the risk of late onset Alzheimer's disease in the population of Eastern Azerbaijan of Iran. A total of 160 patient samples and 163 healthy controls were genotyped by PCR-RFLP and the results confirmed using bidirectional sequencing. Statistical analysis of obtained data revealed non-significant difference between frequency of CCR5?32 in case and control groups. The same result was observed for TNF-? (-863 C/A) genotype and allele frequencies. Contrary to above results, significant differences were detected in frequency of TNF-? (-308 G/A) and CCR2-64I genotypes between the cases and healthy controls. A weak significant difference observed between allele and genotype frequencies of rs2986017 in CALHM1 (+394 C/T; P86L) in patient and control samples. It can be concluded that the T allele of P86L variant in CALHM1 & +190 G/A allele of CCR2 have a protective role against abnormal clinical features of Alzheimer's disease.

scholarly journals Meta-analysis of genetic association with diagnosed Alzheimer’s disease identifies novel risk loci and implicates Abeta, Tau, immunity and lipid processing

2018 ◽  
Author(s):  
BW Kunkle ◽  
B Grenier-Boley ◽  
R Sims ◽  
JC Bis ◽  
AC Naj ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Rare Variants ◽  
Late Onset ◽  
Association Studies ◽  
Meta Analysis ◽  
The Elderly ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Load Risk

IntroductionLate-onset Alzheimer’s disease (LOAD, onset age > 60 years) is the most prevalent dementia in the elderly1, and risk is partially driven by genetics2. Many of the loci responsible for this genetic risk were identified by genome-wide association studies (GWAS)3–8. To identify additional LOAD risk loci, the we performed the largest GWAS to date (89,769 individuals), analyzing both common and rare variants. We confirm 20 previous LOAD risk loci and identify four new genome-wide loci (IQCK, ACE, ADAM10, and ADAMTS1). Pathway analysis of these data implicates the immune system and lipid metabolism, and for the first time tau binding proteins and APP metabolism. These findings show that genetic variants affecting APP and Aβ processing are not only associated with early-onset autosomal dominant AD but also with LOAD. Analysis of AD risk genes and pathways show enrichment for rare variants (P = 1.32 × 10−7) indicating that additional rare variants remain to be identified.

scholarly journals NATURAL SELECTION AT THE MJD LOCUS: PHENOTYPIC DIVERSITY, SURVIVAL AND FERTILITY AMONG MACHADO-JOSEPH DISEASE PATIENTS FROM THE AZORES

2001 ◽  
Vol 33 (3) ◽  
pp. 361-373 ◽  
Author(s):  
M. LIMA ◽  
M. SMITH ◽  
C. SILVA ◽  
A. ABADE ◽  
F. MAYER ◽  
...  
Keyword(s):  
Neurodegenerative Disorder ◽  
Phenotypic Diversity ◽  
Age At Onset ◽  
Cag Repeats ◽  
Early Age ◽  
Coding Region ◽  
Differential Survival ◽  
Clinical Type ◽  
Machado Joseph Disease

Machado-Joseph Disease (MJD) is an autosomal dominant neurodegenerative disorder of adult onset, associated with the expansion of a (CAG)n tract in the coding region of the causative gene, localized on 14q32.1. Machado-Joseph Disease shows non-Mendelian features typical of other triplet repeat disorders, including clinical heterogeneity, variable age at onset and anticipation. Three phenotypes have been proposed (clinical types 1, 2 and 3). Type 1 is associated with early age at onset and a high repeat number of the CAG sequence, and Types 2 and 3 have later onset and lower numbers of CAG repeats. This paper investigates whether there is selection against the MJD gene, acting through differential survival, nuptiality and fertility associated with clinical type and age at onset. The study sample comprised 40 MJD patients from the Azores (Portugal) having fully documented reproductive histories and known dates of death. The proportion of married patients of each clinical type increased from 0·22 among Type 1 patients, to 0·40 in Type 2 and 0·95 in Type 3. Age at onset and length of survival were also associated with marital status, with the married cases having later mean age at onset and longer mean survival time. In the whole sample, clinical type was associated with fertility, with significantly fewer children born to Type 1 patients. Among married patients clinical type was not associated with age at marriage, reproductive span or number of children. No reduction of fertility was detected among married patients in whom the onset of MJD was below the age of 50. The authors’ interpretation of these results is that the high-repeat CAG haplotypes associated with early age at onset and clinical Type 1 are selected against through reduced survival and fertility. The fertility component of selection is mediated by nuptiality rather than marital fertility.

scholarly journals Genomics and Functional Genomics of Alzheimer’s Disease

2021 ◽  
Author(s):  
M. Ilyas Kamboh
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Functional Genomics ◽  
Early Onset ◽  
Late Onset ◽  
Association Studies ◽  
Age At Onset ◽  
Significant Risk ◽  
Major Public Health Problem ◽  
Genome Wide Association Studies

AbstractAlzheimer’s disease (AD) is a complex and multifactorial neurodegenerative disease. Due to its long clinical course and lack of an effective treatment, AD has become a major public health problem in the USA and worldwide. Due to variation in age-at-onset, AD is classified into early-onset (< 60 years) and late-onset (≥ 60 years) forms with early-onset accounting for only 5–10% of all cases. With the exception of a small number of early-onset cases that are afflicted because of high penetrant single gene mutations in APP, PSEN1, and PSEN2 genes, AD is genetically heterogeneous, especially the late-onset form having a polygenic or oligogenic risk inheritance. Since the identification of APOE as the most significant risk factor for late-onset AD in 1993, the path to the discovery of additional AD risk genes had been arduous until 2009 when the use of large genome-wide association studies opened up the discovery gateways that led the identification of ~ 95 additional risk loci from 2009 to early 2022. This article reviews the history of AD genetics followed by the potential molecular pathways and recent application of functional genomics methods to identify the causal AD gene(s) among the many genes that reside within a single locus. The ultimate goal of integrating genomics and functional genomics is to discover novel pathways underlying the AD pathobiology in order to identify drug targets for the therapeutic treatment of this heterogeneous disorder.

scholarly journals Late-onset Huntington’s disease with 40–42 CAG expansion

2019 ◽  
Vol 41 (4) ◽  
pp. 869-876 ◽  
Author(s):  
Elisa Capiluppi ◽  
Luca Romano ◽  
Paola Rebora ◽  
Lorenzo Nanetti ◽  
Anna Castaldo ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Rating Scale ◽  
Neurodegenerative Disorder ◽  
Age Of Onset ◽  
Late Onset ◽  
Age At Onset ◽  
Clinical Manifestations ◽  
Cag Repeats ◽  
Cag Expansion

Abstract Introduction Huntington’s disease (HD) is a rare autosomal dominant neurodegenerative disorder caused by a CAG expansion greater than 35 in the IT-15 gene. There is an inverse correlation between the number of pathological CAG and the age of onset. However, CAG repeats between 40 and 42 showed a wider onset variation. We aimed to investigate potential clinical differences between patients with age at onset ≥ 60 years (late onset-HD) and patients with age at onset between 30 and 59 years (common-onset HD) in a cohort of patients with the same CAG expansions (40–42). Methods A retrospective analysis of 66 HD patients with 40–41–42 CAG expansion was performed. Patients were investigated with the Unified Huntington’s Disease Rating Scale (subitems I–II–III and Total Functional Capacity, Functional Assessment and Stage of Disease). Data were analysed using χ2, Fisher’s test, t test and Pearson’s correlation coefficient. GENMOD analysis and Kaplan-Meier analysis were used to study the disease progression. Results The age of onset ranged from 39 to 59 years in the CO subgroup, whereas the LO subgroup showed an age of onset from 60 to 73 years. No family history was reported in 31% of the late-onset in comparison with 20% in common-onset HD (p = 0.04). No difference emerged in symptoms of onset, in clinical manifestations and in progression of disease between the two groups. Conclusion There were no clinical differences between CO and LO subgroups with 40–42 CAG expansion. There is a need of further studies on environmental as well genetic variables modifying the age at onset.

Hippocampal/amygdala volumes in geriatric depression

1999 ◽  
Vol 29 (3) ◽  
pp. 629-638 ◽  
Author(s):  
M. ASHTARI ◽  
B. S. GREENWALD ◽  
E. KRAMER-GINSBERG ◽  
J. HU ◽  
H. WU ◽  
...  
Keyword(s):  
Major Depression ◽  
Normal Control ◽  
Late Onset ◽  
Age At Onset ◽  
Imaging Study ◽  
The Elderly ◽  
Clinical Population ◽  
Control Subjects ◽  
Depressed Patients ◽  
Depressive Episodes

Background. The hippocampus, amygdala and related functional circuits have been implicated in the regulation of emotional expression and memory processes, which are affected in major depression. Several recent investigations have reported abnormalities in these structures in adult and elderly depressives.Methods. Elderly DSM-III-R unipolar depressives (N=40) and normal controls (N=46) participated in a magnetic resonance imaging study (1.0T). Brain images were obtained in the coronal plane. Using established anatomical guidelines for structure delineation, volumetric measurements of left and right hippocampus and anterior hippocampus/amygdala complex were completed under blinded conditions using a semi-automated computer mensuration system, with patients and controls in random order.Results. Medial temporal volumes did not significantly distinguish either elderly depressed and age-similar normal control subjects, or late onset and early onset depressed patients (ANCOVA). Major overlap of measured volumes existed between patient and control groups. In depressives, hippocampal volumes significantly correlated with age, and cognitive and depression ratings, but not with number of prior depressive episodes or age-at-onset of first depression.Conclusions. Hippocampal volumes do not discriminate a typical clinical population of elderly depressed patients from age-similar normal control subjects. If hippocampal dysfunction contributes to a diagnosis of syndromal depression in the elderly, such dysfunction does not appear to be regularly reflected in structural abnormalities captured by volumetric measurement as conducted. On the other hand, relationships between hippocampal volumes and clinical phenomena in depressives, but not controls, suggest potentially meaningful interactions between hippocampal structure and the expression of major depression in the elderly.

Late onset alcoholism

2003 ◽  
Vol 18 (3) ◽  
pp. 112-118 ◽  
Author(s):  
Tilman Wetterling ◽  
Clemens Veltrup ◽  
Ulrich John ◽  
Martin Driessen
Keyword(s):  
Alcohol Consumption ◽  
Alcohol Dependence ◽  
Early Onset ◽  
Late Onset ◽  
Age At Onset ◽  
The Elderly ◽  
Alcohol Problems ◽  
Elderly Persons ◽  
Harmful Alcohol ◽  
Icd 10

AbstractRather high prevalence rates of alcohol abuse in the elderly have been reported in the literature. However, there is some evidence that many elderly persons with alcohol problems are not identified, probably due to the nonspecificity of alcohol-related presentations in old individuals. Thus, there is an ongoing discussion on appropriate diagnostic criteria for alcohol dependence in elder people who frequently begin to abuse alcohol in late life. This study was aimed to explore whether alcoholics with late onset (beginning after the age of 45) differ from those with an early onset (prior the age of 25). Two hundred and sixty eight subjects consecutively referred to a ward of a general hospital specialized for alcohol detoxification were divided into three groups by the age at onset of harmful alcohol consumption. The duration of harmful drinking was rather similar in all groups. However, alcohol dependence according to the ICD-10 criteria (three or more have to be fulfilled) was diagnosed in 94.1% of the alcoholics with an early onset (≤ 25 years), but only in 62.2% of those with late onset (P < 0.0001). Significant differences between these groups were found for the following criteria: preoccupation with drinking (P < 0.0001), impaired capacity to control drinking (P < 0.01), strong desire to drink alcohol (P < 0.01), and a trend towards a lower rate of lifetime psychiatric comorbidity. The alcoholics with late onset reported fewer previous detoxifications and a lower actual alcohol consumption. Moreover, they showed a higher rate of abstinence in the 12 month follow-up. Regarding the difficulties in comparing groups of different ages at onset of harmful alcohol use our results suggest that the alcoholics with late onset differ in many ways from those with early onset.

scholarly journals Pathway-based integration of multi-omics data reveals lipidomics alterations validated in an Alzheimers Disease mouse model and risk loci carriers

2021 ◽  
Author(s):  
Monica Emili Garcia-Segura ◽  
Brenan R. Durainayagam ◽  
Sonia Liggi ◽  
Goncalo Graca ◽  
Beatriz Jimenez ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Mouse Model ◽  
Neurodegenerative Disorder ◽  
Late Onset ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Omics Data ◽  
Alzheimers Disease ◽  
Data Repositories ◽  
Lipid Species

Alzheimers Disease (AD) is a highly prevalent neurodegenerative disorder. Despite increasing evidence of important metabolic dysregulation in AD, the underlying metabolic changes that may impact amyloid plaque formation are not understood, particularly for late onset AD. This study analyzed genome-wide association studies (GWAS), transcriptomics and proteomics data obtained from several data repositories to obtain differentially expressed (DE) multi-omics elements in mouse models of AD. We characterized the metabolic modulation in these datasets using gene ontology, and transcription factor, pathway and cell-type enrichment analysis. A predicted lipid signature was extracted from genome-scale metabolic networks (GSMN) and subsequently validated in a lipidomic dataset derived from cortical tissue of ABCA7-null mice, a mouse model of one of the genes associated with late onset AD. Moreover, a metabolome-wide association study (MWAS) was performed to further characterize the association between dysregulated lipid metabolism in human blood serum and AD. We found 203 DE transcripts, 164 DE proteins and 58 DE GWAS-derived mouse orthologs associated with significantly enriched metabolic biological processes. Lipid and bioenergetics metabolic pathways were significantly over-represented across the AD multi-omics datasets. Microglia and astrocytes were significantly enriched in the lipid-predominant AD-metabolic transcriptome. We also extracted a predicted lipid signature that was validated and robustly modelled class separation in the ABCA7 mice cortical lipidome, with 11 of these lipid species exhibiting statistically significant modulations. MWAS revealed 298 AD single nucleotide polymorphisms (SNP)-metabolite associations, of which 70% corresponded to lipid classes. These results support the importance of lipid metabolism dysregulation in AD and highlight the suitability of mapping AD multi-omics data into GSMNs to identify metabolic alterations.

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