Amyotrophic lateral sclerosis (ALS) is a paralytic and usually fatal disorder caused by motor-neuron degeneration in the brain and spinal cord. Most cases of ALS are sporadic but about 5-10% are ...familial. Mutations in superoxide dismutase 1 (SOD1), TAR DNA-binding protein (TARDBP, also known as TDP43) and fused in sarcoma (FUS, also known as translocated in liposarcoma (TLS)) account for approximately 30% of classic familial ALS. Mutations in several other genes have also been reported as rare causes of ALS or ALS-like syndromes. The causes of the remaining cases of familial ALS and of the vast majority of sporadic ALS are unknown. Despite extensive studies of previously identified ALS-causing genes, the pathogenic mechanism underlying motor-neuron degeneration in ALS remains largely obscure. Dementia, usually of the frontotemporal lobar type, may occur in some ALS cases. It is unclear whether ALS and dementia share common aetiology and pathogenesis in ALS/dementia. Here we show that mutations in UBQLN2, which encodes the ubiquitin-like protein ubiquilin 2, cause dominantly inherited, chromosome-X-linked ALS and ALS/dementia. We describe novel ubiquilin 2 pathology in the spinal cords of ALS cases and in the brains of ALS/dementia cases with or without UBQLN2 mutations. Ubiquilin 2 is a member of the ubiquilin family, which regulates the degradation of ubiquitinated proteins. Functional analysis showed that mutations in UBQLN2 lead to an impairment of protein degradation. Therefore, our findings link abnormalities in ubiquilin 2 to defects in the protein degradation pathway, abnormal protein aggregation and neurodegeneration, indicating a common pathogenic mechanism that can be exploited for therapeutic intervention.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The risk of Alzheimer disease (AD) increases with age, family history and informative genetic variants. Sadly, there is still no cure or means of prevention. As in other complex diseases, uncovering ...genetic causes of AD could identify underlying pathological mechanisms and lead to potential treatments. Rare, autosomal dominant forms of AD occur in middle age as a result of highly penetrant genetic mutations, but the most common form of AD occurs later in life. Large-scale, genome-wide analyses indicate that 70 or more genes or loci contribute to AD. One of the major factors limiting progress is that most genetic data have been obtained from non-Hispanic white individuals in Europe and North America, preventing the development of personalized approaches to AD in individuals of other ethnicities. Fortunately, emerging genetic data from other regions - including Africa, Asia, India and South America - are now providing information on the disease from a broader range of ethnicities. Here, we summarize the current knowledge on AD genetics in populations across the world. We predominantly focus on replicated genetic discoveries but also include studies in ethnic groups where replication might not be feasible. We attempt to identify gaps that need to be addressed to achieve a complete picture of the genetic and molecular factors that drive AD in individuals across the globe.
Alzheimer's disease (AD) is the most common neurodegenerative disorder and one of the leading causes of disability worldwide. The apolipoprotein E4 gene (APOE4) is the strongest genetic risk factor ...for AD. In 2023, the APOE4 National Institute on Aging/Alzheimer's Disease Sequencing Project working group came together to gather data and discuss the question of whether to reduce or increase APOE4 as a therapeutic intervention for AD. It was the unanimous consensus that cumulative data from multiple studies in humans and animal models support that lowering APOE4 should be a target for therapeutic approaches for APOE4 carriers. ANN NEUROL 2024;95:625-634.
Objective
Polygenic risk scores (PRSs) assess the individual genetic propensity to a condition by combining sparse information scattered across genetic loci, often displaying small effect sizes. Most ...PRSs are constructed in European‐ancestry populations, limiting their use in other ethnicities. Here we constructed and validated a PRS for late‐onset Alzheimer's Disease (LOAD) in Caribbean Hispanics (CH).
Methods
We used a CH discovery (n = 4,312) and independent validation sample (n = 1,850) to construct an ancestry‐specific PRS (“CH‐PRS”) and evaluated its performance alone and with other predictors using the area under curve (AUC) and logistic regression (strength of association with LOAD and statistical significance). We tested if CH‐PRS predicted conversion to LOAD in a subsample with longitudinal data (n = 1,239). We also tested the CH‐PRS in an independent replication CH cohort (n = 200) and brain autopsy cohort (n = 33). Finally, we tested the effect of ancestry on PRS by using European and African American discovery cohorts to construct alternative PRSs (“EUR‐PRS”, “AA‐PRS”).
Results
The full model (LOAD ~ CH‐PRS + sex + age + APOE‐ɛ4), achieved an AUC = 74% (ORCH‐PRS = 1.51 95%CI = 1.36–1.68), raising to >75% in APOE‐ɛ4 non‐carriers. CH‐PRS alone achieved an AUC = 72% in the autopsy cohort, raising to AUC = 83% in full model. Higher CH‐PRS was significantly associated with clinical LOAD in the replication CH cohort (OR = 1.61, 95%CI = 1.19–2.17) and significantly predicted conversion to LOAD (HR = 1.93, CI = 1.70–2.20) in the longitudinal subsample. EUR‐PRS and AA‐PRS reached lower prediction accuracy (AUC = 58% and 53%, respectively).
Interpretation
Enriching diversity in genetic studies is critical to provide an effective PRS in profiling LOAD risk across populations. ANN NEUROL 2021;90:366–376
Objective
Memory and cognitive problems are central to the diagnosis of Alzheimer's disease (AD). Psychometric approaches to defining phenotypes can aid in identify genetic variants associated with ...AD. However, these approaches have mostly been limited to affected individuals. Defining phenotypes of both affected and unaffected individuals may help identify genetic variants associated with both AD and healthy aging. This study compares psychometric methods for developing cognitive phenotypes that are more granular than clinical classifications.
Methods
682 older Old Order Amish individuals were included in the analysis. Adjusted Z‐scores of cognitive tests were used to create four models including (1) global threshold scores or (2) memory threshold scores, and (3) global clusters and (4) memory clusters. An ordinal regression examined the coherence of the models with clinical classifications (cognitively impaired CI, mildly impaired MI, cognitively unimpaired), APOE‐e4, sex, and age. An ANOVA examined the best model phenotypes for differences in clinical classification, APOE‐e4, domain Z‐scores (memory, language, executive function, and processing speed), sex, and age.
Results
The memory cluster identified four phenotypes and had the best fit (χ2 = 491.66). Individuals in the worse performing phenotypes were more likely to be classified as CI or MI and to have APOE‐e4. Additionally, all four phenotypes performed significantly differently from one another on the domains of memory, language, and executive functioning.
Conclusions
Memory cluster stratification identified the cognitive phenotypes that best aligned with clinical classifications, APOE‐e4, and cognitive performance We predict these phenotypes will prove useful in searching for protective genetic variants.
Key points
This study compares psychometric methods for developing cognitive phenotypes that are more granular than clinical classifications in individuals from the Old Order Amish.
We found that the memory cluster model produced four distinct cognitive phenotypes had the best fit with clinical classification, presence of APOE‐e4, age, and sex in the Old Order Amish.
This suggests that stratification of Old Order Amish individuals using cluster analysis based on memory performance performs better than memory threshold stratification, and stratification based on global cognition.
Importantly, our memory cluster model stratified individuals into four distinct cognitive phenotypes with significant differences in cognitive performance across memory, executive functioning, and language, but similar prevalence rates of APOE‐e4 in top three performing phenotypes
Coronary collateral circulation protects cardiac tissues from myocardial infarction damage and decreases sudden cardiac death. So far, it is unclear how coronary collateralization varies by ...race-ethnicity groups and by sex.
We assessed 868 patients with obstructive CAD. Patients were assessed for collateral grades based on Rentrop grading system, as well as other covariates. DNA samples were genotyped using the Affymetrix 6.0 genotyping array. To evaluate genetic contributions to collaterals, we performed admixture mapping using logistic regression with estimated local and global ancestry.
Overall, 53% of participants had collaterals. We found difference between sex and racial-ethnic groups. Men had higher rates of collaterals than women (P-value = 0.000175). White Hispanics/Latinos showed overall higher rates of collaterals than African Americans and non-Hispanic Whites (59%, 50% and 48%, respectively, P-value = 0.017), and especially higher rates in grade 1 and grade 3 collateralization than the other two populations (P-value = 0.0257). Admixture mapping showed Native American ancestry was associated with the presence of collaterals at a region on chromosome 17 (chr17:35,243,142-41,251,931, β = 0.55, P-value = 0.000127). African ancestry also showed association with collaterals at a different region on chromosome 17 (chr17: 32,266,966-34,463,323, β = 0.38, P-value = 0.00072).
In our study, collateralization showed sex and racial-ethnic differences in obstructive CAD patients. We identified two regions on chromosome 17 that were likely to harbor genetic variations that influenced collateralization.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Parkinson's disease is the second most common neurodegenerative disorder without effective treatment. It is generally sporadic with unknown etiology. However, genetic studies of rare familial forms ...have led to the identification of mutations in several genes, which are linked to typical Parkinson's disease or parkinsonian disorders. The pathogenesis of Parkinson's disease remains largely elusive. Here we report a locus for autosomal dominant, clinically typical and Lewy body-confirmed Parkinson's disease on the short arm of chromosome 20 (20pter-p12) and identify TMEM230 as the disease-causing gene. We show that TMEM230 encodes a transmembrane protein of secretory/recycling vesicles, including synaptic vesicles in neurons. Disease-linked TMEM230 mutants impair synaptic vesicle trafficking. Our data provide genetic evidence that a mutant transmembrane protein of synaptic vesicles in neurons is etiologically linked to Parkinson's disease, with implications for understanding the pathogenic mechanism of Parkinson's disease and for developing rational therapies.
Background
Alzheimer disease (AD) is more prevalent in African American (AA) and Hispanic White (HIW) compared to Non‐Hispanic White (NHW) individuals. Similarly, neuropsychiatric symptoms (NPS) vary ...by population in AD. This is likely the result of both sociocultural and genetic ancestral differences. However, the impact of these NPS on AD in different groups is not well understood.
Methods
Self‐declared AA, HIW, and NHW individuals were ascertained as part of ongoing AD genetics studies. Participants who scored higher than 0.5 on the Clinical Dementia Rating (CDR) Scale (CDR) were included. Group similarities and differences on Neuropsychiatric Inventory Questionnaire (NPI‐Q) outcomes (NPI‐Q total score, NPI‐Q items) were evaluated using univariate ANOVAs and post hoc comparisons after controlling for sex and CDR stage.
Results
Our sample consisted of 498 participants (26% AA; 30% HIW; 44% NHW). Overall, NPI‐Q total scores differed significantly between our groups, with HIW having the highest NPI‐Q total scores, and by AD stage as measured by CDR. We found no significant difference in NPI‐Q total score by sex. There were six NPI‐Q items with comparable prevalence in all groups and six items that significantly differed between the groups (Anxiety, Apathy, Depression, Disinhibition, Elation, and Irritability). Further, within the HIW group, differences were found between Puerto Rican and Cuban American Hispanics across several NPI‐Q items. Finally, Six NPI‐Q items were more prevalent in the later stages of AD including Agitation, Appetite, Hallucinations, Irritability, Motor Disturbance, and Nighttime Behavior.
Conclusions
We identified differences in NPS among HIW, AA, and NHW individuals. Most striking was the high burden of NPS in HIW, particularly for mood and anxiety symptoms. We suggest that NPS differences may represent the impact of sociocultural influences on symptom presentation as well as potential genetic factors rooted in ancestral background. Given the complex relationship between AD and NPS it is crucial to discern the presence of NPS to ensure appropriate interventions.
Key points
Our study sought to determine if there are differences in neuropsychiatric symptom prevalence, as measured by the Neuropsychiatric Inventory Questionnaire (NPI‐Q), among self‐declared African American (AA), Hispanic, and Non‐Hispanic White (NHW) individuals with Alzheimer's disease (AD) and Mild Cognitive Impairment (MCI).
While the prevalence of several NPI‐Q symptoms was consistent across the three groups our Hispanic participants showed a greater overall burden of neuropsychiatric symptoms—especially anxiety and mood symptoms (i.e., Anxiety, Depression, Apathy, and Irritability items). By contrast, African Americans reported significantly more behavioral problems as reflected on the Disinhibition and Elation items.
The variability in the prevalence of neuropsychiatric symptoms among different populations (e.g., mood and anxiety symptoms in HIW) represents both underlying genetic factors rooted in ancestral background as well as sociocultural influences on the measurement and reporting of NPS.
Purpose
This study aimed to investigate the correspondence between intraretinal hyperreflective foci (IHRF) identified on optical coherence tomography (OCT) B‐scans with hyperpigmentation on colour ...fundus photography (CFP) or hyperreflectivity on infrared reflectance (IR) images in eyes with age‐related macular degeneration (AMD).
Methods
Flash CFP, IR images and OCT B‐scans obtained at the same visit were evaluated. Individual IHRF identified on OCT B‐scans were assessed for the qualitative presence or absence of a hypotransmission tail into the choroid. The corresponding IR image obtained at the time of OCT acquisition was analysed for the presence or absence of hyperreflectivity in this region. The IR images were manually registered to the CFP image, and CFP images were inspected for the presence or absence of hyperpigmentation at the location of IHRF.
Results
From 122 eyes, a total of 494 IHRF were evaluated. For the primary analysis of qualitative presence or absence of hyperpigmentation on CFP and hyperreflectivity on IR at the locations corresponding to IHRF on OCT, 301 (61.0%) of the IHRFs demonstrated evidence of hyperpigmentation on CFP, while only 115 (23.3%) showed evidence of hyperreflectivity on IR. The qualitative determination of the presence or absence of an abnormality on CFP or IR were significantly different (p < 0.0001). 327 (66.2%) of the IHRF showed hypotransmission, and 80.4% of these IHRF showed hyperpigmentation on CFP, though only 23.9% (p < 0.0001) demonstrated hyperreflectivity on IR.
Conclusions
Less than two‐thirds of IHRF evident on OCT manifest as hyperpigmentation on colour photos, though IHRF with posterior shadowing are more likely to be evident as pigment. IR imaging appears to be even more poorly sensitive for visualizing IHRF.
Improving accuracy in genetic studies would greatly accelerate understanding the genetic basis of complex diseases. One approach to achieve such an improvement for risk variants identified by the ...genome wide association study (GWAS) approach is to incorporate previously known biology when screening variants across the genome. We developed a simple approach for improving the prioritization of candidate disease genes that incorporates a network diffusion of scores from known disease genes using a protein network and a novel integration with GWAS risk scores, and tested this approach on a large Alzheimer disease (AD) GWAS dataset. Using a statistical bootstrap approach, we cross-validated the method and for the first time showed that a network approach improves the expected replication rates in GWAS studies. Several novel AD genes were predicted including CR2, SHARPIN, and PTPN2. Our re-prioritized results are enriched for established known AD-associated biological pathways including inflammation, immune response, and metabolism, whereas standard non-prioritized results were not. Our findings support a strategy of considering network information when investigating genetic risk factors.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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