scholarly journals Rare genetic variants prioritize molecular pathways for semaphorin interactions in Alzheimer’s disease patients

2021 ◽  
pp. 1-7
Author(s):  
Lubomir Balabanski ◽  
Dimitar Serbezov ◽  
Maya Atanasoska ◽  
Sena Karachanak-Yankova ◽  
Savina Hadjidekova ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Genetic Variants ◽  
Molecular Pathways ◽  
Rare Genetic Variants

Rare Genetic Variants of the Transthyretin Gene Are Associated with Alzheimer’s Disease in Han Chinese

2016 ◽  
Vol 54 (7) ◽  
pp. 5192-5200 ◽  
Author(s):  
Qun Xiang ◽  
Rui Bi ◽  
Min Xu ◽  
Deng-Feng Zhang ◽  
Liwen Tan ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Genetic Variants ◽  
Han Chinese ◽  
Rare Genetic Variants

scholarly journals Probability of the Alzheimer’s disease based on common and rare genetic variants

2021 ◽  
Author(s):  
Valentina Escott-Price ◽  
Karl Michael Schmidt
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
High Risk ◽  
Genetic Variants ◽  
Rare Variants ◽  
Disease Risk ◽  
Age Groups ◽  
Disease Prevalence ◽  
Effect Sizes ◽  
Rare Genetic Variants

Abstract Background: Alzheimer’s disease, among other neurodegenerative disorders, spans decades in individuals’ life and exhibits complex progression, symptoms and pathophysiology. Early diagnosis is essential for disease prevention and therapeutic intervention. Genetics may help identify individuals at high risk. As thousands of genetic variants may contribute to the genetic risk of Alzheimer’s disease, the polygenic risk score (PRS) approach has been shown to be useful for disease risk prediction. The APOE- ε4 allele is a known common variant associated with high risk to AD, but also associated with earlier onset. Rare variants usually have higher effect sizes than common ones; their impact may not be well captured by the PRS. Instead of standardised PRS, we propose to calculate the disease probability as a measure of disease risk that allows comparison between individuals. Methods: We estimate AD risk as a probability based on PRS and separately accounting for APOE, AD rare variants and the disease prevalence in age groups. The mathematical framework makes use of genetic variants effect sizes from summary statistics and AD disease prevalence in age groups. Results: The AD probability varies with respect to age, APOE status and presence of rare variants. In age group 65+ the probability of AD grows from 0.03 to 0.18 (without APOE), and 0.07 to 0.7 (APOE e4e4 carriers) as PRS increases. In 85+, these values are 0.08-0.6 and 0.3-0.85. Presence of rare mutations, e.g. in TREM2, may increase the probability (in 65+) from 0.02 at the negative tail of the PRS to 0.3.Conclusions: Our approach accounts for the varying disease prevalence in different genotype and age groups when modelling the APOE and rare genetic variants risk in addition to PRS. This approach can be directly implemented in a clinical setting and easily updated for novel rare variants and for other populations when appropriate ethnic GWASes appear.

scholarly journals Probability of Alzheimer’s disease based on common and rare genetic variants

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Valentina Escott-Price ◽  
Karl Michael Schmidt
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
High Risk ◽  
Genetic Variants ◽  
Rare Variants ◽  
Disease Risk ◽  
Age Groups ◽  
Disease Prevalence ◽  
Effect Sizes ◽  
Rare Genetic Variants

Abstract Background Alzheimer’s disease, among other neurodegenerative disorders, spans decades in individuals’ life and exhibits complex progression, symptoms and pathophysiology. Early diagnosis is essential for disease prevention and therapeutic intervention. Genetics may help identify individuals at high risk. As thousands of genetic variants may contribute to the genetic risk of Alzheimer’s disease, the polygenic risk score (PRS) approach has been shown to be useful for disease risk prediction. The APOE-ε4 allele is a known common variant associated with high risk to AD, but also associated with earlier onset. Rare variants usually have higher effect sizes than common ones; their impact may not be well captured by the PRS. Instead of standardised PRS, we propose to calculate the disease probability as a measure of disease risk that allows comparison between individuals. Methods We estimate AD risk as a probability based on PRS and separately accounting for APOE, AD rare variants and the disease prevalence in age groups. The mathematical framework makes use of genetic variants effect sizes from summary statistics and AD disease prevalence in age groups. Results The AD probability varies with respect to age, APOE status and presence of rare variants. In age group 65+, the probability of AD grows from 0.03 to 0.18 (without APOE) and 0.07 to 0.7 (APOE e4e4 carriers) as PRS increases. In 85+, these values are 0.08–0.6 and 0.3–0.85. Presence of rare mutations, e.g. in TREM2, may increase the probability (in 65+) from 0.02 at the negative tail of the PRS to 0.3. Conclusions Our approach accounts for the varying disease prevalence in different genotype and age groups when modelling the APOE and rare genetic variants risk in addition to PRS. This approach has potential for use in a clinical setting and can easily be updated for novel rare variants and for other populations or confounding factors when appropriate genome-wide association data become available.

Common and Rare Genetic Variants Associated With Alzheimer's Disease

2015 ◽  
Vol 231 (7) ◽  
pp. 1432-1437 ◽  
Author(s):  
Hany E. Marei ◽  
Asmaa Althani ◽  
Jaana Suhonen ◽  
Mohamed E. El Zowalaty ◽  
Mohammad A. Albanna ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Genetic Variants ◽  
Rare Genetic Variants

Aromatase and interleukin-10 genetic variants interactively modulate Alzheimer’s disease risk

2008 ◽  
Vol 115 (6) ◽  
pp. 863-867 ◽  
Author(s):  
O. Combarros ◽  
P. Sánchez-Juan ◽  
J. A. Riancho ◽  
I. Mateo ◽  
E. Rodríguez-Rodríguez ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Genetic Variants ◽  
Disease Risk ◽  
Interleukin 10

scholarly journals Neurobiological substrates underlying the effect of genomic risk for depression on the conversion of amnestic mild cognitive impairment

Brain ◽  
2018 ◽  
Vol 141 (12) ◽  
pp. 3457-3471 ◽  
Author(s):  
Jiayuan Xu ◽  
Qiaojun Li ◽  
Wen Qin ◽  
Mulin Jun Li ◽  
Chuanjun Zhuo ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Major Depressive Disorder ◽  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Depressive Disorder ◽  
Genetic Variants ◽  
Amnestic Mild Cognitive Impairment ◽  
Risk Scores ◽  
Major Depressive

Abstract Depression increases the conversion risk from amnestic mild cognitive impairment to Alzheimer’s disease with unknown mechanisms. We hypothesize that the cumulative genomic risk for major depressive disorder may be a candidate cause for the increased conversion risk. Here, we aimed to investigate the predictive effect of the polygenic risk scores of major depressive disorder-specific genetic variants (PRSsMDD) on the conversion from non-depressed amnestic mild cognitive impairment to Alzheimer’s disease, and its underlying neurobiological mechanisms. The PRSsMDD could predict the conversion from amnestic mild cognitive impairment to Alzheimer’s disease, and amnestic mild cognitive impairment patients with high risk scores showed 16.25% higher conversion rate than those with low risk. The PRSsMDD was correlated with the left hippocampal volume, which was found to mediate the predictive effect of the PRSsMDD on the conversion of amnestic mild cognitive impairment. The major depressive disorder-specific genetic variants were mapped into genes using different strategies, and then enrichment analyses and protein–protein interaction network analysis revealed that these genes were involved in developmental process and amyloid-beta binding. They showed temporal-specific expression in the hippocampus in middle and late foetal developmental periods. Cell type-specific expression analysis of these genes demonstrated significant over-representation in the pyramidal neurons and interneurons in the hippocampus. These cross-scale neurobiological analyses and functional annotations indicate that major depressive disorder-specific genetic variants may increase the conversion from amnestic mild cognitive impairment to Alzheimer’s disease by modulating the early hippocampal development and amyloid-beta binding. The PRSsMDD could be used as a complementary measure to select patients with amnestic mild cognitive impairment with high conversion risk to Alzheimer’s disease.

scholarly journals Genetic Variability in Molecular Pathways Implicated in Alzheimer's Disease: A Comprehensive Review

2021 ◽  
Vol 13 ◽  
Author(s):  
David Vogrinc ◽  
Katja Goričar ◽  
Vita Dolžan
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Age Of Onset ◽  
Association Studies ◽  
The Elderly ◽  
Gene Clustering ◽  
Molecular Pathways ◽  
Genome Wide Association Studies ◽  
Cellular Processes ◽  
Increased Risk

Alzheimer's disease (AD) is a complex neurodegenerative disease, affecting a significant part of the population. The majority of AD cases occur in the elderly with a typical age of onset of the disease above 65 years. AD presents a major burden for the healthcare system and since population is rapidly aging, the burden of the disease will increase in the future. However, no effective drug treatment for a full-blown disease has been developed to date. The genetic background of AD is extensively studied; numerous genome-wide association studies (GWAS) identified significant genes associated with increased risk of AD development. This review summarizes more than 100 risk loci. Many of them may serve as biomarkers of AD progression, even in the preclinical stage of the disease. Furthermore, we used GWAS data to identify key pathways of AD pathogenesis: cellular processes, metabolic processes, biological regulation, localization, transport, regulation of cellular processes, and neurological system processes. Gene clustering into molecular pathways can provide background for identification of novel molecular targets and may support the development of tailored and personalized treatment of AD.

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