TY - JOUR T1 - Interplay between stress-related genes may influence Alzheimer's disease development: The results of genetic interaction analyses of human data. JF - Mechanisms of Ageing and Development Y1 - 2021 A1 - Anatoliy Yashin A1 - Wu, Deqing A1 - Konstantin G Arbeev A1 - Bagley, Olivia A1 - Akushevich, Igor A1 - Duan, Matt A1 - Arseniy P Yashkin A1 - Svetlana Ukraintseva KW - Alzheimer’s disease KW - Genetic interactions KW - Integrated stress response KW - Polygenic risk score AB -

Emerging evidence from experimental and clinical research suggests that stress-related genes may play key roles in AD development. The fact that genome-wide association studies were not able to detect a contribution of such genes to AD indicates the possibility that these genes may influence AD non-linearly, through interactions of their products. In this paper, we selected two stress-related genes (GCN2/EIF2AK4 and APP) based on recent findings from experimental studies which suggest that the interplay between these genes might influence AD in humans. To test this hypothesis, we evaluated the effects of interactions between SNPs in these two genes on AD occurrence, using the Health and Retirement Study data on white indidividuals. We found several interacting SNP-pairs whose associations with AD remained statistically significant after correction for multiple testing. These findings emphasize the importance of nonlinear mechanisms of polygenic AD regulation that cannot be detected in traditional association studies. To estimate collective effects of multiple interacting SNP-pairs on AD, we constructed a new composite index, called Interaction Polygenic Risk Score, and showed that its association with AD is highly statistically significant. These results open a new avenue in the analyses of mechanisms of complex multigenic AD regulation.

VL - 196 ER - TY - JOUR T1 - Roles of interacting stress-related genes in lifespan regulation: Insights for translating experimental findings to humans Y1 - 2021 A1 - Anatoliy Yashin A1 - Wu, Deqing A1 - Konstantin G Arbeev A1 - Arseniy P Yashkin A1 - Akushevich, Igor A1 - Bagley, Olivia A1 - Duan, Matt A1 - Svetlana Ukraintseva KW - amino acids starvation KW - GCN2/EIF2AK4 and CHOP/DDI3T genes KW - GxG interactions KW - Integrated stress response KW - Lifespan AB - Aim: Experimental studies provided numerous evidence that caloric/dietary restriction may improve health and increase the lifespan of laboratory animals, and that the interplay among molecules that sense cellular stress signals and those regulating cell survival can play a crucial role in cell response to nutritional stressors. However, it is unclear whether the interplay among corresponding genes also plays a role in human health and lifespan. Methods: Literature about roles of cellular stressors have been reviewed, such as amino acid deprivation, and the integrated stress response (ISR) pathway in health and aging. Single nucleotide polymorphisms (SNPs) in two candidate genes (GCN2/EIF2AK4 and CHOP/DDI3T) that are closely involved in the cellular stress response to amino acid starvation, have been selected using information from experimental studies. Associations of these SNPs and their interactions with human survival in the Health and Retirement Study data have been estimated. The impact of collective associations of multiple interacting SNP pairs on survival has been evaluated, using a recently developed composite index: the SNP-specific Interaction Polygenic Risk Score (SIPRS). Results: Significant interactions have been found between SNPs from GCN2/EIF2AK4 and CHOP/DDI3T genes that were associated with survival 85+ compared to survival between ages 75 and 85 in the total sample (males and females combined) and in females only. This may reflect sex differences in genetic regulation of the human lifespan. Highly statistically significant associations of SIPRS [constructed for the rs16970024 (GCN2/EIF2AK4) and rs697221 (CHOP/DDIT3)] with survival in both sexes also been found in this study. Conclusion: Identifying associations of the genetic interactions with human survival is an important step in translating the knowledge from experimental to human aging research. Significant associations of multiple SNPxSNP interactions in ISR genes with survival to the oldest old age that have been found in this study, can help uncover mechanisms of multifactorial regulation of human lifespan and its heterogeneity. VL - 5 ER - TY - JOUR T1 - APOE region molecular signatures of Alzheimer's disease across races/ethnicities. JF - Neurobiol Aging Y1 - 2020 A1 - Alexander M Kulminski A1 - Shu, Leonardo A1 - Loika, Yury A1 - Nazarian, Alireza A1 - Konstantin G Arbeev A1 - Svetlana Ukraintseva A1 - Anatoliy Yashin A1 - Culminskaya, Irina KW - Alleles KW - Alzheimer disease KW - Apolipoproteins E KW - Continental Population Groups KW - Haplotypes KW - Heterozygote KW - Homozygote KW - Humans KW - Linkage Disequilibrium KW - Polymorphism, Single Nucleotide KW - Risk Factors AB -

The role of even the strongest genetic risk factor for Alzheimer's disease (AD), the apolipoprotein E (APOE) ε4 allele, in its etiology remains poorly understood. We examined molecular signatures of AD defined as differences in linkage disequilibrium patterns between AD-affected and -unaffected whites (2673/16,246), Hispanics (392/867), and African Americans (285/1789), separately. We focused on 29 polymorphisms from 5 genes in the APOE region emphasizing beneficial and adverse effects of the APOE ε2- and ε4-coding single-nucleotide polymorphisms, respectively, and the differences in the linkage disequilibrium structures involving these alleles between AD-affected and -unaffected subjects. Susceptibility to AD is likely the result of complex interactions of the ε2 and ε4 alleles with other polymorphisms in the APOE region, and these interactions differ across races/ethnicities corroborating differences in the adverse and beneficial effects of the ε4 and ε2 alleles. Our findings support complex race/ethnicity-specific haplotypes promoting and protecting against AD in this region. They contribute to better understanding of polygenic and resilient mechanisms, which can explain why even homozygous ε4 carriers may not develop AD.

VL - 87 U1 - http://www.ncbi.nlm.nih.gov/pubmed/31813627?dopt=Abstract ER - TY - JOUR T1 - Genetic and regulatory architecture of Alzheimer's disease in the APOE region JF - Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring Y1 - 2020 A1 - Alexander M Kulminski A1 - Shu, Leonardo A1 - Loika, Yury A1 - He, Liang A1 - Nazarian, Alireza A1 - Konstantin G Arbeev A1 - Svetlana Ukraintseva A1 - Anatoliy Yashin A1 - Culminskaya, Irina KW - Alzheimer's disease KW - Apolipoprotein E KW - Linkage Disequilibrium AB - Abstract Introduction Apolipoprotein E (APOE) ε2 and ε4 alleles encoded by rs7412 and rs429358 polymorphisms, respectively, are landmark contra and pro “risk” factors for Alzheimer's disease (AD). Methods We examined differences in linkage disequilibrium (LD) structures between (1) AD-affected and unaffected subjects and (2) older AD-unaffected and younger subjects in the 19q13.3 region harboring rs7412 and rs429358. Results AD is associated with sex-nonspecific heterogeneous patterns of decreased and increased LD of rs7412 and rs429358, respectively, with other polymorphisms from five genes in this region in AD-affected subjects. The LD patterns in older AD-unaffected subjects resembled those in younger individuals. Polarization of the ε4- and ε2 allele–related heterogeneous LD clusters differentiated cell types and implicated specific tissues in AD pathogenesis. Discussion Protection and predisposition to AD is characterized by an interplay of rs7412 and rs429358, with multiple polymorphisms in the 19q13.3 region in a tissue-specific manner, which is not driven by common evolutionary forces. VL - 12 UR - https://alz-journals.onlinelibrary.wiley.com/doi/abs/10.1002/dad2.12008 ER - TY - JOUR T1 - Polygenic risk score for disability and insights into disability-related molecular mechanisms JF - GeroScience Y1 - 2019 A1 - Alexander M Kulminski A1 - Kang, Chansuk A1 - Kolpakov, Stanislav A. A1 - Loika, Yury A1 - Nazarian, Alireza A1 - Anatoliy Yashin A1 - Stallard, Eric A1 - Culminskaya, Irina KW - Disabilities KW - Disability KW - Polygenic risk score AB - Late life disability is a highly devastating condition affecting 20% or more of persons aged 65 years and older in the USA; it is an important determinant of acute medical and long-term care costs which represent a growing burden on national economies. Disability is a multifactorial trait that contributes substantially to decline of health/wellbeing. Accordingly, gaining insights into the genetics of disability could help in identifying molecular mechanisms of this devastating condition and age-related processes contributing to a large fraction of specific geriatric conditions, concordantly with geroscience. We performed a genome-wide association study of disability in a sample of 24,068 subjects from five studies with 12,550 disabled individuals. We identified 30 promising disability-associated polymorphisms in 19 loci at p < 10−4; four of them attained suggestive significance, p < 10−5. In contrast, polygenic risk scores aggregating effects of minor alleles of independent SNPs that were adversely or beneficially associated with disability showed highly significant associations in meta-analysi UR - https://doi.org/10.1007/s11357-019-00125-8 ER - TY - JOUR T1 - The Effect of Adherence to Screening Guidelines on the Risk of Alzheimer's Disease in Elderly Individuals Newly Diagnosed With Type 2 Diabetes Mellitus. JF - Gerontology & Geriatric Medicine Y1 - 2018 A1 - Arseniy P Yashkin A1 - Akushevich, Igor A1 - Svetlana Ukraintseva A1 - Anatoliy Yashin KW - Alzheimer's disease KW - Cognitive Ability KW - Diabetes KW - Medicare linkage KW - Screenings AB - The aim of this study was to examine the possibility that type 2 diabetes and Alzheimer's disease may share common behavioral protective factors such as adherence to type 2 diabetes treatment guidelines given that these two diseases have both epidemiological and metabolic similarities. : The method used in this study is a retrospective cohort study of 3,797 U.S. Medicare fee-for-service beneficiaries aged 66+ newly diagnosed with type 2 diabetes and without a prior record of Alzheimer's disease based on the Health and Retirement Study. : Results of a left-truncated Cox model showed that adherence reduces the risk of Alzheimer's disease by 20% to 24%. Other significant effects were college education (hazard ratio [HR]: 0.65; value: .023), stroke (HR: 1.40; value: .013), and 4+ limitations in physical functioning (HR: 1.33; value: .008). : Risk of Alzheimer's disease can be reduced by behavioral factors. Possible mechanisms may include earlier start of interventions to reduce blood glucose levels and improve insulin sensitivity. VL - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/30450369?dopt=Abstract ER - TY - JOUR T1 - Genetics of human longevity from incomplete data: New findings from the long life family study. JF - Journals of Gerontology, Series A: Biological Sciences & Medical Sciences Y1 - 2018 A1 - Anatoliy Yashin A1 - Konstantin G Arbeev A1 - Wu, Deqing A1 - Liubov S Arbeeva A1 - Bagley, Olivia A1 - Stallard, Eric A1 - Alexander M Kulminski A1 - Akushevich, Igor A1 - Fang, Fang A1 - Wojczynski, Mary K A1 - Christensen, Kaare A1 - Anne B Newman A1 - Boudreau, Robert M A1 - Province, Michael A A1 - Stephen M Thielke A1 - Thomas T Perls A1 - An, Ping A1 - Irma Elo A1 - Svetlana Ukraintseva KW - Genetics KW - Longevity AB - The special design of the Long Life Family Study provides a unique opportunity to investigate the genetics of human longevity by analyzing data on exceptional lifespans in families. In this article, we performed two series of genome wide association studies of human longevity which differed with respect to whether missing lifespan data were predicted or not predicted. We showed that the use of predicted lifespan is most beneficial when the follow-up period is relatively short. In addition to detection of strong associations of SNPs in APOE, TOMM40, NECTIN2, and APOC1 genes with longevity, we also detected a strong new association with longevity of rs1927465, located between the CYP26A1 and MYOF genes on chromosome 10. The association was confirmed using data from the Health and Retirement Study. We discuss the biological relevance of the detected SNPs to human longevity. VL - 73 IS - 11 U1 - http://www.ncbi.nlm.nih.gov/pubmed/30299504?dopt=Abstract ER - TY - JOUR T1 - Hidden heterogeneity in Alzheimer's disease: Insights from genetic association studies and other analyses JF - Experimental Gerontology Y1 - 2018 A1 - Anatoliy Yashin A1 - Fang, Fang A1 - Kovtun, Mikhail A1 - Wu, Deqing A1 - Duan, Matt A1 - Konstantin G Arbeev A1 - Akushevich, Igor A1 - Alexander M Kulminski A1 - Culminskaya, Irina A1 - Zhbannikov, Ilya A1 - Arseniy P Yashkin A1 - Stallard, Eric A1 - Svetlana Ukraintseva KW - Alzheimer's disease KW - Cancer screenings KW - Genetics KW - GWAS AB - Despite evident success in clarifying many important features of Alzheimer's disease (AD) the efficient methods of its prevention and treatment are not yet available. The reasons are likely to be the fact that AD is a multifactorial and heterogeneous health disorder with multiple alternative pathways of disease development and progression. The availability of genetic data on individuals participated in longitudinal studies of aging health and longevity, as well as on participants of cross-sectional case-control studies allow for investigating genetic and non-genetic connections with AD and to link the results of these analyses with research findings obtained in clinical, experimental, and molecular biological studies of this health disorder. The objective of this paper is to perform GWAS of AD in several study populations and investigate possible roles of detected genetic factors in developing AD hallmarks and in other health disorders. The data collected in the Framingham Heart Study (FHS), Cardiovascular Health Study (CHS), Health and Retirement Study (HRS) and Late Onset Alzheimer's Disease Family Study (LOADFS) were used in these analyses. The logistic regression and Cox's regression were used as statistical models in GWAS. The results of analyses confirmed strong associations of genetic variants from well-known genes APOE, TOMM40, PVRL2 (NECTIN2), and APOC1 with AD. Possible roles of these genes in pathological mechanisms resulting in development of hallmarks of AD are described. Many genes whose connection with AD was detected in other studies showed nominally significant associations with this health disorder in our study. The evidence on genetic connections between AD and vulnerability to infection, as well as between AD and other health disorders, such as cancer and type 2 diabetes, were investigated. The progress in uncovering hidden heterogeneity in AD would be substantially facilitated if common mechanisms involved in development of AD, its hallmarks, and AD related chronic conditions were investigated in their mutual connection. VL - 107 UR - http://linkinghub.elsevier.com/retrieve/pii/S0531556517304242 JO - Experimental Gerontology ER - TY - JOUR T1 - Time Trends in the Prevalence of Neurocognitive Disorders and Cognitive Impairment in the United States: The Effects of Disease Severity and Improved Ascertainment JF - Journal of Alzheimer's Disease Y1 - 2018 A1 - Akushevich, Igor A1 - Arseniy P Yashkin A1 - Kravchenko, Julia A1 - Svetlana Ukraintseva A1 - Stallard, Eric A1 - Anatoliy Yashin KW - CIND KW - Cognitive Ability KW - Dementia KW - Medicare linkage KW - Medicare/Medicaid/Health Insurance AB - Background: Trends in the prevalence of cognitive impairment (CI) based on cognitive assessment instruments are often inconsistent with those of neurocognitive disorders (ND) based on Medicare claims records. Objective: We hypothesized that improved ascertainment and resulting decrease in disease severity at the time of diagnosis are responsible for this phenomenon. Methods: Using Medicare data linked to the Health and Retirement Study (1992–2012), we performed a joint analysis of trends in CI and ND to test our hypothesis. Results: We identified two major contributors to the divergent directions in CI and ND trends: reductions in disease severity explained more than 60% of the differences between CI and ND prevalence over the study period; the remaining 40% was explained by a decrease in the fraction of undiagnosed individuals. Discussion: Improvements in the diagnoses of ND diseases were a major contributor to reported trends in ND and CI. Recent forecasts of CI and ND trends in the U.S. may be overly pessimistic. VL - 64 UR - http://www.medra.org/servlet/aliasResolver?alias=iospress&doi=10.3233/JAD-180060 IS - 1 JO - JAD ER - TY - JOUR T1 - Pleiotropic Associations of Allelic Variants in a 2q22 Region with Risks of Major Human Diseases and Mortality. JF - PLoS Genet Y1 - 2016 A1 - Alexander M Kulminski A1 - He, Liang A1 - Culminskaya, Irina A1 - Loika, Yury A1 - Kernogitski, Yelena A1 - Konstantin G Arbeev A1 - Loiko, Elena A1 - Liubov S Arbeeva A1 - Bagley, Olivia A1 - Duan, Matt A1 - Arseniy P Yashkin A1 - Fang, Fang A1 - Kovtun, Mikhail A1 - Svetlana Ukraintseva A1 - Wu, Deqing A1 - Anatoliy Yashin ED - Barsh, Gregory S. KW - Activin Receptors, Type II KW - Atherosclerosis KW - Chromosomes, Human, Pair 2 KW - Coronary Disease KW - Diabetes Mellitus KW - Female KW - Genetic Association Studies KW - Genetic Diseases, Inborn KW - Genetic Pleiotropy KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Heart Failure KW - Homeodomain Proteins KW - Humans KW - Male KW - Repressor Proteins KW - Risk Factors KW - Stroke KW - Zinc Finger E-box Binding Homeobox 2 AB -

Gaining insights into genetic predisposition to age-related diseases and lifespan is a challenging task complicated by the elusive role of evolution in these phenotypes. To gain more insights, we combined methods of genome-wide and candidate-gene studies. Genome-wide scan in the Atherosclerosis Risk in Communities (ARIC) Study (N = 9,573) was used to pre-select promising loci. Candidate-gene methods were used to comprehensively analyze associations of novel uncommon variants in Caucasians (minor allele frequency~2.5%) located in band 2q22.3 with risks of coronary heart disease (CHD), heart failure (HF), stroke, diabetes, cancer, neurodegenerative diseases (ND), and mortality in the ARIC study, the Framingham Heart Study (N = 4,434), and the Health and Retirement Study (N = 9,676). We leveraged the analyses of pleiotropy, age-related heterogeneity, and causal inferences. Meta-analysis of the results from these comprehensive analyses shows that the minor allele increases risks of death by about 50% (p = 4.6×10-9), CHD by 35% (p = 8.9×10-6), HF by 55% (p = 9.7×10-5), stroke by 25% (p = 4.0×10-2), and ND by 100% (p = 1.3×10-3). This allele also significantly influences each of two diseases, diabetes and cancer, in antagonistic fashion in different populations. Combined significance of the pleiotropic effects was p = 6.6×10-21. Causal mediation analyses show that endophenotypes explained only small fractions of these effects. This locus harbors an evolutionary conserved gene-desert region with non-coding intergenic sequences likely involved in regulation of protein-coding flanking genes ZEB2 and ACVR2A. This region is intensively studied for mutations causing severe developmental/genetic disorders. Our analyses indicate a promising target region for interventions aimed to reduce risks of many major human diseases and mortality.

VL - 12 UR - https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/27832070/ IS - 11 U1 - http://www.ncbi.nlm.nih.gov/pubmed/27832070?dopt=Abstract JO - PLoS Genet ER -