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Interplay between stress-related genes may influence Alzheimer's disease development: The results of genetic interaction analyses of human data.

ABSTRACT: 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.

SUBMITTER: Yashin AI

PROVIDER: S-EPMC8173104 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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Interplay between stress-related genes may influence Alzheimer's disease development: The results of genetic interaction analyses of human data.

Yashin Anatoliy I AI Wu Deqing D Arbeev Konstantin K Bagley Olivia O Akushevich Igor I Duan Matt M Yashkin Arseniy A Ukraintseva Svetlana S

Mechanisms of ageing and development 20210330

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 i ...[more]

PMID: 33798591

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Project description:IntroductionAlthough the heritability of sporadic Alzheimer's disease (AD) is estimated to be 60-80%, addressing the genetic contribution to AD risk still remains elusive. More specifically, it remains unclear whether genetic variants are able to affect neurodegenerative brain features that can be addressed by in vivo imaging techniques.MethodsTargeted sequencing analysis of the coding and UTR regions of 132 AD susceptibility genes was performed. Neuroimaging data using 11C-Pittsburgh Compound B positron emission tomography (PET), 18F-fluorodeoxyglucose PET, and MRI that are available from the KBASE (Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimer's disease) cohort were acquired. A total of 557 participants consisted of 336 cognitively normal (CN) adults, 137 mild cognitive impairment (MCI), and 84 AD dementia (ADD) groups.ResultsWe called 5391 high-quality single nucleotide variants (SNVs) on AD susceptibility genes and selected significant associations between variants and five in vivo AD pathologies: (1) amyloid β (Aβ) deposition, (2) AD-signature region cerebral glucose metabolism (AD-Cm), (3) posterior cingulate cortex (PCC) cerebral glucose metabolism (PCC-Cm), (4) AD-signature region cortical thickness (AD-Ct), and (5) hippocampal volume (Hv). The association analysis for common variants (allele frequency (AF) > 0.05) yielded several novel loci associated with Aβ deposition (PIWIL1-rs10848087), AD-Cm (NME8-rs2722372 and PSEN2-rs75733498), AD-Ct (PSEN1-rs7523) and, Hv (CASS4-rs3746625). Meanwhile, in a gene-based analysis for rare variants (AF < 0.05), cases carrying rare variants in LPL, FERMT2, NFAT5, DSG2, and ITPR1 displayed associations with the neuroimaging features. Exploratory voxel-based brain morphometry between the variant carriers and non-carriers was performed subsequently. Finally, we document a strong association of previously reported APOE variants with the in vivo AD pathologies and demonstrate that the variants exert a causal effect on AD susceptibility via neuroimaging features.ConclusionsThis study provides novel associations of genetic factors to Aβ accumulation and AD-related neurodegeneration to influence AD susceptibility.

Project description:Quantitative RT-PCR is an important technique for assessing gene expression. However, a proper normalization of reference genes prior to expression analyses of target genes is necessary. The best normalizer is that gene which remains stable in all samples from different treatments. The aim of this study was to identify stable reference genes for normalization of target genes in muscle tissue from three genetically divergent chickens groups (Peloco, Cobb 500® and Caneluda) under environmental (heat stress and comfort) and sex influence. Expressions of ten reference genes were tested for stability in breast muscular tissue (Pectoralis major muscle). Samples were obtained from 36 males and females of two backyard breeds (Caneluda and Peloco) and one commercial line (Cobb 500®) under two environments. The heat stress and comfort temperature were 39 and 23°C, respectively. Animals were housed in the Animal Science Department at Universidade Estadual do Sudoeste da Bahia. We analyzed the expression data by four statistical tools (SLqPCR, NormFinder, Bestkeeper and Comparative CT). According to these tools, genes stability varied according to sex, genetic group and environment, however, some genes remained stable in all analyzes. There was no difference between the most stable genes for sex effect, being MRPS27 more stable for both males and females. In general, MRPS27 was the most stable gene. Within the three genetic groups, the most stable genes were RPL5, HMBS and EEF1 to Cobb 500®, Peloco and Caneluda, respectively. Within the environment, the most stable gene under comfort and heat stress conditions was HMBS and MRPS27, respectively. BestKeeper and Comparative Ct were less correlated (28%) and SLqPCR and NormFinder were the most correlated (98%). MRPS27, RPL5 and MRPS30 genes were considered stable according the overall ranking and can be used as normalizer of relative expression of target genes in muscle tissue of chickens under heat stress.

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Interplay between stress-related genes may influence Alzheimer's disease development: The results of genetic interaction analyses of human data.

Publications

Interplay between stress-related genes may influence Alzheimer's disease development: The results of genetic interaction analyses of human data.

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