scholarly journals Genetic effect estimates in case-control studies when a continuous variable is omitted from the model

2019 ◽  
Author(s):  
Ying Sheng ◽  
Chiung-Yu Huang ◽  
Siarhei Lobach ◽  
Lydia Zablotska ◽  
Iryna Lobach ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Large Scale ◽  
False Positive Rate ◽  
Continuous Variable ◽  
Genetic Effects ◽  
Data Availability ◽  
Conditional Density ◽  
Link Type ◽  
Genome Wide

ABSTRACTLarge-scale genome-wide analyses scans provide massive volumes of genetic variants on large number of cases and controls that can be used to estimate the genetic effects. Yet, the sets of non-genetic variables available in publicly available databases are often brief. It is known that omitting a continuous variable from a logistic regression model can result in biased estimates of odds ratios (OR) (e.g., Gail et al (1984), Neuhaus et al (1993), Hauck et al (1991), Zeger et al (1988)). We are interested to assess what information is needed to recover the bias in the OR estimate of genotype due to omitting a continuous variable in settings when the actual values of the omitted variable are not available. We derive two estimating procedures that can recover the degree of bias based on a conditional density of the omitted variable or knowing the distribution of the omitted variable. Importantly, our derivations show that omitting a continuous variable can result in either under- or over-estimation of the genetic effects. We performed extensive simulation studies to examine bias, variability, false positive rate, and power in the model that omits a continuous variable. We show the application to two genome-wide studies of Alzheimer’s disease.Data Availability StatementThe data that support the findings of this study are openly available in the Database of Genotypes and Phenotypes at [https://www.ncbi.nlm.nih.gov/projects/gap/cgibin/study.cgi?study_id=phs000372.v1.p1], reference number [phs000372.v1.p1] and at the Alzheimer’s Disease Neuroimaging Initiative http://adni.loni.usc.edu/.

scholarly journals Linking molecular pathways and large-scale computational modeling to assess candidate disease mechanisms and pharmacodynamics in Alzheimer’s disease

2019 ◽  
Author(s):  
Leon Stefanovski ◽  
Paul Triebkorn ◽  
Andreas Spiegler ◽  
Margarita-Arimatea Diaz-Cortes ◽  
Ana Solodkin ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Large Scale ◽  
Local Population ◽  
Structural Connectivity ◽  
Neuronal Population ◽  
Neural Function ◽  
Molecular Pathways ◽  
Link Type ◽  
Disease Mechanisms

AbstractIntroductionWhile the prevalence of neurodegenerative diseases associated with dementia such as Alzheimer’s disease (AD) increases, our knowledge on the underlying mechanisms, outcome predictors, or therapeutic targets is limited. In this work, we demonstrate how computational multi-scale brain modelling links phenomena of different scales and therefore identifies potential disease mechanisms leading the way to improved diagnostics and treatment.MethodsThe Virtual Brain (TVB; thevirtualbrain.org) neuroinformatics platform allows standardized large-scale structural connectivity-based simulations of whole brain dynamics. We provide proof of concept for a novel approach that quantitatively links the effects of altered molecular pathways onto neuronal population dynamics. As a novelty, we connect chemical compounds measured with positron emission tomography (PET) with neural function in TVB addressing the phenomenon of hyperexcitability in AD related to the protein amyloid beta (Abeta). We construct personalized virtual brains based on individual PET derived distributions of Abeta in patients with mild cognitive impairment (MCI, N=8) and Alzheimer’s Disease (AD, N=10) and in age-matched healthy controls (HC, N=15) using data from ADNI-3 data base (http://adni.lni.usc.edu). In the personalized virtual brains, individual Abeta burden modulates regional inhibition, leading to disinhibition and hyperexcitation with high Abeta loads. We analyze simulated regional neural activity and electroencephalograms (EEG).ResultsKnown empirical alterations of EEG in patients with AD compared to HCs were reproduced by simulations. The virtual AD group showed slower frequencies in simulated local field potentials and EEG compared to MCI and HC groups. The heterogeneity of the Abeta load is crucial for the virtual EEG slowing which is absent for control models with homogeneous Abeta distributions. Slowing phenomena primarily affect the network hubs, independent of the spatial distribution of Abeta. Modeling the N-methyl-D-aspartate (NMDA) receptor antagonism of memantine in local population models, reveals potential functional reversibility of the observed large-scale alterations (reflected by EEG slowing) in virtual AD brains.DiscussionWe demonstrate how TVB enables the simulation of systems effects caused by pathogenetic molecular candidate mechanisms in human virtual brains.

scholarly journals East Asian-specific novel loci associated with late-onset Alzheimer’s disease: the GARD cohort Genome-wide study

2020 ◽  
Author(s):  
Sarang Kang ◽  
Tamil Iniyan Gunasekaran ◽  
Kyu Yeong Choi ◽  
Jang Jae Lee ◽  
Sungho Won ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Large Scale ◽  
Genetic Factors ◽  
Late Onset ◽  
East Asian ◽  
Genetic Heritability ◽  
Genome Wide ◽  
Japanese Sample ◽  
Genomic Studies

ABSTRACTThe high genetic heritability of Alzheimer’s disease has contributed to the multi-directional and large-scale genomic studies to discover genetic factors, and so far many massive studies have been reported. However, the majority of genetic factors have been identified through European races, and relatively few studies using East Asians to discover genetic factors. In this study, East Asian specific loci is first reported through GWAS using GARD cohorts, which have been intensively recruited and managed by a single institution. ApoE-stratified GWAS with the AD cases and matched controls (n=2,291) in the Korean cohort and validation analysis using a Japanese sample (n=1,956) replicated six previously reported loci (genes) including ApoE and suggested two novel susceptible loci in LRIG1 and CACNA1A gene. This study demonstrates that discovery of AD-associated variants can be accomplished in ethnic groups of a more homogeneous genetic background using samples comprising fewer subjects.

scholarly journals Shared Genetic Architecture Between Alzheimer’s Disease and Gastrointestinal Tract Disorders: A Large-scale Genome-wide Cross-trait Analysis

2021 ◽  
Author(s):  
Emmanuel O Adewuyi ◽  
Eleanor K O’Brien ◽  
Dale R Nyholt ◽  
Tenielle Porter ◽  
Simon M Laws
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Gastrointestinal Tract ◽  
Large Scale ◽  
Association Studies ◽  
Biological Pathways ◽  
Mendelian Randomisation ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Shared Genetic

Abstract Background: Consistent with the concept of the gut-brain phenomenon, observational studies have reported a pattern of co-occurring relationship between Alzheimer’s disease (AD) and a range of gastrointestinal tract (GIT) traits. However, it is not clear whether the reported association reflects a causal or shared genetic aetiology of GIT disorders with AD. While AD has no known curative treatments, and its pathogenesis is not clearly understood, a comprehensive assessment of its shared genetics with diseases (comorbidities) can provide a deeper understanding of its underlying biological mechanisms and enhance potential therapy development. Methods: We analysed large-scale genome-wide association studies (GWAS) summary data (sample size = 34,652 – 456,327) to comprehensively assess shared genetic overlap and causality of GIT disorders with the risk of AD. Further, we performed meta-analyses, pairwise GWAS analysis; and investigated genes and biological pathways shared by AD and GIT disorders.Results: Our analyses reveal significant concordance of SNP risk effects across AD and GIT disorders (Ppermuted = 9.99 × 10−4). Also, we found a significant positive genetic correlation between AD and each of gastroesophageal reflux disease (GERD), peptic ulcer disease (PUD), medications for GERD or PUD (PGM), gastritis-duodenitis, irritable bowel syndrome, and diverticular disease, but not inflammatory bowel disease. Mendelian randomisation analyses found no evidence for a significant causal association between AD and GIT disorders. However, shared independent genome-wide significant (Pmeta-analysis < 5 × 10-8) loci (including 1p31.3 [near gene, PDE4B], 1q32.2 [CD46], 3p21.31 [SEMA3F], 16q22.1 [MTSS2], 17q21.33 [PHB], and 19q13.32 [APOE]) were identified for AD and PGM, six of which are putatively novel. These loci were replicated using GERD and PUD GWAS and reinforced in pairwise GWAS (colocalisation) as well as gene-based analyses. Lipid metabolism, autoimmune system, lipase inhibitors, PD-1 signalling, and statin mechanisms were significantly enriched in pathway-based analyses. Conclusions: These findings support shared genetic susceptibility of GIT disorders with AD risk and provide new insights into their observed association. The identified loci and genes—PDE4B, CD46 and APOE, especially—and biological pathways—statins and lipase inhibitors, in particular—may provide novel therapeutic avenues or targets for further investigation in AD, GIT disorders, or their comorbidity.

scholarly journals Identification of functionally connected multi-omic biomarkers for Alzheimer’s Disease using modularity-constrained Lasso

2019 ◽  
Author(s):  
Linhui Xie ◽  
Pradeep Varathan ◽  
Kwangsik Nho ◽  
Andrew J. Saykin ◽  
Paul Salama ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Performance ◽  
Large Scale ◽  
Association Studies ◽  
Interaction Network ◽  
Real Data ◽  
Genome Wide Association Studies ◽  
Penalty Term ◽  
Genome Wide

AbstractIn the past decade, a large number of genetic biomarkers have been discovered through large-scale genome wide association studies (GWASs) in Alzheimer’s disease (AD), such as APOE, TOMM40 and CLU. Despite this significant progress, existing genetic findings are largely passengers not directly involved in the driver events, which presents challenges for replication and translation into targetable mechanisms. In this paper, leveraging the protein interaction network, we proposed a modularity-constrained Lasso model to jointly analyze the genotype, gene expression and protein expression data. With a prior network capturing the functional relationship between SNPs, genes and proteins, the newly introduced penalty term maximizes the global modularity of the subnetwork involving selected markers and encourages the selection of multi-omic markers with dense functional connectivity, instead of individual markers. We applied this new model to the real data in ROS/MAP cohort for discovery of biomarkers related to cognitive performance. A functionally connected subnetwork involving 276 multi-omic biomarkers, including SNPs, genes and proteins, were identified to bear predictive power. Within this subnetwork, multiple trans-omic paths from SNPs to genes and then proteins were observed, suggesting that cognitive performance can be potentially affected by the genetic mutations due to their cascade effect on the expression of downstream genes and proteins.

Dehydroepiandrosterone (DHEA) and its Sulphate (DHEAS) in Alzheimer’s Disease

2020 ◽  
Vol 17 (2) ◽  
pp. 141-157 ◽  
Author(s):  
Dubravka S. Strac ◽  
Marcela Konjevod ◽  
Matea N. Perkovic ◽  
Lucija Tudor ◽  
Gordana N. Erjavec ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Large Scale ◽  
Therapeutic Potential ◽  
Relevant Literature ◽  
Comprehensive Overview ◽  
Brain Functions ◽  
Specific Effects ◽  
And Behavior

Background: Neurosteroids Dehydroepiandrosterone (DHEA) and Dehydroepiandrosterone Sulphate (DHEAS) are involved in many important brain functions, including neuronal plasticity and survival, cognition and behavior, demonstrating preventive and therapeutic potential in different neuropsychiatric and neurodegenerative disorders, including Alzheimer’s disease. Objective: The aim of the article was to provide a comprehensive overview of the literature on the involvement of DHEA and DHEAS in Alzheimer’s disease. Method: PubMed and MEDLINE databases were searched for relevant literature. The articles were selected considering their titles and abstracts. In the selected full texts, lists of references were searched manually for additional articles. Results: We performed a systematic review of the studies investigating the role of DHEA and DHEAS in various in vitro and animal models, as well as in patients with Alzheimer’s disease, and provided a comprehensive discussion on their potential preventive and therapeutic applications. Conclusion: Despite mixed results, the findings of various preclinical studies are generally supportive of the involvement of DHEA and DHEAS in the pathophysiology of Alzheimer’s disease, showing some promise for potential benefits of these neurosteroids in the prevention and treatment. However, so far small clinical trials brought little evidence to support their therapy in AD. Therefore, large-scale human studies are needed to elucidate the specific effects of DHEA and DHEAS and their mechanisms of action, prior to their applications in clinical practice.

scholarly journals Genome-wide analysis identifies a novel LINC-PINT splice variant associated with vascular amyloid pathology in Alzheimer’s disease

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Joseph S. Reddy ◽  
Mariet Allen ◽  
Charlotte C. G. Ho ◽  
Stephanie R. Oatman ◽  
Özkan İş ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Genome Wide Association Study ◽  
Transcriptome Profiling ◽  
Brain Regions ◽  
Common Finding ◽  
Amyloid Angiopathy ◽  
Genome Wide ◽  
A Genome ◽  
Male Sex

AbstractCerebral amyloid angiopathy (CAA) contributes to accelerated cognitive decline in Alzheimer’s disease (AD) dementia and is a common finding at autopsy. The APOEε4 allele and male sex have previously been reported to associate with increased CAA in AD. To inform biomarker and therapeutic target discovery, we aimed to identify additional genetic risk factors and biological pathways involved in this vascular component of AD etiology. We present a genome-wide association study of CAA pathology in AD cases and report sex- and APOE-stratified assessment of this phenotype. Genome-wide genotypes were collected from 853 neuropathology-confirmed AD cases scored for CAA across five brain regions, and imputed to the Haplotype Reference Consortium panel. Key variables and genome-wide genotypes were tested for association with CAA in all individuals and in sex and APOEε4 stratified subsets. Pathway enrichment was run for each of the genetic analyses. Implicated loci were further investigated for functional consequences using brain transcriptome data from 1,186 samples representing seven brain regions profiled as part of the AMP-AD consortium. We confirmed association of male sex, AD neuropathology and APOEε4 with increased CAA, and identified a novel locus, LINC-PINT, associated with lower CAA amongst APOEε4-negative individuals (rs10234094-C, beta = −3.70 [95% CI −0.49—−0.24]; p = 1.63E-08). Transcriptome profiling revealed higher LINC-PINT expression levels in AD cases, and association of rs10234094-C with altered LINC-PINT splicing. Pathway analysis indicates variation in genes involved in neuronal health and function are linked to CAA in AD patients. Further studies in additional and diverse cohorts are needed to assess broader translation of our findings.

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