Meta-analysis of lipid-traits in Hispanics identifies novel loci, population-specific effects and tissue-specific enrichment of eQTLs

Below, Jennifer E.; Parra, Esteban J.; Gamazon, Eric R.; Torres, Jason; Krithika, S.; Candille, Sophie I.; Lu, Yingchang; Manichakul, Ani W.; Peralta‐Romero, Jesús; Duan, Qing; Li, Yun; Morris, Andrew P.; Gottesman, Omri; Böttinger, Erwin P.; Wang, Xin Qun; Taylor, Kent D.; Chen, Y. D. Ida; Rotter, Jerome I.; Rich, Stephen S.; Loos, Ruth J.F.; Tang, Hua; Cox, Nancy J.; Cruz, Miguel; Hanis, Craig L.; Valladares‐Salgado, Adán

doi:10.1038/srep19429

Cited by 64 publications

(70 citation statements)

References 40 publications

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“…The genes identified by stability selection exhibit connections to a number of intermediate phenotypes and biochemical processes relevant to AD. For instance, common missense variation in PFAS (phosphoribosylformylglycinamidine synthase) has been linked to low-density lipoprotein (LDL) cholesterol measurement through GWAS [31,32]. Additionally, Gene Ontology annotations for PFAS include the term ‘glutamine metabolic process’ (GO:0006541).…”

Section: Discussionmentioning

confidence: 99%

Network propagation of rare mutations in Alzheimer’s disease reveals tissue-specific hub genes and communities

Scelsi

Napolioni

Greicius

et al. 2019

Preprint

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BackgroundState-of-the-art rare variant association testing methods aggregate the contribution of rare variants in biologically relevant genomic regions to boost statistical power. However, testing single genes separately does not consider the complex interaction landscape of genes, nor the downstream effects of non-synonymous variants on protein structure and function. Here we present the NETwork Propagation-based Assessment of Genetic Events (NETPAGE), an integrative approach aimed at investigating the biological pathways through which rare variation results in complex disease phenotypes.ResultsWe applied NETPAGE to sporadic, late-onset Alzheimer’s disease (AD), using whole-genome sequencing from the AD Neuroimaging Initiative (ADNI) cohort, as well as whole-exome sequencing from the AD Sequencing Project (ADSP). NETPAGE is based on network propagation, a framework that models information flow on a graph and simulates the percolation of genetic variation through gene networks. The result of network propagation is a set of smoothed gene scores used to predict disease status through sparse regression. The application of NETPAGE to AD enabled the identification of a set of connected genes whose smoothed mutation profile acted as a robust predictor of case-control status, based on gene interactions in the hippocampus. Additionally, smoothed scores significantly correlated with risk of conversion to AD in Mild Cognitive Impairment (MCI) subjects. Lastly, we showed tissue-specific transcriptional dysregulation of the core genes in two independent RNA-seq datasets, as well as significant enrichments in terms and gene sets with known connections to AD.ConclusionsThe presented framework enables enhanced genetic association testing for a wide range of traits, diseases, and sample sizes.

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Section: Discussionmentioning

confidence: 99%

Network propagation of rare mutations in Alzheimer’s disease reveals tissue-specific hub genes and communities

Scelsi

Napolioni

Greicius

et al. 2019

Preprint

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“…have not been investigated in this cohort to date. Hispanics have a disproportionate disease burden for many common diseases related to vasculature (i.e., diabetes and cardiovascular disease) (82)(83)(84)(85)(86)(87)(88)(89)(90) that have also been shown to have microbiome-related disease variables in many other experimental contexts (91)(92)(93)(94)(95)(96)(97)(98)(99)(100)(101)(102)(103)(104). Dental health, bacterial infection, and peripheral vascular disease have many independent associations (105), and some of the etiology could be affected by systemic loosening of tight junctions as induced by organophosphates (78).…”

Section: Discussionmentioning

confidence: 99%

Human Oral Buccal Microbiomes Are Associated with Farmworker Status and Azinphos-Methyl Agricultural Pesticide Exposure

Stanaway

Wallace

Shojaie

et al. 2017

Appl Environ Microbiol

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In a longitudinal agricultural community cohort sampling of 65 adult farmworkers and 52 adult nonfarmworkers, we investigated agricultural pesticide exposure-associated changes in the oral buccal microbiota. We found a seasonally persistent association between the detected blood concentration of the insecticide azinphos-methyl and the taxonomic composition of the buccal swab oral microbiome. Blood and buccal samples were collected concurrently from individual subjects in two seasons, spring/summer 2005 and winter 2006. Mass spectrometry quantified blood concentrations of the organophosphate insecticide azinphosmethyl. Buccal oral microbiome samples were 16S rRNA gene DNA sequenced, assigned to the bacterial taxonomy, and analyzed after "centered-log-ratio" transformation to handle the compositional nature of the proportional abundances of bacteria per sample. Nonparametric analysis of the transformed microbiome data for individuals with and without azinphos-methyl blood detection showed significant perturbations in seven common bacterial taxa (Ͼ0.5% of sample mean read depth), including significant reductions in members of the common oral bacterial genus Streptococcus. Diversity in centered-log-ratio composition between individuals' microbiomes was also investigated using principal-component analysis (PCA) to reveal two primary PCA clusters of microbiome types. The spring/summer "exposed" microbiome cluster with significantly less bacterial diversity was enriched for farmworkers and contained 27 of the 30 individuals who also had azinphos-methyl agricultural pesticide exposure detected in the blood. IMPORTANCEIn this study, we show in human subjects that organophosphate pesticide exposure is associated with large-scale significant alterations of the oral buccal microbiota composition, with extinctions of whole taxa suggested in some individuals. The persistence of this association from the spring/summer to the winter also suggests that long-lasting effects on the commensal microbiota have occurred. The important health-related outcomes of these agricultural community individuals' pesticide-associated microbiome perturbations are not understood at this time. Future investigations should index medical and dental records for common and chronic diseases that may be interactively caused by this association between pesticide exposure and microbiome alteration.KEYWORDS farmworkers, azinphos-methyl, oral, microbiome, bacteria, buccal mucosa, 16S rRNA, sequencing

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“…We retrieved from the literature loci exhibiting significant marginal genetic effect on blood pressure traits [12][13][14] and lipid traits [15][16][17][18] , and compared those associations against both 1df and 2df test from our stage 1 analysis (as some SNPs were not available at stage 2). Description of these references are provided in Table S3, and the list of SNPs used in Table S4.…”

Section: Comparison Against Marginal Effect Screeningmentioning

confidence: 99%

“…We aimed to test whether SNPs previously identified at genome-wide significance level in marginal effect GWAS tend to display interaction effects. We retrieved from the literature loci exhibiting significant marginal genetic effect on blood pressure traits [12][13][14] and lipid traits [15][16][17][18] . For each locus, we selected only the most associated variants so that all candidate SNPs considered are independent from each other.…”

Section: Univariate and Multivariate Interaction Test At Known Locimentioning

confidence: 99%

Large-scale multivariate multi-ancestry Interaction analyses point towards different genetic mechanisms by population and exposure

Laville

Majarian

Sung³

et al. 2019

Preprint

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The Gene-Lifestyle Interactions Working Group has recently conducted series of multi-ancestry genome-wide association screenings (GWAS) involving up to 610,475 individuals for three lipids (total triglyceride, high-density lipoprotein, and low-density lipoprotein), and four blood pressure traits (diastolic blood pressure, systolic blood pressure, mean arterial pressure, and pulse pressure) while accounting for potential interaction effect with drinking and smoking exposures. These GWAS reported both a 1 degree-of-freedom (df) test of gene-by-exposure (GxE) interaction, and a 2 df test of main genetic effect and interaction effect. Here we synthetized these results and generated a number of cross-studies statistics, providing a global perspective on this unique initiative, and suggesting guidelines for future GxE studies. We first summarized the signals identified across all phenotype-exposure pairs and ancestries considered, highlighting similarity and specificity of gene-environment interaction effects across phenotypes and ancestries. We then performed several follow-up analyses using genome-wide summary statistics, focusing in particular on multi-SNPs approaches and the relationship between interactions effect and marginal genetic effect. Those analyses identified new associations and demonstrated potential alternatives approaches for future GxE screenings. Finally, we explored differences in heritability conditional on the exposures considered. Our work provides new evidences for the potential implication of exposure-specific pathways, opening new paths for future gene-environment interaction studies.

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Meta-analysis of lipid-traits in Hispanics identifies novel loci, population-specific effects and tissue-specific enrichment of eQTLs

Cited by 64 publications

References 40 publications

Network propagation of rare mutations in Alzheimer’s disease reveals tissue-specific hub genes and communities

Network propagation of rare mutations in Alzheimer’s disease reveals tissue-specific hub genes and communities

Human Oral Buccal Microbiomes Are Associated with Farmworker Status and Azinphos-Methyl Agricultural Pesticide Exposure

Large-scale multivariate multi-ancestry Interaction analyses point towards different genetic mechanisms by population and exposure

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