Publications by authors named "Juan R Gonzalez"

118 Publications

Variability of multi-omics profiles in a population-based child cohort.

BMC Med 2021 07 22;19(1):166. Epub 2021 Jul 22.

ISGlobal, Barcelona, Spain.

Background: Multiple omics technologies are increasingly applied to detect early, subtle molecular responses to environmental stressors for future disease risk prevention. However, there is an urgent need for further evaluation of stability and variability of omics profiles in healthy individuals, especially during childhood.

Methods: We aimed to estimate intra-, inter-individual and cohort variability of multi-omics profiles (blood DNA methylation, gene expression, miRNA, proteins and serum and urine metabolites) measured 6 months apart in 156 healthy children from five European countries. We further performed a multi-omics network analysis to establish clusters of co-varying omics features and assessed the contribution of key variables (including biological traits and sample collection parameters) to omics variability.

Results: All omics displayed a large range of intra- and inter-individual variability depending on each omics feature, although all presented a highest median intra-individual variability. DNA methylation was the most stable profile (median 37.6% inter-individual variability) while gene expression was the least stable (6.6%). Among the least stable features, we identified 1% cross-omics co-variation between CpGs and metabolites (e.g. glucose and CpGs related to obesity and type 2 diabetes). Explanatory variables, including age and body mass index (BMI), explained up to 9% of serum metabolite variability.

Conclusions: Methylation and targeted serum metabolomics are the most reliable omics to implement in single time-point measurements in large cross-sectional studies. In the case of metabolomics, sample collection and individual traits (e.g. BMI) are important parameters to control for improved comparability, at the study design or analysis stage. This study will be valuable for the design and interpretation of epidemiological studies that aim to link omics signatures to disease, environmental exposures, or both.
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http://dx.doi.org/10.1186/s12916-021-02027-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8296694PMC
July 2021

The early-life exposome and epigenetic age acceleration in children.

Environ Int 2021 10 15;155:106683. Epub 2021 Jun 15.

ISGlobal, Dr. Aiguader 88, 08003 Barcelona, Spain; Universitat Pompeu Fabra (UPF), Barcelona, Spain; Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88, Barcelona 08003, Spain. Electronic address:

The early-life exposome influences future health and accelerated biological aging has been proposed as one of the underlying biological mechanisms. We investigated the association between more than 100 exposures assessed during pregnancy and in childhood (including indoor and outdoor air pollutants, built environment, green environments, tobacco smoking, lifestyle exposures, and biomarkers of chemical pollutants), and epigenetic age acceleration in 1,173 children aged 7 years old from the Human Early-Life Exposome project. Age acceleration was calculated based on Horvath's Skin and Blood clock using child blood DNA methylation measured by Infinium HumanMethylation450 BeadChips. We performed an exposure-wide association study between prenatal and childhood exposome and age acceleration. Maternal tobacco smoking during pregnancy was nominally associated with increased age acceleration. For childhood exposures, indoor particulate matter absorbance (PM) and parental smoking were nominally associated with an increase in age acceleration. Exposure to the organic pesticide dimethyl dithiophosphate and the persistent pollutant polychlorinated biphenyl-138 (inversely associated with child body mass index) were protective for age acceleration. None of the associations remained significant after multiple-testing correction. Pregnancy and childhood exposure to tobacco smoke and childhood exposure to indoor PM may accelerate epigenetic aging from an early age.
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http://dx.doi.org/10.1016/j.envint.2021.106683DOI Listing
October 2021

DNA methylation as the link between migration and the major noncommunicable diseases: the RODAM study.

Epigenomics 2021 May 23;13(9):653-666. Epub 2021 Apr 23.

Department of Public Health, Amsterdam Public Health Research Institute, Amsterdam University Medical Centers, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.

We assessed epigenome-wide DNA methylation (DNAm) differences between migrant and non-migrant Ghanaians. We used the Illumina Infinium HumanMethylation450 BeadChip to profile DNAm of 712 Ghanaians in whole blood. We used linear models to detect differentially methylated positions (DMPs) associated with migration. We performed multiple post hoc analyses to validate our findings. We identified 13 DMPs associated with migration (delta-beta values: 0.2-4.5%). Seven DMPs in , , , , , and were independent of extrinsic genomic influences in public databases. Two DMPs in were associated with duration of stay in Europe among migrants. All DMPs were biologically linked to migration-related factors. Our findings provide the first insights into DNAm differences between migrants and non-migrants.
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http://dx.doi.org/10.2217/epi-2020-0329DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8173498PMC
May 2021

Publisher Correction: MLIP genotype as a predictor of pharmacological response in primary open-angle glaucoma and ocular hypertension.

Sci Rep 2021 Apr 9;11(1):8237. Epub 2021 Apr 9.

Department of Surgery, School of Medicine and Health Sciences and Hospital Clinic de Barcelona (IDIBAPS), University of Barcelona, Calle Sabino de Arana 1 (2nd floor, Ophthalmology), 08028, Barcelona, Spain.

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http://dx.doi.org/10.1038/s41598-021-87653-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8035325PMC
April 2021

Orchestrating privacy-protected big data analyses of data from different resources with R and DataSHIELD.

PLoS Comput Biol 2021 03 30;17(3):e1008880. Epub 2021 Mar 30.

Barcelona Institute for Global Health (ISGlobal), Barcelona, Spain.

Combined analysis of multiple, large datasets is a common objective in the health- and biosciences. Existing methods tend to require researchers to physically bring data together in one place or follow an analysis plan and share results. Developed over the last 10 years, the DataSHIELD platform is a collection of R packages that reduce the challenges of these methods. These include ethico-legal constraints which limit researchers' ability to physically bring data together and the analytical inflexibility associated with conventional approaches to sharing results. The key feature of DataSHIELD is that data from research studies stay on a server at each of the institutions that are responsible for the data. Each institution has control over who can access their data. The platform allows an analyst to pass commands to each server and the analyst receives results that do not disclose the individual-level data of any study participants. DataSHIELD uses Opal which is a data integration system used by epidemiological studies and developed by the OBiBa open source project in the domain of bioinformatics. However, until now the analysis of big data with DataSHIELD has been limited by the storage formats available in Opal and the analysis capabilities available in the DataSHIELD R packages. We present a new architecture ("resources") for DataSHIELD and Opal to allow large, complex datasets to be used at their original location, in their original format and with external computing facilities. We provide some real big data analysis examples in genomics and geospatial projects. For genomic data analyses, we also illustrate how to extend the resources concept to address specific big data infrastructures such as GA4GH or EGA, and make use of shell commands. Our new infrastructure will help researchers to perform data analyses in a privacy-protected way from existing data sharing initiatives or projects. To help researchers use this framework, we describe selected packages and present an online book (https://isglobal-brge.github.io/resource_bookdown).
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http://dx.doi.org/10.1371/journal.pcbi.1008880DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8034722PMC
March 2021

Performance of approaches relying on multidimensional intermediary data to decipher causal relationships between the exposome and health: A simulation study under various causal structures.

Environ Int 2021 08 25;153:106509. Epub 2021 Mar 25.

Team of Environmental Epidemiology, IAB, Institute for Advanced Biosciences, Inserm, CNRS, CHU-Grenoble-Alpes, University Grenoble-Alpes, Grenoble, France. Electronic address:

Challenges in the assessment of the health effects of the exposome, defined as encompassing all environmental exposures from the prenatal period onwards, include a possibly high rate of false positive signals. It might be overcome using data dimension reduction techniques. Data from the biological layers lying between the exposome and its possible health consequences, such as the methylome, may help reducing exposome dimension. We aimed to quantify the performances of approaches relying on the incorporation of an intermediary biological layer to relate the exposome and health, and compare them with agnostic approaches ignoring the intermediary layer. We performed a Monte-Carlo simulation, in which we generated realistic exposome and intermediary layer data by sampling with replacement real data from the Helix exposome project. We generated a Gaussian outcome assuming linear relationships between the three data layers, in 2381 scenarios under five different causal structures, including mediation and reverse causality. We tested 3 agnostic methods considering only the exposome and the health outcome: ExWAS (for Exposome-Wide Association study), DSA, LASSO; and 3 methods relying on an intermediary layer: two implementations of our new oriented Meet-in-the-Middle (oMITM) design, using ExWAS and DSA, and a mediation analysis using ExWAS. Methods' performances were assessed through their sensitivity and FDP (False-Discovery Proportion). The oMITM-based methods generally had lower FDP than the other approaches, possibly at a cost in terms of sensitivity; FDP was in particular lower under a structure of reverse causality and in some mediation scenarios. The oMITM-DSA implementation showed better performances than oMITM-ExWAS, especially in terms of FDP. Among the agnostic approaches, DSA showed the highest performance. Integrating information from intermediary biological layers can help lowering FDP in studies of the exposome health effects; in particular, oMITM seems less sensitive to reverse causality than agnostic exposome-health association studies.
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http://dx.doi.org/10.1016/j.envint.2021.106509DOI Listing
August 2021

Early-life environmental exposure determinants of child behavior in Europe: A longitudinal, population-based study.

Environ Int 2021 08 25;153:106523. Epub 2021 Mar 25.

Bradford Institute for Health Research, Bradford Teaching Hospitals NHS Foundation Trust, Bradford, UK.

Background: Environmental exposures in early life influence the development of behavioral outcomes in children, but research has not considered multiple exposures. We therefore aimed to investigate the impact of a broad spectrum of pre- and postnatal environmental exposures on child behavior.

Methods And Findings: We used data from the HELIX (Human Early Life Exposome) project, which was based on six longitudinal population-based birth cohorts in Europe. At 6-11 years, children underwent a follow-up to characterize their exposures and assess behavioral problems. We measured 88 prenatal and 123 childhood environmental factors, including outdoor, indoor, chemical, lifestyle and social exposures. Parent-reported behavioral problems included (1) internalizing, (2) externalizing scores, using the child behavior checklist (CBCL), and (3) the Conner's Attention Deficit Hyperactivity Disorder (ADHD) index, all outcomes being discrete raw counts. We applied LASSO penalized negative binomial regression models to identify which exposures were associated with the outcomes, while adjusting for co-exposures. In the 1287 children (mean age 8.0 years), 7.3% had a neuropsychiatric medical diagnosis according to parent's reports. During pregnancy, smoking and car traffic showing the strongest associations (e.g. smoking with ADHD index, aMR:1.31 [1.09; 1.59]) among the 13 exposures selected by LASSO, for at least one of the outcomes. During childhood, longer sleep duration, healthy diet and higher family social capital were associated with reduced scores whereas higher exposure to lead, copper, indoor air pollution, unhealthy diet were associated with increased scores. Unexpected decreases in behavioral scores were found with polychlorinated biphenyls (PCBs) and organophosphate (OP) pesticides.

Conclusions: Our systematic exposome approach identified several environmental contaminants and healthy lifestyle habits that may influence behavioral problems in children. Modifying environmental exposures early in life may limit lifetime mental health risk.
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http://dx.doi.org/10.1016/j.envint.2021.106523DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8140407PMC
August 2021

MLIP genotype as a predictor of pharmacological response in primary open-angle glaucoma and ocular hypertension.

Sci Rep 2021 01 15;11(1):1583. Epub 2021 Jan 15.

Department of Surgery, School of Medicine and Health Sciences and Hospital Clinic de Barcelona (IDIBAPS), University of Barcelona, Calle Sabino de Arana 1 (2nd floor, Ophthalmology), 08028, Barcelona, Spain.

Predicting the therapeutic response to ocular hypotensive drugs is crucial for the clinical treatment and management of glaucoma. Our aim was to identify a possible genetic contribution to the response to current pharmacological treatments of choice in a white Mediterranean population with primary open-angle glaucoma (POAG) or ocular hypertension (OH). We conducted a prospective, controlled, randomized, partial crossover study that included 151 patients of both genders, aged 18 years and older, diagnosed with and requiring pharmacological treatment for POAG or OH in one or both eyes. We sought to identify copy number variants (CNVs) associated with differences in pharmacological response, using a DNA pooling strategy of carefully phenotyped treatment responders and non-responders, treated for a minimum of 6 weeks with a beta-blocker (timolol maleate) and/or prostaglandin analog (latanoprost). Diurnal intraocular pressure reduction and comparative genome wide CNVs were analyzed. Our finding that copy number alleles of an intronic portion of the MLIP gene is a predictor of pharmacological response to beta blockers and prostaglandin analogs could be used as a biomarker to guide first-tier POAG and OH treatment. Our finding improves understanding of the genetic factors modulating pharmacological response in POAG and OH, and represents an important contribution to the establishment of a personalized approach to the treatment of glaucoma.
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http://dx.doi.org/10.1038/s41598-020-80954-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7810753PMC
January 2021

DNA methylation signatures of aggression and closely related constructs: A meta-analysis of epigenome-wide studies across the lifespan.

Mol Psychiatry 2021 06 8;26(6):2148-2162. Epub 2021 Jan 8.

Department of Clinical Chemistry, Fimlab Laboratories, and Finnish Cardiovascular Research Center-Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, 33520, Finland.

DNA methylation profiles of aggressive behavior may capture lifetime cumulative effects of genetic, stochastic, and environmental influences associated with aggression. Here, we report the first large meta-analysis of epigenome-wide association studies (EWAS) of aggressive behavior (N = 15,324 participants). In peripheral blood samples of 14,434 participants from 18 cohorts with mean ages ranging from 7 to 68 years, 13 methylation sites were significantly associated with aggression (alpha = 1.2 × 10; Bonferroni correction). In cord blood samples of 2425 children from five cohorts with aggression assessed at mean ages ranging from 4 to 7 years, 83% of these sites showed the same direction of association with childhood aggression (r = 0.74, p = 0.006) but no epigenome-wide significant sites were found. Top-sites (48 at a false discovery rate of 5% in the peripheral blood meta-analysis or in a combined meta-analysis of peripheral blood and cord blood) have been associated with chemical exposures, smoking, cognition, metabolic traits, and genetic variation (mQTLs). Three genes whose expression levels were associated with top-sites were previously linked to schizophrenia and general risk tolerance. At six CpGs, DNA methylation variation in blood mirrors variation in the brain. On average 44% (range = 3-82%) of the aggression-methylation association was explained by current and former smoking and BMI. These findings point at loci that are sensitive to chemical exposures with potential implications for neuronal functions. We hope these results to be a starting point for studies leading to applications as peripheral biomarkers and to reveal causal relationships with aggression and related traits.
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http://dx.doi.org/10.1038/s41380-020-00987-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8263810PMC
June 2021

Urinary metabolite quantitative trait loci in children and their interaction with dietary factors.

Hum Mol Genet 2021 02;29(23):3830-3844

ISGlobal, Barcelona 08003, Spain.

Human metabolism is influenced by genetic and environmental factors. Previous studies have identified over 23 loci associated with more than 26 urine metabolites levels in adults, which are known as urinary metabolite quantitative trait loci (metabQTLs). The aim of the present study is the identification for the first time of urinary metabQTLs in children and their interaction with dietary patterns. Association between genome-wide genotyping data and 44 urine metabolite levels measured by proton nuclear magnetic resonance spectroscopy was tested in 996 children from the Human Early Life Exposome project. Twelve statistically significant urine metabQTLs were identified, involving 11 unique loci and 10 different metabolites. Comparison with previous findings in adults revealed that six metabQTLs were already known, and one had been described in serum and three were involved the same locus as other reported metabQTLs but had different urinary metabolites. The remaining two metabQTLs represent novel urine metabolite-locus associations, which are reported for the first time in this study [single nucleotide polymorphism (SNP) rs12575496 for taurine, and the missense SNP rs2274870 for 3-hydroxyisobutyrate]. Moreover, it was found that urinary taurine levels were affected by the combined action of genetic variation and dietary patterns of meat intake as well as by the interaction of this SNP with beverage intake dietary patterns. Overall, we identified 12 urinary metabQTLs in children, including two novel associations. While a substantial part of the identified loci affected urinary metabolite levels both in children and in adults, the metabQTL for taurine seemed to be specific to children and interacted with dietary patterns.
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http://dx.doi.org/10.1093/hmg/ddaa257DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7861015PMC
February 2021

MADloy: robust detection of mosaic loss of chromosome Y from genotype-array-intensity data.

BMC Bioinformatics 2020 Nov 23;21(1):533. Epub 2020 Nov 23.

Genetics Unit, Universitat Pompeu Fabra, Barcelona, Spain.

Background: Accurate protocols and methods to robustly detect the mosaic loss of chromosome Y (mLOY) are needed given its reported role in cancer, several age-related disorders and overall male mortality. Intensity SNP-array data have been used to infer mLOY status and to determine its prominent role in male disease. However, discrepancies of reported findings can be due to the uncertainty and variability of the methods used for mLOY detection and to the differences in the tissue-matrix used.

Results: We created a publicly available software tool called MADloy (Mosaic Alteration Detection for LOY) that incorporates existing methods and includes a new robust approach, allowing efficient calling in large studies and comparisons between methods. MADloy optimizes mLOY calling by correctly modeling the underlying reference population with no-mLOY status and incorporating B-deviation information. We observed improvements in the calling accuracy to previous methods, using experimentally validated samples, and an increment in the statistical power to detect associations with disease and mortality, using simulation studies and real dataset analyses. To understand discrepancies in mLOY detection across different tissues, we applied MADloy to detect the increment of mLOY cellularity in blood on 18 individuals after 3 years and to confirm that its detection in saliva was sub-optimal (41%). We additionally applied MADloy to detect the down-regulation genes in the chromosome Y in kidney and bladder tumors with mLOY, and to perform pathway analyses for the detection of mLOY in blood.

Conclusions: MADloy is a new software tool implemented in R for the easy and robust calling of mLOY status across different tissues aimed to facilitate its study in large epidemiological studies.
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http://dx.doi.org/10.1186/s12859-020-03768-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7682048PMC
November 2020

Identifying chromosomal subpopulations based on their recombination histories advances the study of the genetic basis of phenotypic traits.

Genome Res 2020 12 17;30(12):1802-1814. Epub 2020 Nov 17.

Instituto de Salud Global de Barcelona, Barcelona 08003, Spain.

Recombination is a main source of genetic variability. However, the potential role of the variation generated by recombination in phenotypic traits, including diseases, remains unexplored because there is currently no method to infer chromosomal subpopulations based on recombination pattern differences. We developed , a method that uses SNP-phased data to detect differences in historic recombination in a chromosome population. We validated our method by performing simulations and by using real data to accurately predict the alleles of well-known recombination modifiers, including common inversions in and human, and the chromosomes under selective pressure at the lactase locus in humans. We then applied to the complex human 1q21.1 region, where nonallelic homologous recombination produces deleterious phenotypes. We discovered and validated the presence of two different recombination histories in these regions that significantly associated with the differential expression of in whole blood and that were in high linkage with variants previously associated with hypertension. By detecting differences in historic recombination, our method opens a way to assess the influence of recombination variation in phenotypic traits.
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http://dx.doi.org/10.1101/gr.258301.119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7706724PMC
December 2020

Female-specific risk of Alzheimer's disease is associated with tau phosphorylation processes: A transcriptome-wide interaction analysis.

Neurobiol Aging 2020 12 2;96:104-108. Epub 2020 Sep 2.

Division of Noncommunicable Diseases, Instituto de Salud Global de Barcelona (ISGlobal), Barcelona, Spain; Centro de Investigación Biomédica en Red en Epidemiología y Salud Pública (CIBERESP), Madrid, Spain; Department of Mathematics, Universitat Autònoma de Barcelona, Barcelona, Spain.

The levels of tau phosphorylation differ between sexes in Alzheimer's disease (AD). Transcriptome-wide associations of sex by disease interaction could indicate whether specific genes underlie sex differences in tau pathology; however, no such study has been reported yet. We report the first analysis of the effect of the interaction between disease status and sex on differential gene expression, meta-analyzing transcriptomic data from the 3 largest publicly available case-control studies (N = 785) in the brain to date. A total of 128 genes, significantly associated with sex-AD interactions, were enriched in phosphoproteins (false discovery rate (FDR) = 0.001). High and consistent associations were found for the overexpressions of NCL (FDR = 0.002), whose phosphorylated protein generates an epitope against neurofibrillary tangles and KIF2A (FDR = 0.005), a microtubule-associated motor protein gene. Transcriptome-wide interaction analyses suggest sex-modulated tau phosphorylation, at sites like Thr231, Ser199, or Ser202 that could increase the risk of women to AD and indicate sex-specific strategies for intervention and prevention.
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http://dx.doi.org/10.1016/j.neurobiolaging.2020.08.020DOI Listing
December 2020

methylclock: a Bioconductor package to estimate DNA methylation age.

Bioinformatics 2021 07;37(12):1759-1760

Barcelona Research Institute for Global Health (ISGlobal), Barcelona, Spain.

Motivation: Ageing is a biological and psychosocial process related to diseases and mortality. It correlates with changes in DNA methylation (DNAm) in all human tissues. Therefore, epigenetic markers can be used to estimate biological age using DNAm profiling across tissues.

Results: We developed a Bioconductor package that allows computation of several existing DNAm adult/childhood and gestational age clocks. Functions to visualize the DNAm age prediction versus chronological age and the correlation between DNAm clocks are also available as well as other features, such as missing data imputation of cell types' estimates, that are required for DNAm age clocks.

Availability And Implementation: https://github.com/isglobal-brge/methylclock.

Supplementary Information: Supplementary data are available at Bioinformatics online.
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http://dx.doi.org/10.1093/bioinformatics/btaa825DOI Listing
July 2021

In utero and childhood exposure to tobacco smoke and multi-layer molecular signatures in children.

BMC Med 2020 08 19;18(1):243. Epub 2020 Aug 19.

ISGlobal, Barcelona, Spain.

Background: The adverse health effects of early life exposure to tobacco smoking have been widely reported. In spite of this, the underlying molecular mechanisms of in utero and postnatal exposure to tobacco smoke are only partially understood. Here, we aimed to identify multi-layer molecular signatures associated with exposure to tobacco smoke in these two exposure windows.

Methods: We investigated the associations of maternal smoking during pregnancy and childhood secondhand smoke (SHS) exposure with molecular features measured in 1203 European children (mean age 8.1 years) from the Human Early Life Exposome (HELIX) project. Molecular features, covering 4 layers, included blood DNA methylation and gene and miRNA transcription, plasma proteins, and sera and urinary metabolites.

Results: Maternal smoking during pregnancy was associated with DNA methylation changes at 18 loci in child blood. DNA methylation at 5 of these loci was related to expression of the nearby genes. However, the expression of these genes themselves was only weakly associated with maternal smoking. Conversely, childhood SHS was not associated with blood DNA methylation or transcription patterns, but with reduced levels of several serum metabolites and with increased plasma PAI1 (plasminogen activator inhibitor-1), a protein that inhibits fibrinolysis. Some of the in utero and childhood smoking-related molecular marks showed dose-response trends, with stronger effects with higher dose or longer duration of the exposure.

Conclusion: In this first study covering multi-layer molecular features, pregnancy and childhood exposure to tobacco smoke were associated with distinct molecular phenotypes in children. The persistent and dose-dependent changes in the methylome make CpGs good candidates to develop biomarkers of past exposure. Moreover, compared to methylation, the weak association of maternal smoking in pregnancy with gene expression suggests different reversal rates and a methylation-based memory to past exposures. Finally, certain metabolites and protein markers evidenced potential early biological effects of postnatal SHS, such as fibrinolysis.
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http://dx.doi.org/10.1186/s12916-020-01686-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7437049PMC
August 2020

Cadmium, Smoking, and Human Blood DNA Methylation Profiles in Adults from the Strong Heart Study.

Environ Health Perspect 2020 06 2;128(6):67005. Epub 2020 Jun 2.

Department of Environmental Health and Engineering, Johns Hopkins University, Baltimore, Maryland, USA.

Background: The epigenetic effects of individual environmental toxicants in tobacco remain largely unexplored. Cadmium (Cd) has been associated with smoking-related health effects, and its concentration in tobacco smoke is higher in comparison with other metals.

Objectives: We studied the association of Cd and smoking exposures with human blood DNA methylation (DNAm) profiles. We also evaluated the implication of findings to relevant methylation pathways and the potential contribution of Cd exposure from smoking to explain the association between smoking and site-specific DNAm.

Methods: We conducted an epigenome-wide association study of urine Cd and self-reported smoking (current and former vs. never, and cumulative smoking dose) with blood DNAm in 790,026 CpGs (methylation sites) measured with the Illumina Infinium Human MethylationEPIC (Illumina Inc.) platform in 2,325 adults 45-74 years of age who participated in the Strong Heart Study in 1989-1991. In a mediation analysis, we estimated the amount of change in DNAm associated with smoking that can be independently attributed to increases in urine Cd concentrations from smoking. We also conducted enrichment analyses and protein-protein interaction networks to explore the biological relevance of the findings.

Results: At a false discovery rate (FDR)-corrected level of 0.05, we found 6 differentially methylated positions (DMPs) for Cd; 288 and 17, respectively, for current and former smoking status; and 77 for cigarette pack-years. Enrichment analyses of these DMPs displayed enrichment of 58 and 6 Gene Ontology and Kyoto Encyclopedia of Genes and Genomes gene sets, respectively, including biological pathways for cancer and cardiovascular disease. In protein-to-protein networks, we observed key proteins in DNAm pathways directly and indirectly connected to Cd- and smoking-DMPs. Among DMPs that were significant for both Cd and current smoking (annotated to PRSS23, AHRR, F2RL3, RARA, and 2q37.1), we found statistically significant contributions of Cd to smoking-related DNAm.

Conclusions: Beyond replicating well-known smoking epigenetic signatures, we found novel DMPs related to smoking. Moreover, increases in smoking-related Cd exposure were associated with differential DNAm. Our integrative analysis supports a biological link for Cd and smoking-associated health effects, including the possibility that Cd is partly responsible for smoking toxicity through epigenetic changes. https://doi.org/10.1289/EHP6345.
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http://dx.doi.org/10.1289/EHP6345DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7265996PMC
June 2020

Polymorphic Inversions Underlie the Shared Genetic Susceptibility of Obesity-Related Diseases.

Am J Hum Genet 2020 06 28;106(6):846-858. Epub 2020 May 28.

IMIM (Hospital del Mar Research Institute), Barcelona 08003, Spain; Department of Experimental and Health Sciences (CEXS), Universitat Pompeu Fabra, Barcelona 08003, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona 08003, Spain; Women's and Children's Hospital, South Australian Health and Medical Research Institute & University of Adelaide, Adelaide, SA 5005, Australia.

The burden of several common diseases including obesity, diabetes, hypertension, asthma, and depression is increasing in most world populations. However, the mechanisms underlying the numerous epidemiological and genetic correlations among these disorders remain largely unknown. We investigated whether common polymorphic inversions underlie the shared genetic influence of these disorders. We performed an inversion association analysis including 21 inversions and 25 obesity-related traits on a total of 408,898 Europeans and validated the results in 67,299 independent individuals. Seven inversions were associated with multiple diseases while inversions at 8p23.1, 16p11.2, and 11q13.2 were strongly associated with the co-occurrence of obesity with other common diseases. Transcriptome analysis across numerous tissues revealed strong candidate genes for obesity-related traits. Analyses in human pancreatic islets indicated the potential mechanism of inversions in the susceptibility of diabetes by disrupting the cis-regulatory effect of SNPs from their target genes. Our data underscore the role of inversions as major genetic contributors to the joint susceptibility to common complex diseases.
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http://dx.doi.org/10.1016/j.ajhg.2020.04.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7273535PMC
June 2020

Genomic analysis of diet composition finds novel loci and associations with health and lifestyle.

Mol Psychiatry 2021 06 11;26(6):2056-2069. Epub 2020 May 11.

Department of Endocrinology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands.

We conducted genome-wide association studies (GWAS) of relative intake from the macronutrients fat, protein, carbohydrates, and sugar in over 235,000 individuals of European ancestries. We identified 21 unique, approximately independent lead SNPs. Fourteen lead SNPs are uniquely associated with one macronutrient at genome-wide significance (P < 5 × 10), while five of the 21 lead SNPs reach suggestive significance (P < 1 × 10) for at least one other macronutrient. While the phenotypes are genetically correlated, each phenotype carries a partially unique genetic architecture. Relative protein intake exhibits the strongest relationships with poor health, including positive genetic associations with obesity, type 2 diabetes, and heart disease (r ≈ 0.15-0.5). In contrast, relative carbohydrate and sugar intake have negative genetic correlations with waist circumference, waist-hip ratio, and neighborhood deprivation (|r| ≈ 0.1-0.3) and positive genetic correlations with physical activity (r ≈ 0.1 and 0.2). Relative fat intake has no consistent pattern of genetic correlations with poor health but has a negative genetic correlation with educational attainment (r ≈-0.1). Although our analyses do not allow us to draw causal conclusions, we find no evidence of negative health consequences associated with relative carbohydrate, sugar, or fat intake. However, our results are consistent with the hypothesis that relative protein intake plays a role in the etiology of metabolic dysfunction.
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http://dx.doi.org/10.1038/s41380-020-0697-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7767645PMC
June 2021

Using methylome data to inform exposome-health association studies: An application to the identification of environmental drivers of child body mass index.

Environ Int 2020 05 14;138:105622. Epub 2020 Mar 14.

Team of Environmental Epidemiology, IAB, Institute for Advanced Biosciences, Inserm, CNRS, CHU-Grenoble-Alpes, University Grenoble-Alpes, Grenoble, France. Electronic address:

Background: The exposome is defined as encompassing all environmental exposures one undergoes from conception onwards. Challenges of the application of this concept to environmental-health association studies include a possibly high false-positive rate.

Objectives: We aimed to reduce the dimension of the exposome using information from DNA methylation as a way to more efficiently characterize the relation between exposome and child body mass index (BMI).

Methods: Among 1,173 mother-child pairs from HELIX cohort, 216 exposures ("whole exposome") were characterized. BMI and DNA methylation from immune cells of peripheral blood were assessed in children at age 6-10 years. A priori reduction of the methylome to preselect BMI-relevant CpGs was performed using biological pathways. We then implemented a tailored Meet-in-the-Middle approach to identify from these CpGs candidate mediators in the exposome-BMI association, using univariate linear regression models corrected for multiple testing: this allowed to point out exposures most likely to be associated with BMI ("reduced exposome"). Associations of this reduced exposome with BMI were finally tested. The approach was compared to an agnostic exposome-wide association study (ExWAS) ignoring the methylome.

Results: Among the 2284 preselected CpGs (0.6% of the assessed CpGs), 62 were associated with BMI. Four factors (3 postnatal and 1 prenatal) of the exposome were associated with at least one of these CpGs, among which postnatal blood level of copper and PFOS were directly associated with BMI, with respectively positive and negative estimated effects. The agnostic ExWAS identified 18 additional postnatal exposures, including many persistent pollutants, generally unexpectedly associated with decreased BMI.

Discussion: Our approach incorporating a priori information identified fewer significant associations than an agnostic approach. We hypothesize that this smaller number corresponds to a higher specificity (and possibly lower sensitivity), compared to the agnostic approach. Indeed, the latter cannot distinguish causal relations from reverse causation, e.g. for persistent compounds stored in fat, whose circulating level is influenced by BMI.
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http://dx.doi.org/10.1016/j.envint.2020.105622DOI Listing
May 2020

Association of Fish Consumption and Mercury Exposure During Pregnancy With Metabolic Health and Inflammatory Biomarkers in Children.

JAMA Netw Open 2020 03 2;3(3):e201007. Epub 2020 Mar 2.

Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles.

Importance: The balance of mercury risk and nutritional benefit from fish intake during pregnancy for the metabolic health of offspring to date is unknown.

Objective: To assess the associations of fish intake and mercury exposure during pregnancy with metabolic syndrome in children and alterations in biomarkers of inflammation in children.

Design, Setting, And Participants: This population-based prospective birth cohort study used data from studies performed in 5 European countries (France, Greece, Norway, Spain, and the UK) between April 1, 2003, and February 26, 2016, as part of the Human Early Life Exposome (HELIX) project. Mothers and their singleton offspring were followed up until the children were aged 6 to 12 years. Data were analyzed between March 1 and August 2, 2019.

Exposures: Maternal fish intake during pregnancy (measured in times per week) was assessed using validated food frequency questionnaires, and maternal mercury concentration (measured in micrograms per liter) was assessed using maternal whole blood and cord blood samples.

Main Outcomes And Measures: An aggregate metabolic syndrome score for children was calculated using the z scores of waist circumference, systolic and diastolic blood pressures, and levels of triglyceride, high-density lipoprotein cholesterol, and insulin. A higher metabolic syndrome score (score range, -4.9 to 7.5) indicated a poorer metabolic profile. Three protein panels were used to measure several cytokines and adipokines in the plasma of children.

Results: The study included 805 mothers and their singleton children. Among mothers, the mean (SD) age at cohort inclusion or delivery of their infant was 31.3 (4.6) years. A total of 400 women (49.7%) had a high educational level, and 432 women (53.7%) were multiparous. Among children, the mean (SD) age was 8.4 (1.5) years (age range, 6-12 years). A total of 453 children (56.3%) were boys, and 734 children (91.2%) were of white race/ethnicity. Fish intake consistent with health recommendations (1 to 3 times per week) during pregnancy was associated with a 1-U decrease in metabolic syndrome score in children (β = -0.96; 95% CI, -1.49 to -0.42) compared with low fish consumption (<1 time per week) after adjusting for maternal mercury levels and other covariates. No further benefit was observed with fish intake of more than 3 times per week. A higher maternal mercury concentration was independently associated with an increase in the metabolic syndrome score of their offspring (β per 2-fold increase in mercury concentration = 0.18; 95% CI, 0.01-0.34). Compared with low fish intake, moderate and high fish intake during pregnancy were associated with reduced levels of proinflammatory cytokines and adipokines in children. An integrated analysis identified a cluster of children with increased susceptibility to metabolic disease, which was characterized by low fish consumption during pregnancy, high maternal mercury levels, decreased levels of adiponectin in children, and increased levels of leptin, tumor necrosis factor α, and the cytokines interleukin 6 and interleukin 1β in children.

Conclusions And Relevance: Results of this study suggest that moderate fish intake consistent with current health recommendations during pregnancy was associated with improvements in the metabolic health of children, while high maternal mercury exposure was associated with an unfavorable metabolic profile in children.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.1007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7076335PMC
March 2020

Association between the pregnancy exposome and fetal growth.

Int J Epidemiol 2020 04;49(2):572-586

Inserm, CNRS, University Grenoble Alpes, Team of Environmental Epidemiology Applied to Reproduction and Respiratory Health, IAB, Grenoble, France.

Background: Several environmental contaminants were shown to possibly influence fetal growth, generally from single exposure family studies, which are prone to publication bias and confounding by co-exposures. The exposome paradigm offers perspectives to avoid selective reporting of findings and to control for confounding by co-exposures. We aimed to characterize associations of fetal growth with the pregnancy chemical and external exposomes.

Methods: Within the Human Early-Life Exposome project, 131 prenatal exposures were assessed using biomarkers and environmental models in 1287 mother-child pairs from six European cohorts. We investigated their associations with fetal growth using a deletion-substitution-addition (DSA) algorithm considering all exposures simultaneously, and an exposome-wide association study (ExWAS) considering each exposure independently. We corrected for exposure measurement error and tested for exposure-exposure and sex-exposure interactions.

Results: The DSA model identified lead blood level, which was associated with a 97 g birth weight decrease for each doubling in lead concentration. No exposure passed the multiple testing-corrected significance threshold of ExWAS; without multiple testing correction, this model was in favour of negative associations of lead, fine particulate matter concentration and absorbance with birth weight, and of a positive sex-specific association of parabens with birth weight in boys. No two-way interaction between exposure variables was identified.

Conclusions: This first large-scale exposome study of fetal growth simultaneously considered >100 environmental exposures. Compared with single exposure studies, our approach allowed making all tests (usually reported in successive publications) explicit. Lead exposure is still a health concern in Europe and parabens health effects warrant further investigation.
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http://dx.doi.org/10.1093/ije/dyaa017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7266545PMC
April 2020

Extreme downregulation of chromosome Y and Alzheimer's disease in men.

Neurobiol Aging 2020 06 13;90:150.e1-150.e4. Epub 2020 Feb 13.

ISGlobal, Barcelona, Spain; Centro de Investigación Biomédica en Red en Epidemiología y Salud Pública (CIBERESP), Madrid, Spain; Department of Mathematics, Universitat Autònoma de Barcelona, Barcelona, Spain. Electronic address:

Research has revealed scarcely any biological factors of Alzheimer's disease (AD) that are specific to men. Here, we found that the extreme downregulation of chromosome Y (EDY) increases the age-related risk of AD in men. We considered that EDY was a possible male-specific pathway toward AD because EDY is the most likely consequence of the mosaic loss of chromosome Y, which has been recently associated with AD. We studied EDY in the undiseased brain of 371 individuals and observed that it co-occurred across multiple brain regions (p < 10) and associated with rs114241159 (p = 1.53 × 10) within ACSS3/PPFIA2, previously linked to amyloid beta concentrations. We also analyzed the 5 largest transcriptomic case-control studies, publicly available to date on AD (cases/controls = 556/462) and found a significant interaction with age (OR = 1.22, p = 0.0038). Our analyses suggest that aging men who live longer by avoiding EDY are more resilient to AD than those who do not.
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http://dx.doi.org/10.1016/j.neurobiolaging.2020.02.003DOI Listing
June 2020

Extreme Downregulation of Chromosome Y and Cancer Risk in Men.

J Natl Cancer Inst 2020 09;112(9):913-920

Barcelona Institute for Global Health (ISGlobal), Barcelona, Spain.

Background: Understanding the biological differences between sexes in cancer is essential for personalized treatment and prevention. We hypothesized that the extreme downregulation of chromosome Y gene expression (EDY) is a signature of cancer risk in men and the functional mediator of the reported association between the mosaic loss of chromosome Y (LOY) and cancer.

Methods: We advanced a method to measure EDY from transcriptomic data. We studied EDY across 47 nondiseased tissues from the Genotype Tissue-Expression Project (n = 371) and its association with cancer status across 12 cancer studies from The Cancer Genome Atlas (n = 1774) and seven other studies (n = 7562). Associations of EDY with cancer status and presence of loss-off function mutations in chromosome X were tested with logistic regression models, and a Fisher's test was used to assess genome-wide association of EDY with the proportion of copy number gains. All statistical tests were two-sided.

Results: EDY was likely to occur in multiple nondiseased tissues (P < .001) and was statistically significantly associated with the EGFR tyrosine kinase inhibitor resistance pathway (false discovery rate = 0.028). EDY strongly associated with cancer risk in men (odds ratio [OR] = 3.66, 95% confidence interval [CI] = 1.58 to 8.46, P = .002), adjusted by LOY and age, and its variability was largely explained by several genes of the nonrecombinant region whose chromosome X homologs showed loss-of-function mutations that co-occurred with EDY during cancer (OR = 2.82, 95% CI = 1.32 to 6.01, P = .007). EDY associated with a high proportion of EGFR amplifications (OR = 5.64, 95% CI = 3.70 to 8.59, false discovery rate < 0.001) and EGFR overexpression along with SRY hypomethylation and nonrecombinant region hypermethylation, indicating alternative causes of EDY in cancer other than LOY. EDY associations were independently validated for different cancers and exposure to smoking, and its status was accurately predicted from individual methylation patterns.

Conclusions: EDY is a male-specific signature of cancer susceptibility that supports the escape from X-inactivation tumor suppressor hypothesis for genes that protect women compared with men from cancer risk.
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http://dx.doi.org/10.1093/jnci/djz232DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7492764PMC
September 2020

Common polymorphic inversions at 17q21.31 and 8p23.1 associate with cancer prognosis.

Hum Genomics 2019 11 21;13(1):57. Epub 2019 Nov 21.

Barcelona Institute for Global Health, ISGlobal, Doctor Aiguader 88, 08003, Barcelona, Spain.

Background: Chromosomal inversions are structural genetic variants where a chromosome segment changes its orientation. While sporadic de novo inversions are known genetic risk factors for cancer susceptibility, it is unknown if common polymorphic inversions are also associated with the prognosis of common tumors, as they have been linked to other complex diseases. We studied the association of two well-characterized human inversions at 17q21.31 and 8p23.1 with the prognosis of lung, liver, breast, colorectal, and stomach cancers.

Results: Using data from The Cancer Genome Atlas (TCGA), we observed that inv8p23.1 was associated with overall survival in breast cancer and that inv17q21.31 was associated with overall survival in stomach cancer. In the meta-analysis of two independent studies, inv17q21.31 heterozygosity was significantly associated with colorectal disease-free survival. We found that the association was mediated by the de-methylation of cg08283464 and cg03999934, also linked to lower disease-free survival.

Conclusions: Our results suggest that chromosomal inversions are important genetic factors of tumor prognosis, likely affecting changes in methylation patterns.
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http://dx.doi.org/10.1186/s40246-019-0242-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6873427PMC
November 2019

scoreInvHap: Inversion genotyping for genome-wide association studies.

PLoS Genet 2019 07 3;15(7):e1008203. Epub 2019 Jul 3.

ISGlobal, Centre for Research in Environmental Epidemiology (CREAL), Barcelona, Spain.

Polymorphic inversions contribute to adaptation and phenotypic variation. However, large multi-centric association studies of inversions remain challenging. We present scoreInvHap, a method to genotype inversions from SNP data for genome-wide association studies (GWASs), overcoming important limitations of current methods and outperforming them in accuracy and applicability. scoreInvHap calls individual inversion-genotypes from a similarity score to the SNPs of experimentally validated references. It can be used on different sources of SNP data, including those with low SNP coverage such as exome sequencing, and is easily adaptable to genotype new inversions, either in humans or in other species. We present 20 human inversions that can be reliably and easily genotyped with scoreInvHap to discover their role in complex human traits, and illustrate a first genome-wide association study of experimentally-validated human inversions. scoreInvHap is implemented in R and it is freely available from Bioconductor.
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http://dx.doi.org/10.1371/journal.pgen.1008203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6608898PMC
July 2019

Comprehensive study of the exposome and omic data using rexposome Bioconductor Packages.

Bioinformatics 2019 12;35(24):5344-5345

ISGlobal, Centre for Research in Environmental Epidemiology (CREAL), Barcelona, Spain.

Summary: Genomics has dramatically improved our understanding of the molecular origins of certain human diseases. Nonetheless, our health is also influenced by the cumulative impact of exposures experienced across the life course (termed 'exposome'). The study of the high-dimensional exposome offers a new paradigm for investigating environmental contributions to disease etiology. However, there is a lack of bioinformatics tools for managing, visualizing and analyzing the exposome. The analysis data should include both association with health outcomes and integration with omic layers. We provide a generic framework called rexposome project, developed in the R/Bioconductor architecture that includes object-oriented classes and methods to leverage high-dimensional exposome data in disease association studies including its integration with a variety of high-throughput data types. The usefulness of the package is illustrated by analyzing a real dataset including exposome data, three health outcomes related to respiratory diseases and its integration with the transcriptome and methylome.

Availability And Implementation: rexposome project is available at https://isglobal-brge.github.io/rexposome/.

Supplementary Information: Supplementary data are available at Bioinformatics online.
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http://dx.doi.org/10.1093/bioinformatics/btz526DOI Listing
December 2019

Independent Multiple Factor Association Analysis for Multiblock Data in Imaging Genetics.

Neuroinformatics 2019 10;17(4):583-592

Barcelona Institute for Global Health (ISGlobal), Barcelona, Spain.

Multivariate methods have the potential to better capture complex relationships that may exist between different biological levels. Multiple Factor Analysis (MFA) is one of the most popular methods to obtain factor scores and measures of discrepancy between data sets. However, singular value decomposition in MFA is based on PCA, which is adequate only if the data is normally distributed, linear or stationary. In addition, including strongly correlated variables can overemphasize the contribution of the estimated components. In this work, we introduced a novel method referred as Independent Multifactorial Analysis (ICA-MFA) to derive relevant features from multiscale data. This method is an extended implementation of MFA, where the component value decomposition is based on Independent Component Analysis. In addition, ICA-MFA incorporates a predictive step based on an Independent Component Regression. We evaluated and compared the performance of ICA-MFA with both, the MFA method and traditional univariate analyses, in a simulation study. We showed how ICA-MFA explained up to 10-fold more variance than MFA and univariate methods. We applied the proposed algorithm in a study of 4057 individuals belonging to the population-based Rotterdam Study with available genetic and neuroimaging data, as well as information about executive cognitive functioning. Specifically, we used ICA-MFA to detect relevant genetic features related to structural brain regions, which in turn were involved, in the mechanisms of executive cognitive function. The proposed strategy makes it possible to determine the degree to which the whole set of genetic and/or neuroimaging markers contribute to the variability of the symptomatology jointly, rather than individually. While univariate results and MFA combinations only explained a limited proportion of variance (less than 2%), our method increased the explained variance (10%) and allowed the identification of significant components that maximize the variance explained in the model. The potential application of the ICA-MFA algorithm constitutes an important aspect of integrating multivariate multiscale data, specifically in the field of Neurogenetics.
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http://dx.doi.org/10.1007/s12021-019-09416-zDOI Listing
October 2019

Genome-wide association analyses of risk tolerance and risky behaviors in over 1 million individuals identify hundreds of loci and shared genetic influences.

Nat Genet 2019 02 14;51(2):245-257. Epub 2019 Jan 14.

Team Loyalty BV, Hoofddorp, the Netherlands.

Humans vary substantially in their willingness to take risks. In a combined sample of over 1 million individuals, we conducted genome-wide association studies (GWAS) of general risk tolerance, adventurousness, and risky behaviors in the driving, drinking, smoking, and sexual domains. Across all GWAS, we identified hundreds of associated loci, including 99 loci associated with general risk tolerance. We report evidence of substantial shared genetic influences across risk tolerance and the risky behaviors: 46 of the 99 general risk tolerance loci contain a lead SNP for at least one of our other GWAS, and general risk tolerance is genetically correlated ([Formula: see text] ~ 0.25 to 0.50) with a range of risky behaviors. Bioinformatics analyses imply that genes near SNPs associated with general risk tolerance are highly expressed in brain tissues and point to a role for glutamatergic and GABAergic neurotransmission. We found no evidence of enrichment for genes previously hypothesized to relate to risk tolerance.
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http://dx.doi.org/10.1038/s41588-018-0309-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6713272PMC
February 2019

A measure of agreement across numerous conditions: assessing when changes in network structures are tissue-specific.

BMC Genomics 2019 Jan 9;20(1):26. Epub 2019 Jan 9.

ISGlobal, Doctor Aiguader, Barcelona, 08003, Spain.

Background: There is great interest to study how gene pathways change their structure across different tissues. The assessment of inter-study reliability of pathway changes across tissues can inform on the fraction of tissues with specific functional changes in network structure. However, there is a lack of agreement measures among studies that independently observe how a group of observations change across conditions. We, therefore, propose λ, a new inter-study reliability measure that determines the consistency to distinguish observations by condition.

Results: We derived λ's distributional characteristics, determine its reliability properties and compared it with Cohen's κ. We studied the co-expression structure of 287 gene pathways across four brain regions in two transcriptomic studies and applied λ to assess the inter-study reliability of the pathways' brain-regional changes. Brain-related pathways showed highest λ; the top value was for the nicotine addiction pathway whose structure was reliably distinguishable among regions with dopaminergic projections.

Conclusion: Our results offer novel substantial evidence that changes in network structure across tissues can be inferred independently of samples, algorithms and experiments (RNA-sequencing or microarrays). Reliability measures, such as λ, can inform on the tissues where changes in a network's structure are likely functional. An R package is available at https://github.com/isglobal-brge/lambda .
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http://dx.doi.org/10.1186/s12864-018-5340-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6327576PMC
January 2019

When pitch adds to volume: coregulation of transcript diversity predicts gene function.

BMC Genomics 2018 Dec 13;19(1):926. Epub 2018 Dec 13.

ISGlobal, 08003, Barcelona, Spain.

Background: Genes corregulate their overall transcript volumes to perform their physiological functions. However, it is unknown if they additionally coregulate their transcript diversities. We studied the reliability, consistency and functional associations of co-splicing correlations of genes of interest, across two independent studies, multiple tissues and two statistical methods. We thoroughly investigated the reproducibility of co-splicing correlations of APP, the candidate gene of Azheimer's disease (AD). We then studied how co-splicing correlations in different tissues contributed to predict functional interactions of three other genes and finally computed co-splicing frequency for 17 thousand genes across 52 human tissues.

Results: We replicated co-splicing correlations between APP and 5 AD-related genes and reproduced expected enrichment of APP co-splicing in synaptic vesicle cycle and proteosome pathways. We observed novel associations for tissue vulnerability to disease with enrichment in APP co-splicing, co-expression and epistasis in AD. APP co-splicing was the strongest predictor and replicated between studies. We confirmed known gene interactions of PRPF8 and GRIA1 in testis and brain cortex, and observed a novel interaction of FGFR2, in breast and prostate, modulated by cancer risk-variants. We produced a co-splicing map across 52 human tissues to help predict the function of over 17 thousand genes.

Conclusions: We show that coregulation of transcript diversities provides novel biological insights in gene physiology and helps to interpret GWAS results. Co-splicing correlations are reliable and frequent and should be further pursued to help predict gene function. Our results additionally support current AD interventions aiming at the ubiquitin proteosome pathway but unveil the need to consider transcript diversity in addition to volume to assess treatment response and susceptibility to the disease.
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http://dx.doi.org/10.1186/s12864-018-5263-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6293560PMC
December 2018
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