Biology subjects

Nicolae, D. L.

Publications and source records attributed to Nicolae, D. L..

6 recordsLinked to original sources

bioRxiv2018

Shared and distinct genetic risk factors for childhood onset and adult onset asthma

BackgroundChildhood and adult onset asthma differ with respect to severity and co-morbidities. Whether they also differ with respect to genetic risk factors has not been previously investigated.\n\nMethodsWe used data from the UK Biobank to conduct genome-wide association studies (GWASs) in 9,433 childhood onset asthma (onset before age 12) and 21,564 adult onset asthma (onset between ages 26 and 65) cases, each compared to 318,237 non-asthmatic controls (older than age 38), and for age of onset in 37,846 asthma cases. Enrichment studies determined the tissues in which genes at GWAS loci were most highly expressed, and PrediXcan, a transcriptome-wide gene-based test, was used to identify candidate risk genes.\n\nFindingsWe detected 61 independent asthma loci: 23 were childhood onset specific, one was adult onset specific, and 37 were shared. Nineteen loci were associated with age of asthma onset. Genes at the childhood onset loci were most highly expressed in skin, blood and small intestine; genes at the adult onset loci were most highly expressed in lung, blood, small intestine and spleen. PrediXcan identified 113 unique candidate genes at 22 of the 61 GWAS loci.\n\nInterpretationGenetic risk factors for adult onset asthma are largely a subset of the genetic risk for childhood onset asthma but with overall smaller effects, suggesting a greater role for non-genetic risk factors in adult onset asthma. In contrast, the onset of disease in childhood is associated with additional genes with relatively large effect sizes. Combined with gene expression and tissue enrichment patterns, we suggest that the establishment of disease in children is driven more by allergy and epithelial barrier dysfunction whereas the etiology of adult onset asthma is more lung-centered, with immune mediated pathways driving disease progression in both children and adults.\n\nFundingThis work was supported by the National Institutes of Health grants R01 MH107666 and P30 DK20595 to H.K.I., R01 HL129735, R01 HL122712, P01 HL070831, and UG3 OD023282 to C.O.; N.S. was supported by T32 HL007605.

genetics↗

bioRxiv2018

Parent of origin gene expression in a founder population identifies two new imprinted genes at known imprinted regions

Genomic imprinting is the phenomena that leads to silencing of one copy of a gene inherited from a specific parent. Mutations in imprinted regions have been involved in diseases showing parent of origin effects. Identifying genes with evidence of parent of origin expression patterns in family studies allows the detection of more subtle imprinting. Here, we use allele specific expression in lymphoblastoid cell lines from 306 Hutterites related in a single pedigree to provide formal evidence for parent of origin effects. We take advantage of phased genotype data to assign parent of origin to RNA-seq reads in individuals with gene expression data. Our approach identified known imprinted genes, two putative novel imprinted genes, and 14 genes with asymmetrical parent of origin gene expression. We used gene expression in peripheral blood leukocytes (PBL) to validate our findings, and then confirmed imprinting control regions (ICRs) using DNA methylation levels in the PBLs.\n\nAuthor SummaryLarge scale gene expression studies have identified known and novel imprinted genes through allele specific expression without knowing the parental origins of each allele. Here, we take advantage of phased genotype data to assign parent of origin to RNA-seq reads in 306 individuals with gene expression data. We identified known imprinted genes as well as two novel imprinted genes in lymphoblastoid cell line gene expression. We used gene expression in PBLs to validate our findings, and DNA methylation levels in PBLs to confirm previously characterized imprinting control regions that could regulate these imprinted genes.

genetics↗

bioRxiv2018

Integrating Predicted Transcriptome From Multiple Tissues Improves Association Detection

Integration of genome-wide association studies (GWAS) and expression quantitative trait loci (eQTL) studies is needed to improve our understanding of the biological mechanisms underlying GWAS hits, and our ability to identify therapeutic targets. Gene-level association test methods such as PrediXcan can prioritize candidate targets. However, limited eQTL sample sizes and absence of relevant developmental and disease context restricts our ability to detect associations. Here we propose an efficient statistical method that leverages the substantial sharing of eQTLs across tissues and contexts to improve our ability to identify potential target genes: MulTiXcan. MulTiXcan integrates evidence across multiple panels while taking into account their correlation. We apply our method to a broad set of complex traits available from the UK Biobank and show that we can detect a larger set of significantly associated genes than using each panel separately. To improve applicability, we developed an extension to work on summary statistics: S-MulTiXcan, which we show yields highly concordant results with the individual level version. Results from our analysis as well as software and necessary resources to apply our method are publicly available.

genomics↗

bioRxiv2017

Gene co-expression networks in whole blood implicate multiple interrelated molecular pathways in obese asthma

BackgroundAsthmatic children who develop obesity have poorer outcomes compared to those that do not, including poorer control, more severe symptoms, and greater resistance to standard treatment. Gene expression networks are powerful statistical tools for characterizing the underpinnings of human disease that leverage the putative co-regulatory relationships of genes to infer biological pathways altered in disease states.\n\nObjectiveThe aim of this study was to characterize the biology of childhood asthma complicated by adult obesity.\n\nMethodsWe performed weighted gene co-expression network analysis (WGCNA) of gene expression data in whole blood from 514 adult subjects from the Childhood Asthma Management Program (CAMP). We then performed module preservation and association replication analyses in 418 subjects from two independent asthma cohorts (one pediatric and one adult).\n\nResultsWe identified a multivariate model in which four gene co-expression network modules were associated with incident obesity in CAMP (each P < 0.05). The module memberships were enriched for genes in pathways related to platelets, integrins, extracellular matrix, smooth muscle, NF-{kappa}B signaling, and Hedgehog signaling. The network structures of each of the four obese asthma modules were significantly preserved in both replication cohorts (permutation P = 9.999E-05). The corresponding module gene sets were significantly enriched for differential expression in obese subjects in both replication cohorts (each P < 0.05).\n\nConclusionsOur gene co-expression network profiles thus implicate multiple interrelated pathways in the biology of an important endotype of obese asthma.\n\nKey MessagesO_LIWe hypothesized that individuals with asthma complicated by obesity had distinct blood gene expression signatures.\nC_LIO_LIGene co-expression network analysis implicated several inflammatory biological pathways in one form of obese asthma.\nC_LI\n\nCapsule SummaryThis work addresses a knowledge gap about the molecular relationship between asthma and obesity, suggesting that an endotype of obese asthma, known as asthma complicated by obesity, is underpinned by coherent biological mechanisms.\n\nAbbreviations

genomics↗

bioRxiv2017

Parent of Origin Effects on Quantitative Phenotypes in a Founder Population

The impact of the parental origin of associated alleles in GWAS has been largely ignored. Yet sequence variants could affect traits differently depending on whether they are inherited from the mother or the father. To explore this possibility, we studied 21 quantitative phenotypes in a large Hutterite pedigree. We first identified variants with significant single parent (maternal-only or paternal-only) effects, and then used a novel statistical model to identify variants with opposite parental effects. Overall, we identified parent of origin effects (POEs) on 11 phenotypes, most of which are risk factors for cardiovascular disease. Many of the loci with POEs have features of imprinted regions and many of the variants with POE are associated with the expression of nearby genes. Overall, our results indicate that POEs, which are often opposite in direction, are relatively common in humans, have potentially important clinical effects, and will be missed in traditional GWAS.

genetics↗

bioRxiv2017

Genome-wide association study of asthma in individuals of African ancestry reveals novel asthma susceptibility loci

BACKGROUNDAsthma is a complex disease with striking disparities across racial and ethnic groups, which may be partly attributable to genetic factors. One of the main goals of the Consortium on Asthma among African-ancestry Populations in the Americas (CAAPA) is to discover genes conferring risk to asthma in populations of African descent.\n\nMETHODSWe performed a genome-wide meta-analysis of asthma across 11 CAAPA datasets (4,827 asthma cases and 5,397 controls), genotyped on the African Diaspora Power Chip (ADPC) and including existing GWAS array data. The genotype data were imputed up to a whole genome sequence reference panel from n=880 African ancestry individuals for a total of 61,904,576 SNPs. Statistical models appropriate to each study design were used to test for association, and results were combined using the weighted Z-score method. We also used admixture mapping as a complementary approach to identify loci involved in asthma pathogenesis in subjects of African ancestry.\n\nRESULTSSNPs rs787160 and rs17834780 on chromosome 2q22.3 were significantly associated with asthma (p=6.57 x 10-9 and 2.97 x 10-8, respectively). These SNPs lie in the intergenic region between the Rho GTPase Activating Protein 15 (ARHGAP15) and Glycosyltransferase Like Domain Containing 1 (GTDC1) genes. Four low frequency variants on chromosome 1q21.3, which may be involved in the \"atopic march\" and which are not polymorphic in Europeans, also showed evidence for association with asthma (1.18 x10-6 [≤] p [≤] 3.06 x10-6). SNP rs11264909 on chromosome 1q23.1, close to a region previously identified by the EVE asthma meta-analysis as having a putative African ancestry specific effect, only showed differences in counts in subjects homozygous for alleles of African ancestry. Admixture mapping also identified a significantly associated region on chromosome 6q23.2, which includes the Transcription Factor 21 (TCF21) gene, previously shown to be differentially expressed in bronchial tissues of asthmatics and non-asthmatics.\n\nCONCLUSIONSWe have identified a number of novel asthma association signals warranting further investigation.

bioinformatics↗