ORCID Profile
0000-0003-1789-1893
Current Organisation
Imperial College London
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Publisher: Springer Science and Business Media LLC
Date: 05-06-2012
Publisher: Cold Spring Harbor Laboratory
Date: 09-04-2013
Abstract: Nearly three-quarters of the 143 genetic signals associated with platelet and erythrocyte phenotypes identified by meta-analyses of genome-wide association (GWA) studies are located at non-protein-coding regions. Here, we assessed the role of candidate regulatory variants associated with cell type–restricted, closely related hematological quantitative traits in biologically relevant hematopoietic cell types. We used formaldehyde-assisted isolation of regulatory elements followed by next-generation sequencing (FAIRE-seq) to map regions of open chromatin in three primary human blood cells of the myeloid lineage. In the precursors of platelets and erythrocytes, as well as in monocytes, we found that open chromatin signatures reflect the corresponding hematopoietic lineages of the studied cell types and associate with the cell type–specific gene expression patterns. Dependent on their signal strength, open chromatin regions showed correlation with promoter and enhancer histone marks, distance to the transcription start site, and ontology classes of nearby genes. Cell type–restricted regions of open chromatin were enriched in sequence variants associated with hematological indices. The majority (63.6%) of such candidate functional variants at platelet quantitative trait loci (QTLs) coincided with binding sites of five transcription factors key in regulating megakaryopoiesis. We experimentally tested 13 candidate regulatory variants at 10 platelet QTLs and found that 10 (76.9%) affected protein binding, suggesting that this is a frequent mechanism by which regulatory variants influence quantitative trait levels. Our findings demonstrate that combining large-scale GWA data with open chromatin profiles of relevant cell types can be a powerful means of dissecting the genetic architecture of closely related quantitative traits.
Publisher: Springer Science and Business Media LLC
Date: 12-2012
DOI: 10.1038/NATURE11677
Publisher: Public Library of Science (PLoS)
Date: 18-09-2014
Publisher: Elsevier BV
Date: 08-2013
Publisher: Springer Science and Business Media LLC
Date: 06-04-2016
DOI: 10.1038/NCOMMS11008
Abstract: Myopia is the most common human eye disorder and it results from complex genetic and environmental causes. The rapidly increasing prevalence of myopia poses a major public health challenge. Here, the CREAM consortium performs a joint meta-analysis to test single-nucleotide polymorphism (SNP) main effects and SNP × education interaction effects on refractive error in 40,036 adults from 25 studies of European ancestry and 10,315 adults from 9 studies of Asian ancestry. In European ancestry in iduals, we identify six novel loci ( FAM150B-ACP1 , LINC00340 , FBN1 , DIS3L-MAP2K1 , ARID2-SNAT1 and SLC14A2 ) associated with refractive error. In Asian populations, three genome-wide significant loci AREG , GABRR1 and PDE10A also exhibit strong interactions with education ( P .5 × 10 −5 ), whereas the interactions are less evident in Europeans. The discovery of these loci represents an important advance in understanding how gene and environment interactions contribute to the heterogeneity of myopia.
Publisher: Oxford University Press (OUP)
Date: 07-03-2013
DOI: 10.1093/HMG/DDT116
Publisher: Springer Science and Business Media LLC
Date: 04-11-2014
Publisher: Oxford University Press (OUP)
Date: 09-03-2018
DOI: 10.1093/IJE/DYY031
Publisher: F1000 Research Ltd
Date: 06-2020
DOI: 10.12688/WELLCOMEOPENRES.15846.1
Abstract: Background: Lung function is highly heritable and differs between the sexes throughout life. However, little is known about sex-differential genetic effects on lung function. We aimed to conduct the first genome-wide genotype-by-sex interaction study on lung function to identify genetic effects that differ between males and females. Methods: We tested for interactions between 7,745,864 variants and sex on spirometry-based measures of lung function in UK Biobank (N=303,612), and sought replication in 75,696 independent in iduals from the SpiroMeta consortium. Results: Five independent single-nucleotide polymorphisms (SNPs) showed genome-wide significant (P x10 -8 ) interactions with sex on lung function, and 21 showed suggestive interactions (P x10 -6 ). The strongest signal, from rs7697189 (chr4:145436894) on forced expiratory volume in 1 second (FEV 1 ) (P=3.15x10 -15 ), was replicated (P=0.016) in SpiroMeta. The C allele increased FEV 1 more in males (untransformed FEV 1 β=0.028 [SE 0.0022] litres) than females (β=0.009 [SE 0.0014] litres), and this effect was not accounted for by differential effects on height, smoking or pubertal age. rs7697189 resides upstream of the hedgehog-interacting protein ( HHIP ) gene and was previously associated with lung function and HHIP lung expression. We found HHIP expression was significantly different between the sexes (P=6.90x10 -6 ), but we could not detect sex differential effects of rs7697189 on expression. Conclusions: We identified a novel genotype-by-sex interaction at a putative enhancer region upstream of the HHIP gene. Establishing the mechanism by which HHIP SNPs have different effects on lung function in males and females will be important for our understanding of lung health and diseases in both sexes.
Publisher: Springer Science and Business Media LLC
Date: 10-02-2013
DOI: 10.1038/NG.2554
Publisher: F1000 Research Ltd
Date: 24-05-2021
DOI: 10.12688/WELLCOMEOPENRES.15846.2
Abstract: Background: Lung function is highly heritable and differs between the sexes throughout life. However, little is known about sex-differential genetic effects on lung function. We aimed to conduct the first genome-wide genotype-by-sex interaction study on lung function to identify genetic effects that differ between males and females. Methods: We tested for interactions between 7,745,864 variants and sex on spirometry-based measures of lung function in UK Biobank (N=303,612), and sought replication in 75,696 independent in iduals from the SpiroMeta consortium. Results: Five independent single-nucleotide polymorphisms (SNPs) showed genome-wide significant (P x10 -8 ) interactions with sex on lung function, and 21 showed suggestive interactions (P x10 -6 ). The strongest signal, from rs7697189 (chr4:145436894) on forced expiratory volume in 1 second (FEV 1 ) (P=3.15x10 -15 ), was replicated (P=0.016) in SpiroMeta. The C allele increased FEV 1 more in males (untransformed FEV 1 β=0.028 [SE 0.0022] litres) than females (β=0.009 [SE 0.0014] litres), and this effect was not accounted for by differential effects on height, smoking or pubertal age. rs7697189 resides upstream of the hedgehog-interacting protein ( HHIP ) gene and was previously associated with lung function and HHIP lung expression. We found HHIP expression was significantly different between the sexes (P=6.90x10 -6 ), but we could not detect sex differential effects of rs7697189 on expression. Conclusions: We identified a novel genotype-by-sex interaction at a putative enhancer region upstream of the HHIP gene. Establishing the mechanism by which HHIP SNPs have different effects on lung function in males and females will be important for our understanding of lung health and diseases in both sexes.
Publisher: Springer Science and Business Media LLC
Date: 11-02-2015
DOI: 10.1038/NATURE14177
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-12-2016
Abstract: Parathyroid hormone (PTH) is a primary calcium regulatory hormone. Elevated serum PTH concentrations in primary and secondary hyperparathyroidism have been associated with bone disease, hypertension, and in some studies, cardiovascular mortality. Genetic causes of variation in circulating PTH concentrations are incompletely understood. We performed a genome-wide association study of serum PTH concentrations among 29,155 participants of European ancestry from 13 cohort studies ( n =22,653 and n =6502 in discovery and replication analyses, respectively). We evaluated the association of single nucleotide polymorphisms (SNPs) with natural log-transformed PTH concentration adjusted for age, sex, season, study site, and principal components of ancestry. We discovered associations of SNPs from five independent regions with serum PTH concentration, including the strongest association with rs6127099 upstream of CYP24A1 ( P =4.2 × 10 −53 ), a gene that encodes the primary catabolic enzyme for 1,25-dihydroxyvitamin D and 25-dihydroxyvitamin D. Each additional copy of the minor allele at this SNP associated with 7% higher serum PTH concentration. The other SNPs associated with serum PTH concentration included rs4074995 within RGS14 ( P =6.6 × 10 −17 ), rs219779 adjacent to CLDN14 ( P =3.5 × 10 −16 ), rs4443100 near RTDR1 ( P =8.7 × 10 −9 ), and rs73186030 near CASR ( P =4.8 × 10 −8 ). Of these five SNPs, rs6127099, rs4074995, and rs219779 replicated. Thus, common genetic variants located near genes involved in vitamin D metabolism and calcium and renal phosphate transport associated with differences in circulating PTH concentrations. Future studies could identify the causal variants at these loci, and the clinical and functional relevance of these variants should be pursued.
Publisher: Springer Science and Business Media LLC
Date: 23-12-2012
DOI: 10.1038/NG.2500
Publisher: Springer Science and Business Media LLC
Date: 11-02-2015
DOI: 10.1038/NATURE14132
Publisher: Elsevier BV
Date: 11-2018
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Laura Portas.