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1. Large-scale cis- and trans-eQTL analyses identify thousands of genetic loci and polygenic scores that regulate blood gene expression

Author

Vosa, U. (Urmo), Claringbould, A. (Annique), Westra, H.-J. (Harm-Jan), Bonder, M. J. (Marc Jan), Deelen, P. (Patrick), Zeng, B. (Biao), Kirsten, H. (Holger), Saha, A. (Ashis), Kreuzhuber, R. (Roman), Yazar, S. (Seyhan), Brugge, H. (Harm), Oelen, R. (Roy), de Vries, D. H. (Dylan H.), van der Wijst, M. G. (Monique G. P.), Kasela, S. (Silva), Pervjakova, N. (Natalia), Alves, I. (Isabel), Fave, M.-J. (Marie-Julie), Agbessi, M. (Mawusse), Christiansen, M. W. (Mark W.), Jansen, R. (Rick), Seppala, I. (Ilkka), Tong, L. (Lin), Teumer, A. (Alexander), Schramm, K. (Katharina), Hemani, G. (Gibran), Verlouw, J. (Joost), Yaghootkar, H. (Hanieh), Flitman, R. S. (Reyhan Sonmez), Brown, A. (Andrew), Kukushkina, V. (Viktorija), Kalnapenkis, A. (Anette), Rueger, S. (Sina), Porcu, E. (Eleonora), Kronberg, J. (Jaanika), Kettunen, J. (Johannes), Lee, B. (Bernett), Zhang, F. (Futao), Qi, T. (Ting), Hernandez, J. A. (Jose Alquicira), Arindrarto, W. (Wibowo), Beutner, F. (Frank), Dmitrieva, J. (Julia), Elansary, M. (Mahmoud), Fairfax, B. P. (Benjamin P.), Georges, M. (Michel), Heijmans, B. T. (Bastiaan T.), Hewitt, A. W. (Alex W.), Kahonen, M. (Mika), Kim, Y. (Yungil), Knight, J. C. (Julian C.), Kovacs, P. (Peter), Krohn, K. (Knut), Li, S. (Shuang), Loeffler, M. (Markus), Marigorta, U. M. (Urko M.), Mei, H. (Hailang), Momozawa, Y. (Yukihide), Mueller-Nurasyid, M. (Martina), Nauck, M. (Matthias), Nivard, M. G. (Michel G.), Penninx, B. W. (Brenda W. J. H.), Pritchard, J. K. (Jonathan K.), Raitakari, O. T. (Olli T.), Rotzschke, O. (Olaf), Slagboom, E. P. (Eline P.), Stehouwer, C. D. (Coen D. A.), Stumvoll, M. (Michael), Sullivan, P. (Patrick), Thiery, J. (Joachim), Tonjes, A. (Anke), van Dongen, J. (Jenny), van Iterson, M. (Maarten), Veldink, J. H. (Jan H.), Voelker, U. (Uwe), Warmerdam, R. (Robert), Wijmenga, C. (Cisca), Swertz, M. (Morris), Andiappan, A. (Anand), Montgomery, G. W. (Grant W.), Ripatti, S. (Samuli), Perola, M. (Markus), Kutalik, Z. (Zoltan), Dermitzakis, E. (Emmanouil), Bergmann, S. (Sven), Frayling, T. (Timothy), van Meurs, J. (Joyce), Prokisch, H. (Holger), Ahsan, H. (Habibul), Pierce, B. L. (Brandon L.), Lehtimaki, T. (Terho), Boomsma, D. I. (Dorret, I), Psaty, B. M. (Bruce M.), Gharib, S. A. (Sina A.), Awadalla, P. (Philip), Milani, L. (Lili), Ouwehand, W. H. (Willem H.), Downes, K. (Kate), Stegle, O. (Oliver), Battle, A. (Alexis), Visscher, P. M. (Peter M.), Yang, J. (Jian), Scholz, M. (Markus), Powell, J. (Joseph), Gibson, G. (Greg), Esko, T. (Tonu), and Franke, L. (Lude)

Abstract

Trait-associated genetic variants affect complex phenotypes primarily via regulatory mechanisms on the transcriptome. To investigate the genetics of gene expression, we performed cis- and trans-expression quantitative trait locus (eQTL) analyses using blood-derived expression from 31,684 individuals through the eQTLGen Consortium. We detected cis-eQTL for 88% of genes, and these were replicable in numerous tissues. Distal trans-eQTL (detected for 37% of 10,317 trait-associated variants tested) showed lower replication rates, partially due to low replication power and confounding by cell type composition. However, replication analyses in single-cell RNA-seq data prioritized intracellular trans-eQTL. Trans-eQTL exerted their effects via several mechanisms, primarily through regulation by transcription factors. Expression of 13% of the genes correlated with polygenic scores for 1,263 phenotypes, pinpointing potential drivers for those traits. In summary, this work represents a large eQTL resource, and its results serve as a starting point for in-depth interpretation of complex phenotypes.

Published
2021

2. Rare and low-frequency exonic variants and gene-by-smoking interactions in pulmonary function

Author

Yang, T. (Tianzhong), Jackson, V. E. (Victoria E.), Smith, A. V. (Albert V.), Chen, H. (Han), Bartz, T. M. (Traci M.), Sitlani, C. M. (Colleen M.), Psaty, B. M. (Bruce M.), Gharib, S. A. (Sina A.), O’Connor, G. T. (George T.), Dupuis, J. (Josée), Xu, J. (Jiayi), Lohman, K. (Kurt), Liu, Y. (Yongmei), Kritchevsky, S. B. (Stephen B.), Cassano, P. A. (Patricia A.), Flexeder, C. (Claudia), Gieger, C. (Christian), Karrasch, S. (Stefan), Peters, A. (Annette), Schulz, H. (Holger), Harris, S. E. (Sarah E.), Starr, J. M. (John M.), Deary, I. J. (Ian J.), Manichaikul, A. (Ani), Oelsner, E. C. (Elizabeth C.), Barr, R. G. (R. G.), Taylor, K. D. (Kent D.), Rich, S. S. (Stephen S.), Bonten, T. N. (Tobias N.), Mook-Kanamori, D. O. (Dennis O.), Noordam, R. (Raymond), Li-Gao, R. (Ruifang), Jarvelin, M.-R. (Marjo-Riitta), Wielscher, M. (Matthias), Terzikhan, N. (Natalie), Lahousse, L. (Lies), Brusselle, G. (Guy), Weiss, S. (Stefan), Ewert, R. (Ralf), Gläser, S. (Sven), Homuth, G. (Georg), Shrine, N. (Nick), Hall, I. P. (Ian P.), Tobin, M. (Martin), London, S. J. (Stephanie J.), Wei, P. (Peng), Morrison, A. C. (Alanna C.), Yang, T. (Tianzhong), Jackson, V. E. (Victoria E.), Smith, A. V. (Albert V.), Chen, H. (Han), Bartz, T. M. (Traci M.), Sitlani, C. M. (Colleen M.), Psaty, B. M. (Bruce M.), Gharib, S. A. (Sina A.), O’Connor, G. T. (George T.), Dupuis, J. (Josée), Xu, J. (Jiayi), Lohman, K. (Kurt), Liu, Y. (Yongmei), Kritchevsky, S. B. (Stephen B.), Cassano, P. A. (Patricia A.), Flexeder, C. (Claudia), Gieger, C. (Christian), Karrasch, S. (Stefan), Peters, A. (Annette), Schulz, H. (Holger), Harris, S. E. (Sarah E.), Starr, J. M. (John M.), Deary, I. J. (Ian J.), Manichaikul, A. (Ani), Oelsner, E. C. (Elizabeth C.), Barr, R. G. (R. G.), Taylor, K. D. (Kent D.), Rich, S. S. (Stephen S.), Bonten, T. N. (Tobias N.), Mook-Kanamori, D. O. (Dennis O.), Noordam, R. (Raymond), Li-Gao, R. (Ruifang), Jarvelin, M.-R. (Marjo-Riitta), Wielscher, M. (Matthias), Terzikhan, N. (Natalie), Lahousse, L. (Lies), Brusselle, G. (Guy), Weiss, S. (Stefan), Ewert, R. (Ralf), Gläser, S. (Sven), Homuth, G. (Georg), Shrine, N. (Nick), Hall, I. P. (Ian P.), Tobin, M. (Martin), London, S. J. (Stephanie J.), Wei, P. (Peng), and Morrison, A. C. (Alanna C.)

Abstract

Genome-wide association studies have identified numerous common genetic variants associated with spirometric measures of pulmonary function, including forced expiratory volume in one second (FEV₁), forced vital capacity, and their ratio. However, variants with lower minor allele frequencies are less explored. We conducted a large-scale gene-smoking interaction meta-analysis on exonic rare and low-frequency variants involving 44,429 individuals of European ancestry in the discovery stage and sought replication in the UK BiLEVE study with 45,133 European ancestry samples and UK Biobank study with 59,478 samples. We leveraged data on cigarette smoking, the major environmental risk factor for reduced lung function, by testing gene-by-smoking interaction effects only and simultaneously testing the genetic main effects and interaction effects. The most statistically significant signal that replicated was a previously reported low-frequency signal in GPR126, distinct from common variant associations in this gene. Although only nominal replication was obtained for a top rare variant signal rs142935352 in one of the two studies, interaction and joint tests for current smoking and PDE3B were significantly associated with FEV₁. This study investigates the utility of assessing gene-by-smoking interactions and underscores their effects on potential pulmonary function.

Published
2021

3. Mendelian randomization integrating GWAS and eQTL data reveals genetic determinants of complex and clinical traits

Author

Porcu, E. (Eleonora), Rueger, S. (Sina), Lepik, K. (Kaido), Agbessi, M. (Mawusse), Ahsan, H. (Habibul), Alves, I. (Isabel), Andiappan, A. (Anand), Arindrarto, W. (Wibowo), Awadalla, P. (Philip), Battle, A. (Alexis), Beutner, F. (Frank), Bonder, M. J. (Marc Jan), Boomsma, D. (Dorret), Christiansen, M. (Mark), Claringbould, A. (Annique), Deelen, P. (Patrick), Esko, T. (Tonu), Fave, M.-J. (Marie-Julie), Franke, L. (Lude), Frayling, T. (Timothy), Gharib, S. A. (Sina A.), Gibson, G. (Gregory), Heijmans, B. T. (Bastiaan T.), Hemani, G. (Gibran), Jansen, R. (Rick), Kahonen, M. (Mika), Kalnapenkis, A. (Anette), Kasela, S. (Silva), Kettunen, J. (Johannes), Kim, Y. (Yungil), Kirsten, H. (Holger), Kovacs, P. (Peter), Krohn, K. (Knut), Kronberg-Guzman, J. (Jaanika), Kukushkina, V. (Viktorija), Lee, B. (Bernett), Lehtimaki, T. (Terho), Loeffler, M. (Markus), Marigorta, U. M. (Urko M.), Mei, H. (Hailang), Milani, L. (Lili), Montgomery, G. W. (Grant W.), Mueler-Nurasyid, M. (Martina), Nauck, M. (Matthias), Nivard, M. (Michel), Penninx, B. (Brenda), Perola, M. (Markus), Pervjakova, N. (Natalia), Pierce, B. L. (Brandon L.), Powell, J. (Joseph), Prokisch, H. (Holger), Psaty, B. M. (Bruce M.), Raitakari, O. T. (Olli T.), Ripatti, S. (Samuli), Rotzschke, O. (Olaf), Saha, A. (Ashis), Scholz, M. (Markus), Schramm, K. (Katharina), Seppala, I. (Ilkka), Slagboom, E. P. (Eline P.), Stehouwer, C. D. (Coen D. A.), Stumvoll, M. (Michael), Sullivan, P. (Patrick), Teumer, A. (Alexander), Thiery, J. (Joachim), Tong, L. (Lin), Tonjes, A. (Anke), van Dongen, J. (Jenny), van Iterson, M. (Maarten), van Meurs, J. (Joyce), Veldink, J. H. (Jan H.), Verlouw, J. (Joost), Visscher, P. M. (Peter M.), Volker, U. (Uwe), Vosa, U. (Urmo), Westra, H.-J. (Harm-Jan), Wijmenga, C. (Cisca), Yaghootkar, H. (Hanieh), Yang, J. (Jian), Zeng, B. (Biao), Zhang, F. (Futao), Beekman, M. (Marian), Boomsma, D. I. (Dorret I.), Bot, J. (Jan), Deelen, J. (Joris), Hofman, B. A. (Bert A.), Hottenga, J. J. (Jouke J.), Isaacs, A. (Aaron), Jhamai, P. M. (P. Mila), Kielbasa, S. M. (Szymon M.), Lakenberg, N. (Nico), Luijk, R. (Rene), Mei, H. (Hailiang), Moed, M. (Matthijs), Nooren, I. (Irene), Pool, R. (Rene), Schalkwijk, C. G. (Casper G.), Slagboom, P. E. (P. Eline), Suchiman, H. E. (H. Eka D.), Swertz, M. A. (Morris A.), Tigchelaar, E. F. (Ettje F.), Uitterlinden, A. G. (Andre G.), van den Berg, L. H. (Leonard H.), van der Breggen, R. (Ruud), van der Kallen, C. J. (Carla J. H.), van Dijk, F. (Freerk), van Duijn, C. M. (Cornelia M.), van Galen, M. (Michiel), van Greevenbroek, M. M. (Marleen M. J.), van Heemst, D. (Diana), van Rooij, J. (Jeroen), Van't Hof, P. (Peter), van Zwet, E. W. (Erik. W.), Vermaat, M. (Martijn), Verbiest, M. (Michael), Verkerk, M. (Marijn), Zhernakova, D. V. (Dasha V.), Zhernakova, S. (Sasha), Santoni, F. A. (Federico A.), Reymond, A. (Alexandre), and Kutalik, Z. (Zoltan)

Abstract

Genome-wide association studies (GWAS) have identified thousands of variants associated with complex traits, but their biological interpretation often remains unclear. Most of these variants overlap with expression QTLs, indicating their potential involvement in regulation of gene expression. Here, we propose a transcriptome-wide summary statistics-based Mendelian Randomization approach (TWMR) that uses multiple SNPs as instruments and multiple gene expression traits as exposures, simultaneously. Applied to 43 human phenotypes, it uncovers 3,913 putatively causal gene–trait associations, 36% of which have no genome-wide significant SNP nearby in previous GWAS. Using independent association summary statistics, we find that the majority of these loci were missed by GWAS due to power issues. Noteworthy among these links is educational attainment-associated BSCL2, known to carry mutations leading to a Mendelian form of encephalopathy. We also find pleiotropic causal effects suggestive of mechanistic connections. TWMR better accounts for pleiotropy and has the potential to identify biological mechanisms underlying complex traits.

Published
2019

4. Evidence for large-scale gene-by-smoking interaction effects on pulmonary function

Author

Aschard, H. (Hugues), Tobin, M. D. (Martin D), Hancock, D. B. (Dana B), Skurnik, D. (David), Sood, A. (Akshay), James, A. (Alan), Smith, A. V. (Albert Vernon), Manichaikul, A. W. (Ani W), Campbell, A. (Archie), Prins, B. P. (Bram P), Hayward, C. (Caroline), Loth, D. W. (Daan W), Porteous, D. J. (David J), Strachan, D. P. (David P), Zeggini, E. (Eleftheria), O’Connor, G. T. (George T), Brusselle, G. G. (Guy G), Boezen, H. M. (H Marike), Schulz, H. (Holger), Deary, I. J. (Ian J), Hall, I. P. (Ian P), Rudan, I. (Igor), Kaprio, J. (Jaakko), Wilson, J. F. (James F), Wilk, J. B. (Jemma B), Huffman, J. E. (Jennifer E), Zhao, J. H. (Jing Hua), de Jong, K. (Kim), Lyytikäinen, L.-P. (Leo-Pekka), Wain, L. V. (Louise V), Järvelin, M.-R. (Marjo-Riitta), Kähönen, M. (Mika), Fornage, M. (Myriam), Polasek, O. (Ozren), Cassano, P. A. (Patricia A), Barr, R. G. (R Graham), Rawal, R. (Rajesh), Harris, S. E. (Sarah E), Gharib, S. A. (Sina A), Enroth, S. (Stefan), Heckbert, S. R. (Susan R), Lehtimäki, T. (Terho), Gyllensten, U. (Ulf), Understanding Society Scientific Group, Jackson, V. E. (Victoria E), Gudnason, V. (Vilmundur), Tang, W. (Wenbo), Dupuis, J. (Josée), Artigas, M. S. (María Soler), Joshi, A. D. (Amit D), London, S. J. (Stephanie J), Kraft, P. (Peter), Groningen Research Institute for Asthma and COPD (GRIAC), and Life Course Epidemiology (LCE)

Subjects
RISK, Medicin och hälsovetenskap, Science & Technology, PREDICTION, 0104 Statistics, respiratory system, genetic risk score, Medical and Health Sciences, DISEASE, smoking, gene-environment interaction, respiratory tract diseases, LUNG-FUNCTION, OPPORTUNITIES, 1117 Public Health And Health Services, FEV1/FVC, EPIDEMIOLOGY, OBSTRUCTION, GENOME-WIDE ASSOCIATION, ENVIRONMENT INTERACTIONS, gene–environment interaction, Life Sciences & Biomedicine, Public, Environmental & Occupational Health
Abstract

Background: Smoking is the strongest environmental risk factor for reduced pulmonary function. The genetic component of various pulmonary traits has also been demonstrated, and at least 26 loci have been reproducibly associated with either FEV1 (forced expiratory volume in 1 second) or FEV1/FVC (FEV1/forced vital capacity). Although the main effects of smoking and genetic loci are well established, the question of potential gene-by-smoking interaction effect remains unanswered. The aim of the present study was to assess, using a genetic risk score approach, whether the effect of these 26 loci on pulmonary function is influenced by smoking. Methods: We evaluated the interaction between smoking exposure, considered as either ever vs never or pack-years, and a 26-single nucleotide polymorphisms (SNPs) genetic risk score in relation to FEV1 or FEV1/FVC in 50 047 participants of European ancestry from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) and SpiroMeta consortia. Results: We identified an interaction (βint = −0.036, 95% confidence interval, −0.040 to −0.032, P = 0.00057) between an unweighted 26 SNP genetic risk score and smoking status (ever/never) on the FEV1/FVC ratio. In interpreting this interaction, we showed that the genetic risk of falling below the FEV1/FVC threshold used to diagnose chronic obstructive pulmonary disease is higher among ever smokers than among never smokers. A replication analysis in two independent datasets, although not statistically significant, showed a similar trend in the interaction effect. Conclusions: This study highlights the benefit of using genetic risk scores for identifying interactions missed when studying individual SNPs and shows, for the first time, that persons with the highest genetic risk for low FEV1/FVC may be more susceptible to the deleterious effects of smoking.

Published
2017

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