Search

Your search keyword '"Erin N. Smith"' showing total 114 results
Start Over Author "Erin N. Smith"
114 results on '"Erin N. Smith"'

1. Investigation of genetic determinants of cognitive change in later life

Author

Liam Mahedy, Emma L. Anderson, Kate Tilling, Zak A. Thornton, Andrew R. Elmore, Sándor Szalma, Arthur Simen, Meredith Culp, Stephen Zicha, Brian T. Harel, George Davey Smith, Erin N. Smith, and Lavinia Paternoster

Subjects
Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Abstract Cognitive decline is a major health concern and identification of genes that may serve as drug targets to slow decline is important to adequately support an aging population. Whilst genetic studies of cross-sectional cognition have been carried out, cognitive change is less well-understood. Here, using data from the TOMMORROW trial, we investigate genetic associations with cognitive change in a cognitively normal older cohort. We conducted a genome-wide association study of trajectories of repeated cognitive measures (using generalised estimating equation (GEE) modelling) and tested associations with polygenic risk scores (PRS) of potential risk factors. We identified two genetic variants associated with change in attention domain scores, rs534221751 (p = 1 × 10−8 with slope 1) and rs34743896 (p = 5 × 10−10 with slope 2), implicating NCAM2 and CRIPT/ATP6V1E2 genes, respectively. We also found evidence for the association between an education PRS and baseline cognition (at >65 years of age), particularly in the language domain. We demonstrate the feasibility of conducting GWAS of cognitive change using GEE modelling and our results suggest that there may be novel genetic associations for cognitive change that have not previously been associated with cross-sectional cognition. We also show the importance of the education PRS on cognition much later in life. These findings warrant further investigation and demonstrate the potential value of using trial data and trajectory modelling to identify genetic variants associated with cognitive change.

Published
2024
Full Text
View/download PDF

2. Discovery and quality analysis of a comprehensive set of structural variants and short tandem repeats

Author

David Jakubosky, Erin N. Smith, Matteo D’Antonio, Marc Jan Bonder, William W. Young Greenwald, Agnieszka D’Antonio-Chronowska, Hiroko Matsui, i2QTL Consortium, Oliver Stegle, Stephen B. Montgomery, Christopher DeBoever, and Kelly A. Frazer

Subjects
Science
Abstract

The complexity of structural variation (SV) and short tandem repeats (STRs) makes it necessary to apply different calling and filtering strategies to sequencing datasets. Here, Jakubosky et al. report a comprehensive SV and STR callset from whole-genome sequencing of 477 individuals from iPSCORE and HipSci using five algorithms.

Published
2020
Full Text
View/download PDF

3. Properties of structural variants and short tandem repeats associated with gene expression and complex traits

Author

David Jakubosky, Matteo D’Antonio, Marc Jan Bonder, Craig Smail, Margaret K. R. Donovan, William W. Young Greenwald, Hiroko Matsui, i2QTL Consortium, Agnieszka D’Antonio-Chronowska, Oliver Stegle, Erin N. Smith, Stephen B. Montgomery, Christopher DeBoever, and Kelly A. Frazer

Subjects
Science
Abstract

Genetic variation associated with gene expression changes has mostly been studied in the context of single nucleotide variants. Here, Jakubosky et al. report eQTL analysis of structural variants and short tandem repeats and find properties, such as length of variation, that affect the association.

Published
2020
Full Text
View/download PDF

4. Association of Human iPSC Gene Signatures and X Chromosome Dosage with Two Distinct Cardiac Differentiation Trajectories

Author

Agnieszka D'Antonio-Chronowska, Margaret K.R. Donovan, William W. Young Greenwald, Jennifer Phuong Nguyen, Kyohei Fujita, Sherin Hashem, Hiroko Matsui, Francesca Soncin, Mana Parast, Michelle C. Ward, Florence Coulet, Erin N. Smith, Eric Adler, Matteo D'Antonio, and Kelly A. Frazer

Subjects
Medicine (General), R5-920, Biology (General), QH301-705.5
Abstract

Summary: Despite the importance of understanding how variability across induced pluripotent stem cell (iPSC) lines due to non-genetic factors (clone and passage) influences their differentiation outcome, large-scale studies capable of addressing this question have not yet been conducted. Here, we differentiated 191 iPSC lines to generate iPSC-derived cardiovascular progenitor cells (iPSC-CVPCs). We observed cellular heterogeneity across the iPSC-CVPC samples due to varying fractions of two cell types: cardiomyocytes (CMs) and epicardium-derived cells (EPDCs). Comparing the transcriptomes of CM-fated and EPDC-fated iPSCs, we discovered that 91 signature genes and X chromosome dosage differences are associated with these two distinct cardiac developmental trajectories. In an independent set of 39 iPSCs differentiated into CMs, we confirmed that sex and transcriptional differences affect cardiac-fate outcome. Our study provides novel insights into how iPSC transcriptional and X chromosome gene dosage differences influence their response to differentiation stimuli and, hence, cardiac cell fate. : In this article, D'Antonio-Chronowska, Donovan and colleagues differentiated 191 iPSC lines to generate iPSC-derived cardiovascular progenitor cells (iPSC-CVPCs). The iPSC-CVPC samples showed cellular heterogeneity due to varying fractions of cardiomyocytes (CMs) and epicardium-derived cells (EPDCs). Donor sex and expression levels of signature genes in iPSCs played a role in the relative proportions of CMs and EPDCs present in the derived CVPCs. Keywords: iPSC, iPSC-derived cardiovascular progenitor cells, iPSC-derived cardiomyocytes, iPSC-derived epicardium, scRNA-seq, single-cell transcriptomics, X chromosome inactivation, X chromosome erosion, iPSC differentiation

Published
2019
Full Text
View/download PDF

5. Human iPSC-Derived Retinal Pigment Epithelium: A Model System for Prioritizing and Functionally Characterizing Causal Variants at AMD Risk Loci

Author

Erin N. Smith, Agnieszka D'Antonio-Chronowska, William W. Greenwald, Victor Borja, Lana R. Aguiar, Robert Pogue, Hiroko Matsui, Paola Benaglio, Shyamanga Borooah, Matteo D'Antonio, Radha Ayyagari, and Kelly A. Frazer

Subjects
Medicine (General), R5-920, Biology (General), QH301-705.5
Abstract

Summary: We evaluate whether human induced pluripotent stem cell-derived retinal pigment epithelium (iPSC-RPE) cells can be used to prioritize and functionally characterize causal variants at age-related macular degeneration (AMD) risk loci. We generated iPSC-RPE from six subjects and show that they have morphological and molecular characteristics similar to those of native RPE. We generated RNA-seq, ATAC-seq, and H3K27ac ChIP-seq data and observed high similarity in gene expression and enriched transcription factor motif profiles between iPSC-RPE and human fetal RPE. We performed fine mapping of AMD risk loci by integrating molecular data from the iPSC-RPE, adult retina, and adult RPE, which identified rs943080 as the probable causal variant at VEGFA. We show that rs943080 is associated with altered chromatin accessibility of a distal ATAC-seq peak, decreased overall gene expression of VEGFA, and allele-specific expression of a non-coding transcript. Our study thus provides a potential mechanism underlying the association of the VEGFA locus with AMD. : Smith, D'Antonio-Chronowska, and colleagues integrate newly generated epigenetic and transcriptomic data from iPSC-derived retinal pigment epithelium with data from adult samples to prioritize potential causal variants associated with age-related macular degeneration. They prioritize rs943080 at the VEGFA locus and show that the risk allele may reduce VEGFA gene expression by altering activity of a distal regulatory region. Keywords: induced pluripotent stem cells, retinal pigment epithelium, age-related macular degeneration, VEGFA, chromatin accessibility, fine mapping, regulatory variants, genome-wide association, iPSC-RPE

Published
2019
Full Text
View/download PDF

6. Subtle changes in chromatin loop contact propensity are associated with differential gene regulation and expression

Author

William W. Greenwald, He Li, Paola Benaglio, David Jakubosky, Hiroko Matsui, Anthony Schmitt, Siddarth Selvaraj, Matteo D’Antonio, Agnieszka D’Antonio-Chronowska, Erin N. Smith, and Kelly A. Frazer

Subjects
Science
Abstract

It is currently unclear how quantitative changes in chromatin loop propensity contribute to differential gene regulation. Here, the authors use phased Hi-C, RNA-seq, and ChIP-seq to show that subtle changes in loop propensity associate with differential gene regulation across cell types and haplotypes.

Published
2019
Full Text
View/download PDF

7. Fibrinogen gamma gene rs2066865 and risk of cancer-related venous thromboembolism

Author

Benedikte Paulsen, Hanne Skille, Erin N. Smith, Kristian Hveem, Maiken E. Gabrielsen, Sigrid K. Brækkan, Frits R. Rosendaal, Kelly A. Frazer, Olga V. Gran, and John-Bjarne Hansen

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Abstract

Venous thromboembolism (VTE) is a frequent complication in patients with cancer. Homozygous carriers of the fibrinogen gamma gene (FGG) rs2066865 have a moderately increased risk of VTE, but the effect of the FGG variant in cancer is unknown. We aimed to investigate the effect of the FGG variant and active cancer on the risk of VTE. Cases with incident VTE (n=640) and a randomly selected age-weighted sub-cohort (n=3,734) were derived from a population-based cohort (the Tromsø study). Cox-regression was used to estimate hazard ratios (HR) with 95% confidence intervals (CI) for VTE according to categories of cancer and FGG. In those without cancer, homozygosity at the FGG variant was associated with a 70% (HR 1.7, 95% CI: 1.2–2.3) increased risk of VTE compared to non-carriers. Cancer patients homozygous for the FGG variant had a two-fold (HR 2.0, 95% CI: 1.1–3.6) higher risk of VTE than cancer patients without the variant. Moreover, the six-months cumulative incidence of VTE among cancer patients was 6.4% (95% CI: 3.5–11.6) in homozygous carriers of FGG and 3.1% (95% CI: 2.3–4.7) in those without risk alleles. A synergistic effect was observed between rs2066865 and active cancer on the risk of VTE (synergy index: 1.81, 95% CI: 1.02–3.21, attributable proportion: 0.43, 95% CI: 0.11–0.74). In conclusion, homozygosity at the FGG variant and active cancer yielded a synergistic effect on the risk of VTE.

Published
2020
Full Text
View/download PDF

8. Pgltools: a genomic arithmetic tool suite for manipulation of Hi-C peak and other chromatin interaction data

Author

William W. Greenwald, He Li, Erin N. Smith, Paola Benaglio, Naoki Nariai, and Kelly A. Frazer

Subjects
Hi-CChIA-PET, Chromatin conformation capture, Peak, Paired-genomic-loci, Tool suite, Bedtools, Computer applications to medicine. Medical informatics, R858-859.7, Biology (General), QH301-705.5
Abstract

Abstract Background Genomic interaction studies use next-generation sequencing (NGS) to examine the interactions between two loci on the genome, with subsequent bioinformatics analyses typically including annotation, intersection, and merging of data from multiple experiments. While many file types and analysis tools exist for storing and manipulating single locus NGS data, there is currently no file standard or analysis tool suite for manipulating and storing paired-genomic-loci: the data type resulting from “genomic interaction” studies. As genomic interaction sequencing data are becoming prevalent, a standard file format and tools for working with these data conveniently and efficiently are needed. Results This article details a file standard and novel software tool suite for working with paired-genomic-loci data. We present the paired-genomic-loci (PGL) file standard for genomic-interactions data, and the accompanying analysis tool suite “pgltools”: a cross platform, pypy compatible python package available both as an easy-to-use UNIX package, and as a python module, for integration into pipelines of paired-genomic-loci analyses. Conclusions Pgltools is a freely available, open source tool suite for manipulating paired-genomic-loci data. Source code, an in-depth manual, and a tutorial are available publicly at www.github.com/billgreenwald/pgltools , and a python module of the operations can be installed from PyPI via the PyGLtools module.

Published
2017
Full Text
View/download PDF

9. iPSCORE: A Resource of 222 iPSC Lines Enabling Functional Characterization of Genetic Variation across a Variety of Cell Types

Author

Athanasia D. Panopoulos, Matteo D'Antonio, Paola Benaglio, Roy Williams, Sherin I. Hashem, Bernhard M. Schuldt, Christopher DeBoever, Angelo D. Arias, Melvin Garcia, Bradley C. Nelson, Olivier Harismendy, David A. Jakubosky, Margaret K.R. Donovan, William W. Greenwald, KathyJean Farnam, Megan Cook, Victor Borja, Carl A. Miller, Jonathan D. Grinstein, Frauke Drees, Jonathan Okubo, Kenneth E. Diffenderfer, Yuriko Hishida, Veronica Modesto, Carl T. Dargitz, Rachel Feiring, Chang Zhao, Aitor Aguirre, Thomas J. McGarry, Hiroko Matsui, He Li, Joaquin Reyna, Fangwen Rao, Daniel T. O'Connor, Gene W. Yeo, Sylvia M. Evans, Neil C. Chi, Kristen Jepsen, Naoki Nariai, Franz-Josef Müller, Lawrence S.B. Goldstein, Juan Carlos Izpisua Belmonte, Eric Adler, Jeanne F. Loring, W. Travis Berggren, Agnieszka D'Antonio-Chronowska, Erin N. Smith, and Kelly A. Frazer

Subjects
Medicine (General), R5-920, Biology (General), QH301-705.5
Abstract

Summary: Large-scale collections of induced pluripotent stem cells (iPSCs) could serve as powerful model systems for examining how genetic variation affects biology and disease. Here we describe the iPSCORE resource: a collection of systematically derived and characterized iPSC lines from 222 ethnically diverse individuals that allows for both familial and association-based genetic studies. iPSCORE lines are pluripotent with high genomic integrity (no or low numbers of somatic copy-number variants) as determined using high-throughput RNA-sequencing and genotyping arrays, respectively. Using iPSCs from a family of individuals, we show that iPSC-derived cardiomyocytes demonstrate gene expression patterns that cluster by genetic background, and can be used to examine variants associated with physiological and disease phenotypes. The iPSCORE collection contains representative individuals for risk and non-risk alleles for 95% of SNPs associated with human phenotypes through genome-wide association studies. Our study demonstrates the utility of iPSCORE for examining how genetic variants influence molecular and physiological traits in iPSCs and derived cell lines. : Working as part of the NHLBI NextGen consortium, Panopoulos and colleagues report the derivation and characterization of 222 publicly available iPSCs from ethnically diverse individuals with corresponding genomic data including SNP arrays, RNA-seq, and whole-genome sequencing. This collection provides a powerful resource to investigate the function of genetic variants. Keywords: iPSCORE, iPSC, GWAS, molecular traits, physiological traits, cardiac disease, NHLBI Next Gen, LQT2, KCNH2, iPSC-derived cardiomyocytes

Published
2017
Full Text
View/download PDF

10. Joint effects of cancer and variants in the factor 5 gene on the risk of venous thromboembolism

Author

Olga V. Gran, Erin N. Smith, Sigrid K. Brækkan, Hilde Jensvoll, Terry Solomon, Kristian Hindberg, Tom Wilsgaard, Frits R. Rosendaal, Kelly A. Frazer, and John-Bjarne Hansen

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Abstract

Venous thromboembolism occurs frequently in cancer patients. Two variants in the factor 5 gene (F5), rs6025 encoding for the factor V Leiden mutation R506Q, and rs4524 encoding K858R, have been found to be associated with venous thromboembolism. We assessed the joint effect of active cancer and these two F5 variants on venous thromboembolism risk in a case-cohort study. Cases with a first venous thromboembolism (n=609) and a randomly selected age-weighted cohort (n=1,691) were sampled from the general population in Tromsø, Norway. Venous thromboembolism was classified as cancer-related if it occurred in the period 6 months before to 2 years after a diagnosis of cancer. Active cancer was associated with an 8.9-fold higher risk of venous thromboembolism (95% CI 7.2–10.9). The risk of cancer-related venous thromboembolism was 16.7-fold (95% CI 9.9–28.0) higher in subjects heterozygous for rs6025 compared with non-carriers of this variant without active cancer. In subjects with active cancer the risk of venous thromboembolism was 15.9-fold higher (95% CI 9.1–27.9) in those with one risk allele at rs4524, and 21.1-fold (95% CI 12.4–35.8) higher in those with two risk alleles compared with non-carriers without active cancer. A synergistic interaction was observed between active cancer and factor V Leiden (relative excess risk due to interaction 7.0; 95% CI 0.5–14.4) and rs4524 (relative excess risk due to interaction 15.0; 95% CI 7.5–29.2). The incidence of venous thromboembolism during the initial 6 months following a diagnosis of cancer was particularly high in subjects with risk alleles at these loci. This implies that the combination of cancer and F5 variants synergistically increases venous thromboembolism risk.

Published
2016
Full Text
View/download PDF

11. Plasma neurofilament light levels show elevation prior to diagnosis of sporadic motor neuron disease in the UK Biobank cohort

Author

Erin N. Smith, Jonghun Lee, Daria Prilutsky, Stephen Zicha, Zemin Wang, Steve Han, and Neta Zach

Abstract

ObjectiveMotor neuron disease (MND) is a debilitating neurodegenerative disease with profound unmet need. In pre-symptomatic mutation carriers, elevations in neurofilament light (NfL) precede symptom onset, however, the presence and timing of elevation is much more difficult to study in sporadic cases.MethodsUsing the UK Biobank cohort, we tested whether plasma NfL predicted risk of diagnosis of sporadic MND using survival analysis.ResultsWe identified 241 MND patients with pre-diagnosis NfL data, of which 203 (84%) lacked predicted loss of function or deleterious missense variants in established ALS genes. A total of 42,752 controls without MND were obtained from a random sample of UK Biobank participants. At two years pre-diagnosis, we found that NfL levels in patients exceeded the 95thpercentile of controls and that patients could be discriminated from controls at high accuracy (AUC = 0.95 (95% CI 0.89-1.01)). In participants with hospital record follow-up after study enrollment, a 2-fold increase in NfL levels was associated with a 3.4 fold risk of receiving an MND diagnosis per year (95% CI 2.9-3.9, P = 4 × 10−64)).DiscussionOur findings show that NfL can identify sporadic MND as early as 2 years prior to diagnosis.

Published
2023

12. Genome-wide CRISPR Screening to Identify Drivers of TGF-β-Induced Liver Fibrosis in Human Hepatic Stellate Cells

Author

Shan Yu, Matthew Ericson, Andrea Fanjul, Derek M. Erion, Maria Paraskevopoulou, Erin N. Smith, Banumathi Cole, Ryan Feaver, Corine Holub, Narender Gavva, Shane R. Horman, and Jie Huang

Subjects
Liver Cirrhosis, Liver, Transforming Growth Factor beta, Hepatic Stellate Cells, Humans, Molecular Medicine, General Medicine, Fibrosis, Biochemistry, Signal Transduction
Abstract

Liver fibrosis progression in chronic liver disease leads to cirrhosis, liver failure, or hepatocellular carcinoma and often ends in liver transplantation. Even with an increased understanding of liver fibrogenesis and many attempts to generate therapeutics specifically targeting fibrosis, there is no approved treatment for liver fibrosis. To further understand and characterize the driving mechanisms of liver fibrosis, we developed a high-throughput genome-wide CRISPR/Cas9 screening platform to identify hepatic stellate cell (HSC)-derived mediators of transforming growth factor (TGF)-β-induced liver fibrosis. The functional genomics phenotypic screening platform described here revealed the novel biology of TGF-β-induced fibrogenesis and potential drug targets for liver fibrosis.

Published
2022

13. Multi-phenotype analyses of hemostatic traits with cardiovascular events reveal novel genetic associations

Author

Gerard Temprano‐Sagrera, Colleen M. Sitlani, William P. Bone, Miguel Martin‐Bornez, Benjamin F. Voight, Alanna C. Morrison, Scott M. Damrauer, Paul S. de Vries, Nicholas L. Smith, Maria Sabater‐Lleal, Abbas Dehghan, Adam S Heath, Alanna C Morrison, Alex P Reiner, Andrew Johnson, Anne Richmond, Annette Peters, Astrid van Hylckama Vlieg, Barbara McKnight, Bruce M Psaty, Caroline Hayward, Cavin Ward‐Caviness, Christopher O’Donnell, Daniel Chasman, David P Strachan, David A Tregouet, Dennis Mook‐Kanamori, Dipender Gill, Florian Thibord, Folkert W Asselbergs, Frank W.G. Leebeek, Frits R Rosendaal, Gail Davies, Georg Homuth, Gerard Temprano, Harry Campbell, Herman A Taylor, Jan Bressler, Jennifer E Huffman, Jerome I Rotter, Jie Yao, James F Wilson, Joshua C Bis, Julie M Hahn, Karl C Desch, Kerri L Wiggins, Laura M Raffield, Lawrence F Bielak, Lisa R Yanek, Marcus E Kleber, Martina Mueller, Maryam Kavousi, Massimo Mangino, Melissa Liu, Michael R Brown, Matthew P Conomos, Min‐A Jhun, Ming‐Huei Chen, Moniek P.M. de Maat, Nathan Pankratz, Nicholas L Smith, Patricia A Peyser, Paul Elliot, Paul S de Vries, Peng Wei, Philipp S Wild, Pierre E Morange, Pim van der Harst, Qiong Yang, Ngoc‐Quynh Le, Riccardo Marioni, Ruifang Li, Scott M Damrauer, Simon R Cox, Stella Trompet, Stephan B Felix, Uwe Völker, Weihong Tang, Wolfgang Koenig, J. Wouter Jukema, Xiuqing Guo, Sara Lindstrom, Lu Wang, Erin N Smith, William Gordon, Mariza de Andrade, Jennifer A Brody, Jack W Pattee, Jeffrey Haessler, Ben M Brumpton, Daniel I Chasman, Pierre Suchon, Constance Turman, Marine Germain, James MacDonald, Sigrid K Braekkan, Sebastian M Armasu, Rabecca D Jackson, Jonas B Nielsen, Franco Giulianini, Marja K Puurunen, Manal Ibrahim, Susan R Heckbert, Theo K Bammler, Kelly A Frazer, Bryan M McCauley, Kent Taylor, James S Pankow, Alexander P Reiner, Maiken E Gabrielsen, Jean‐François Deleuze, Chris J O’Donnell, Jihye Kim, Peter Kraft, John‐Bjarne Hansen, John A Heit, Charles Kooperberg, Kristian Hveem, Paul M Ridker, Pierre‐Emmanuel Morange, Andrew D Johnson, Christopher Kabrhel, David‐Alexandre Trégouët, Rainer Malik, Ganesh Chauhan, Matthew Traylor, Muralidharan Sargurupremraj, Yukinori Okada, Aniket Mishra, Loes Rutten‐Jacobs, Anne‐Katrin Giese, Sander W van der Laan, Solveig Gretarsdottir, Christopher D Anderson, Michael Chong, Hieab HH Adams, Tetsuro Ago, Peter Almgren, Philippe Amouyel, Hakan Ay, Traci M Bartz, Oscar R Benavente, Steve Bevan, Giorgio B Boncoraglio, Robert D Brown, Adam S Butterworth, Caty Carrera, Cara L Carty, Wei‐Min Chen, John W Cole, Adolfo Correa, Ioana Cotlarciuc, Carlos Cruchaga, John Danesh, Paul IW de Bakker, Anita L DeStefano, Marcel den Hoed, Qing Duan, Stefan T Engelter, Guido J Falcone, Rebecca F Gottesman, Raji P Grewal, Vilmundur Gudnason, Stefan Gustafsson, Tamara B Harris, Ahamad Hassan, Aki S Havulinna, Elizabeth G Holliday, George Howard, Fang‐Chi Hsu, Hyacinth I Hyacinth, M Arfan Ikram, Erik Ingelsson, Marguerite R Irvin, Xueqiu Jian, Jordi Jiménez‐Conde, Julie A Johnson, J Wouter Jukema, Masahiro Kanai, Keith L Keene, Brett M Kissela, Dawn O Kleindorfer, Michiaki Kubo, Leslie A Lange, Carl D Langefeld, Claudia Langenberg, Lenore J Launer, Jin‐Moo Lee, Robin Lemmens, Didier Leys, Cathryn M Lewis, Wei‐Yu Lin, Arne G Lindgren, Erik Lorentzen, Patrik K Magnusson, Jane Maguire, Ani Manichaikul, Patrick F McArdle, James F Meschia, Braxton D Mitchell, Thomas H Mosley, Michael A Nalls, Toshiharu Ninomiya, Martin J O’Donnell, Sara L Pulit, Kristiina Rannikmäe, Kathryn M Rexrode, Kenneth Rice, Stephen S Rich, Natalia S Rost, Peter M Rothwell, Tatjana Rundek, Ralph L Sacco, Saori Sakaue, Michele M Sale, Veikko Salomaa, Bishwa R Sapkota, Reinhold Schmidt, Carsten O Schmidt, Ulf Schminke, Pankaj Sharma, Agnieszka Slowik, Cathie LM Sudlow, Christian Tanislav, Turgut Tatlisumak, Kent D Taylor, Vincent NS Thijs, Gudmar Thorleifsson, Unnur Thorsteinsdottir, Steffen Tiedt, Christophe Tzourio, Cornelia M van Duijn, Matthew Walters, Nicholas J Wareham, Sylvia Wassertheil‐Smoller, James G Wilson, Salim Yusuf, Najaf Amin, Hugo S Aparicio, Donna K Arnett, John Attia, Alexa S Beiser, Claudine Berr, Julie E Buring, Mariana Bustamante, Valeria Caso, Yu‐Ching Cheng, Seung Hoan Choi, Ayesha Chowhan, Natalia Cullell, Jean‐François Dartigues, Hossein Delavaran, Pilar Delgado, Marcus Dörr, Gunnar Engström, Ian Ford, Wander S Gurpreet, Anders Hamsten, Laura Heitsch, Atsushi Hozawa, Laura Ibanez, Andreea Ilinca, Martin Ingelsson, Motoki Iwasaki, Rebecca D Jackson, Katarina Jood, Pekka Jousilahti, Sara Kaffashian, Lalit Kalra, Masahiro Kamouchi, Takanari Kitazono, Olafur Kjartansson, Manja Kloss, Peter J Koudstaal, Jerzy Krupinski, Daniel L Labovitz, Cathy C Laurie, Christopher R Levi, Linxin Li, Lars Lind, Cecilia M Lindgren, Vasileios Lioutas, Yong Mei Liu, Oscar L Lopez, Hirata Makoto, Nicolas Martinez‐Majander, Koichi Matsuda, Naoko Minegishi, Joan Montaner, Andrew P Morris, Elena Muiño, Martina Müller‐Nurasyid, Bo Norrving, Soichi Ogishima, Eugenio A Parati, Leema Reddy Peddareddygari, Nancy L Pedersen, Joanna Pera, Markus Perola, Alessandro Pezzini, Silvana Pileggi, Raquel Rabionet, Iolanda Riba‐Llena, Marta Ribasés, Jose R Romero, Jaume Roquer, Anthony G Rudd, Antti‐Pekka Sarin, Ralhan Sarju, Chloe Sarnowski, Makoto Sasaki, Claudia L Satizabal, Mamoru Satoh, Naveed Sattar, Norie Sawada, Gerli Sibolt, Ásgeir Sigurdsson, Albert Smith, Kenji Sobue, Carolina Soriano‐Tárraga, Tara Stanne, O Colin Stine, David J Stott, Konstantin Strauch, Takako Takai, Hideo Tanaka, Kozo Tanno, Alexander Teumer, Liisa Tomppo, Nuria P Torres‐Aguila, Emmanuel Touze, Shoichiro Tsugane, Andre G Uitterlinden, Einar M Valdimarsson, Sven J van der Lee, Henry Völzke, Kenji Wakai, David Weir, Stephen R Williams, Charles DA Wolfe, Quenna Wong, Huichun Xu, Taiki Yamaji, Dharambir K Sanghera, Olle Melander, Christina Jern, Daniel Strbian, Israel Fernandez‐Cadenas, W T Longstreth, Arndt Rolfs, Jun Hata, Daniel Woo, Jonathan Rosand, Guillaume Pare, Jemma C Hopewell, Danish Saleheen, Kari Stefansson, Bradford B Worrall, Steven J Kittner, Sudha Seshadri, Myriam Fornage, Hugh S Markus, Joanna MM Howson, Yoichiro Kamatani, Stephanie Debette, Martin Dichgans, and VU University medical center

Subjects
Hemostasis, genome-wide association study, genetic pleiotropy, Hematology, Polymorphism, Single Nucleotide, Hemostatics, blood coagulation, cardiovascular diseases, Phenotype, Cardiovascular Diseases, Tissue Plasminogen Activator, hemostasis, Humans, Genetic Predisposition to Disease, Factor XI, Genome-Wide Association Study
Abstract

Background: Multi-phenotype analysis of genetically correlated phenotypes can increase the statistical power to detect loci associated with multiple traits, leading to the discovery of novel loci. This is the first study to date to comprehensively analyze the shared genetic effects within different hemostatic traits, and between these and their associated disease outcomes. Objectives: To discover novel genetic associations by combining summary data of correlated hemostatic traits and disease events. Methods: Summary statistics from genome wide-association studies (GWAS) from seven hemostatic traits (factor VII [FVII], factor VIII [FVIII], von Willebrand factor [VWF] factor XI [FXI], fibrinogen, tissue plasminogen activator [tPA], plasminogen activator inhibitor 1 [PAI-1]) and three major cardiovascular (CV) events (venous thromboembolism [VTE], coronary artery disease [CAD], ischemic stroke [IS]), were combined in 27 multi-trait combinations using metaUSAT. Genetic correlations between phenotypes were calculated using Linkage Disequilibrium Score Regression (LDSC). Newly associated loci were investigated for colocalization. We considered a significance threshold of 1.85 × 10−9 obtained after applying Bonferroni correction for the number of multi-trait combinations performed (n = 27). Results: Across the 27 multi-trait analyses, we found 4 novel pleiotropic loci (XXYLT1, KNG1, SUGP1/MAU2, TBL2/MLXIPL) that were not significant in the original individual datasets, were not described in previous GWAS for the individual traits, and that presented a common associated variant between the studied phenotypes. Conclusions: The discovery of four novel loci contributes to the understanding of the relationship between hemostasis and CV events and elucidate common genetic factors between these traits.

Published
2022

14. Association of Human iPSC Gene Signatures and X Chromosome Dosage with Two Distinct Cardiac Differentiation Trajectories

Author

Hiroko Matsui, Jennifer Nguyen, William W. Greenwald, Mana Parast, Florence Coulet, Erin N. Smith, Kyohei Fujita, Margaret K.R. Donovan, Agnieszka D'Antonio-Chronowska, Michelle C. Ward, Francesca Soncin, Eric Adler, Matteo D’Antonio, Kelly A. Frazer, and Sherin Hashem

Subjects
0301 basic medicine, Male, Clone (cell biology), Cardiovascular, Biochemistry, Transcriptome, iPSC-derived epicardium, 0302 clinical medicine, X Chromosome Inactivation, iPSC-derived cardiomyocytes, Myocytes, Cardiac, Induced pluripotent stem cell, lcsh:QH301-705.5, X chromosome, Cells, Cultured, X chromosome erosion, lcsh:R5-920, Cultured, iPSC, Stem Cell Research - Induced Pluripotent Stem Cell - Human, Cell Differentiation, Cell biology, Heart Disease, Female, lcsh:Medicine (General), Pericardium, Cardiac, Human, Biotechnology, Cell type, Cells, 1.1 Normal biological development and functioning, Induced Pluripotent Stem Cells, Clinical Sciences, Biology, Gene dosage, X-inactivation, Article, Chromosomes, 03 medical and health sciences, scRNA-seq, Genetics, Humans, Progenitor cell, Chromosomes, Human, X, Myocytes, Stem Cell Research - Induced Pluripotent Stem Cell, Cell Biology, iPSC-derived cardiovascular progenitor cells, Stem Cell Research, 030104 developmental biology, lcsh:Biology (General), iPSC differentiation, Biochemistry and Cell Biology, single-cell transcriptomics, 030217 neurology & neurosurgery, Developmental Biology
Abstract

Summary Despite the importance of understanding how variability across induced pluripotent stem cell (iPSC) lines due to non-genetic factors (clone and passage) influences their differentiation outcome, large-scale studies capable of addressing this question have not yet been conducted. Here, we differentiated 191 iPSC lines to generate iPSC-derived cardiovascular progenitor cells (iPSC-CVPCs). We observed cellular heterogeneity across the iPSC-CVPC samples due to varying fractions of two cell types: cardiomyocytes (CMs) and epicardium-derived cells (EPDCs). Comparing the transcriptomes of CM-fated and EPDC-fated iPSCs, we discovered that 91 signature genes and X chromosome dosage differences are associated with these two distinct cardiac developmental trajectories. In an independent set of 39 iPSCs differentiated into CMs, we confirmed that sex and transcriptional differences affect cardiac-fate outcome. Our study provides novel insights into how iPSC transcriptional and X chromosome gene dosage differences influence their response to differentiation stimuli and, hence, cardiac cell fate., Graphical Abstract, Highlights • Cellular heterogeneity across iPSC-CVPCs due to varying fractions of CMs and EPDCs • iPSC non-genetic factors (clone and passage) associated with cardiac cell fate • Expression levels of signature genes in iPSCs associated with cardiac lineage fate • iPSC donor sex plays a role in cardiac lineage fate, In this article, D'Antonio-Chronowska, Donovan and colleagues differentiated 191 iPSC lines to generate iPSC-derived cardiovascular progenitor cells (iPSC-CVPCs). The iPSC-CVPC samples showed cellular heterogeneity due to varying fractions of cardiomyocytes (CMs) and epicardium-derived cells (EPDCs). Donor sex and expression levels of signature genes in iPSCs played a role in the relative proportions of CMs and EPDCs present in the derived CVPCs.

Published
2019

15. Fibrinogen gamma gene rs2066865 and risk of cancer-related venous thromboembolism

Author

Erin N. Smith, Olga Vikhammer Gran, Benedikte Paulsen, Kelly A. Frazer, Frits R. Rosendaal, John-Bjarne Hansen, Maiken Elvestad Gabrielsen, Sigrid Kufaas Brækkan, Hanne Skille, and Kristian Hveem

Subjects
medicine.medical_specialty, Immunology, Population, Cardiorespiratory Medicine and Haematology, Gastroenterology, 03 medical and health sciences, Rare Diseases, 0302 clinical medicine, Risk Factors, Clinical Research, Neoplasms, Internal medicine, Genetics, medicine, Humans, 2.1 Biological and endogenous factors, VDP::Medisinske Fag: 700, Cumulative incidence, cardiovascular diseases, Aetiology, education, Alleles, Cancer, education.field_of_study, business.industry, Incidence, Prevention, Hazard ratio, Fibrinogen, Venous Thromboembolism, Hematology, equipment and supplies, medicine.disease, Confidence interval, VDP::Medical disciplines: 700, Cohort, Complication, business, Venous thromboembolism, 030215 immunology
Abstract

Venous thromboembolism (VTE) is a frequent complication in patients with cancer. Homozygous carriers of the fibrinogen gamma gene (FGG) rs2066865 have a moderately increased risk of VTE, but the effect of the FGG variant in cancer is unknown. We aimed to investigate the effect of the FGG variant and active cancer on the risk of VTE. Cases with incident VTE (n=640) and a randomly selected age-weighted sub-cohort (n=3,734) were derived from a population-based cohort (the Tromsø study). Cox-regression was used to estimate hazard ratios (HR) with 95% confidence intervals (CI) for VTE according to categories of cancer and FGG. In those without cancer, homozygosity at the FGG variant was associated with a 70% (HR 1.7, 95% CI: 1.2–2.3) increased risk of VTE compared to non-carriers. Cancer patients homozygous for the FGG variant had a two-fold (HR 2.0, 95% CI: 1.1–3.6) higher risk of VTE than cancer patients without the variant. Moreover, the six-months cumulative incidence of VTE among cancer patients was 6.4% (95% CI: 3.5–11.6) in homozygous carriers of FGG and 3.1% (95% CI: 2.3–4.7) in those without risk alleles. A synergistic effect was observed between rs2066865 and active cancer on the risk of VTE (synergy index: 1.81, 95% CI: 1.02–3.21, attributable proportion: 0.43, 95% CI: 0.11–0.74). In conclusion, homozygosity at the FGG variant and active cancer yielded a synergistic effect on the risk of VTE. Copyright© 2020 Ferrata Storti Foundation Material published in Haematologica is covered by copyright. All rights are reserved to the Ferrata Storti Foundation. Use of published material is allowed under the following terms and conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode. Copies of published material are allowed for personal or internal use. Sharing published material for non-commercial purposes is subject to the following conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode, sect. 3. Reproducing and sharing published material for commercial purposes is not allowed without permission in writing from the publisher.

Published
2019

16. Human iPSC-Derived Retinal Pigment Epithelium: A Model System for Prioritizing and Functionally Characterizing Causal Variants at AMD Risk Loci

Author

Paola Benaglio, Hiroko Matsui, Radha Ayyagari, Matteo D’Antonio, Kelly A. Frazer, Erin N. Smith, Robert Pogue, Victor Borja, Shyamanga Borooah, Lana Ribeiro Aguiar, William W. Greenwald, and Agnieszka D'Antonio-Chronowska

Subjects
Vascular Endothelial Growth Factor A, 0301 basic medicine, Aging, retinal pigment epithelium, Genome-wide association study, Retinal Pigment Epithelium, Neurodegenerative, Eye, Biochemistry, Macular Degeneration, 0302 clinical medicine, Gene expression, 2.1 Biological and endogenous factors, Aetiology, regulatory variants, Induced pluripotent stem cell, lcsh:QH301-705.5, Genetics, lcsh:R5-920, Stem Cell Research - Induced Pluripotent Stem Cell - Human, Human Fetal Tissue, Chromatin, medicine.anatomical_structure, Female, lcsh:Medicine (General), Sequence Analysis, VEGFA, induced pluripotent stem cells, Clinical Sciences, Induced Pluripotent Stem Cells, Locus (genetics), Biology, Article, 03 medical and health sciences, medicine, Humans, Stem Cell Research - Embryonic - Human, age-related macular degeneration, Eye Disease and Disorders of Vision, Gene, Retina, Retinal pigment epithelium, Stem Cell Research - Induced Pluripotent Stem Cell, Sequence Analysis, RNA, Human Genome, Neurosciences, Cell Biology, Stem Cell Research, eye diseases, 030104 developmental biology, lcsh:Biology (General), chromatin accessibility, Genetic Loci, fine mapping, genome-wide association, RNA, Biochemistry and Cell Biology, sense organs, iPSC-RPE, 030217 neurology & neurosurgery, Developmental Biology
Abstract

Summary: We evaluate whether human induced pluripotent stem cell-derived retinal pigment epithelium (iPSC-RPE) cells can be used to prioritize and functionally characterize causal variants at age-related macular degeneration (AMD) risk loci. We generated iPSC-RPE from six subjects and show that they have morphological and molecular characteristics similar to those of native RPE. We generated RNA-seq, ATAC-seq, and H3K27ac ChIP-seq data and observed high similarity in gene expression and enriched transcription factor motif profiles between iPSC-RPE and human fetal RPE. We performed fine mapping of AMD risk loci by integrating molecular data from the iPSC-RPE, adult retina, and adult RPE, which identified rs943080 as the probable causal variant at VEGFA. We show that rs943080 is associated with altered chromatin accessibility of a distal ATAC-seq peak, decreased overall gene expression of VEGFA, and allele-specific expression of a non-coding transcript. Our study thus provides a potential mechanism underlying the association of the VEGFA locus with AMD. : Smith, D'Antonio-Chronowska, and colleagues integrate newly generated epigenetic and transcriptomic data from iPSC-derived retinal pigment epithelium with data from adult samples to prioritize potential causal variants associated with age-related macular degeneration. They prioritize rs943080 at the VEGFA locus and show that the risk allele may reduce VEGFA gene expression by altering activity of a distal regulatory region. Keywords: induced pluripotent stem cells, retinal pigment epithelium, age-related macular degeneration, VEGFA, chromatin accessibility, fine mapping, regulatory variants, genome-wide association, iPSC-RPE

Published
2019

17. Identification of rare and common regulatory variants in pluripotent cells using population-scale transcriptomics

Author

Nicole M. Ferraro, Erin N. Smith, Ivan Carcamo-Orive, Chunli Zhao, Joshua W. Knowles, Diane B. Zastrow, Bogdan Mirauta, Dara Vakili, Oliver Stegle, Danilo Horta, David Jakubosky, Laure Fresard, Matteo D’Antonio, Kelly A. Frazer, Daniel D Seaton, Stephen B. Montgomery, Craig Smail, Devon Bonner, Xin Li, Helena Kilpinen, Marc Jan Bonder, Matthew T. Wheeler, Na Cai, and Michael J. Gloudemans

Subjects
Somatic cell, HipSci Consortium, Arabidopsis, Gene Expression, Regenerative Medicine, Medical and Health Sciences, Transcriptome, 0302 clinical medicine, 2.1 Biological and endogenous factors, Stem Cell Research - Induced Pluripotent Stem Cell - Non-Human, Aetiology, Induced pluripotent stem cell, 0303 health sciences, education.field_of_study, Stem Cell Research - Induced Pluripotent Stem Cell - Human, Stem Cells, Single Nucleotide, Biological Sciences, DNA methylation, iPSCORE consortium, Sequence Analysis, Cell type, Cerebellar Ataxia, 1.1 Normal biological development and functioning, Population, Quantitative Trait Loci, Induced Pluripotent Stem Cells, Computational biology, PhLiPS consortium, Quantitative trait locus, Biology, Article, Cell Line, 03 medical and health sciences, Rare Diseases, Underpinning research, Genetics, Humans, Polymorphism, Stem Cell Research - Embryonic - Human, education, Gene, Bardet-Biedl Syndrome, 030304 developmental biology, Nucleic Acid, Whole Genome Sequencing, Stem Cell Research - Induced Pluripotent Stem Cell, Human Genome, Proteins, Genetic Variation, Undiagnosed Diseases Network, DNA Methylation, Stem Cell Research, RNA, Calcium Channels, Generic health relevance, Regulatory Sequences, 030217 neurology & neurosurgery, Developmental Biology
Abstract

Induced pluripotent stem cells (iPSCs) are an established cellular system to study the impact of genetic variants in derived cell types and developmental contexts. However, in their pluripotent state, the disease impact of genetic variants is less well known. Here, we integrate data from 1,367 human iPSC lines to comprehensively map common and rare regulatory variants in human pluripotent cells. Using this population-scale resource, we report hundreds of new colocalization events for human traits specific to iPSCs, and find increased power to identify rare regulatory variants compared with somatic tissues. Finally, we demonstrate how iPSCs enable the identification of causal genes for rare diseases.

Published
2021

18. Advancing human genetics research and drug discovery through exome sequencing of the UK Biobank

Author

Joseph D, Szustakowski, Suganthi, Balasubramanian, Erika, Kvikstad, Shareef, Khalid, Paola G, Bronson, Ariella, Sasson, Emily, Wong, Daren, Liu, J, Wade Davis, Carolina, Haefliger, A, Katrina Loomis, Rajesh, Mikkilineni, Hyun Ji, Noh, Samir, Wadhawan, Xiaodong, Bai, Alicia, Hawes, Olga, Krasheninina, Ricardo, Ulloa, Alex E, Lopez, Erin N, Smith, Jeffrey F, Waring, Christopher D, Whelan, Ellen A, Tsai, John D, Overton, William J, Salerno, Howard, Jacob, Sandor, Szalma, Heiko, Runz, Gregory, Hinkle, Paul, Nioi, Slavé, Petrovski, Melissa R, Miller, Aris, Baras, Lyndon J, Mitnaul, Jeffrey G, Reid, and Zhan, Ye

Subjects
Research, Drug Discovery, Exome Sequencing, Humans, Human Genetics, Genomics, United Kingdom, Biological Specimen Banks
Abstract

The UK Biobank Exome Sequencing Consortium (UKB-ESC) is a private-public partnership between the UK Biobank (UKB) and eight biopharmaceutical companies that will complete the sequencing of exomes for all ~500,000 UKB participants. Here, we describe the early results from ~200,000 UKB participants and the features of this project that enabled its success. The biopharmaceutical industry has increasingly used human genetics to improve success in drug discovery. Recognizing the need for large-scale human genetics data, as well as the unique value of the data access and contribution terms of the UKB, the UKB-ESC was formed. As a result, exome data from 200,643 UKB enrollees are now available. These data include ~10 million exonic variants-a rich resource of rare coding variation that is particularly valuable for drug discovery. The UKB-ESC precompetitive collaboration has further strengthened academic and industry ties and has provided teams with an opportunity to interact with and learn from the wider research community.

Published
2020

19. Discovery and quality analysis of a comprehensive set of structural variants and short tandem repeats

Author

Oliver Stegle, Kelly A. Frazer, Agnieszka D'Antonio-Chronowska, Erin N. Smith, William W. Greenwald, Matteo D’Antonio, Marc Jan Bonder, Christopher DeBoever, Hiroko Matsui, David Jakubosky, and Stephen B. Montgomery

Subjects
0301 basic medicine, Genotype, Computer science, Bioinformatics, Science, Sequencing data, General Physics and Astronomy, Computational biology, General Biochemistry, Genetics and Molecular Biology, Article, Set (abstract data type), 03 medical and health sciences, 0302 clinical medicine, i2QTL Consortium, Genetics, Humans, Genotyping and haplotyping, DNA sequencing, lcsh:Science, Whole genome sequencing, Genetic diversity, Multidisciplinary, Whole Genome Sequencing, Haplotype, Human Genome, Computational Biology, High-Throughput Nucleotide Sequencing, General Chemistry, Data processing, 030104 developmental biology, Haplotypes, Next-generation sequencing, Microsatellite, lcsh:Q, 030217 neurology & neurosurgery, Algorithms, Microsatellite Repeats
Abstract

Structural variants (SVs) and short tandem repeats (STRs) are important sources of genetic diversity but are not routinely analyzed in genetic studies because they are difficult to accurately identify and genotype. Because SVs and STRs range in size and type, it is necessary to apply multiple algorithms that incorporate different types of evidence from sequencing data and employ complex filtering strategies to discover a comprehensive set of high-quality and reproducible variants. Here we assemble a set of 719 deep whole genome sequencing (WGS) samples (mean 42×) from 477 distinct individuals which we use to discover and genotype a wide spectrum of SV and STR variants using five algorithms. We use 177 unique pairs of genetic replicates to identify factors that affect variant call reproducibility and develop a systematic filtering strategy to create of one of the most complete and well characterized maps of SVs and STRs to date., The complexity of structural variation (SV) and short tandem repeats (STRs) makes it necessary to apply different calling and filtering strategies to sequencing datasets. Here, Jakubosky et al. report a comprehensive SV and STR callset from whole-genome sequencing of 477 individuals from iPSCORE and HipSci using five algorithms.

Published
2020

20. Interleukin-6 Signaling Effects on Ischemic Stroke and Other Cardiovascular Outcomes

Author

Marios K. Georgakis, Rainer Malik, Dipender Gill, Nora Franceschini, Cathie L. M. Sudlow, Martin Dichgans, Sara Lindstrom, Lu Wang, Erin N. Smith, William Gordon, Astrid van Hylckama Vlieg, Mariza de Andrade, Jennifer A. Brody, Jack W. Pattee, Jeffrey Haessler, Ben M. Brumpton, Daniel I. Chasman, Pierre Suchon, Ming-Huei Chen, Constance Turman, Marine Germain, Kerri L. Wiggins, and James MacDonald

Published
2020
Full Text
View/download PDF

21. Properties of structural variants and short tandem repeats associated with gene expression and complex traits

Author

Oliver Stegle, Erin N. Smith, William W. Greenwald, Stephen B. Montgomery, Agnieszka D'Antonio-Chronowska, Craig Smail, Matteo D’Antonio, Kelly A. Frazer, Marc Jan Bonder, Christopher DeBoever, Hiroko Matsui, David Jakubosky, and Margaret K.R. Donovan

Subjects
0301 basic medicine, Linkage disequilibrium, Quantitative trait loci, Multifactorial Inheritance, Science, Quantitative Trait Loci, General Physics and Astronomy, Genome-wide association study, Computational biology, Quantitative trait locus, Biology, Quantitative trait, Genome, Polymorphism, Single Nucleotide, General Biochemistry, Genetics and Molecular Biology, Article, Linkage Disequilibrium, Cell Line, 03 medical and health sciences, 0302 clinical medicine, Polymorphism (computer science), Genetic variation, i2QTL Consortium, Genetics, Humans, Polymorphism, lcsh:Science, Transcriptomics, Multidisciplinary, Human Genome, Genetic Variation, General Chemistry, Single Nucleotide, Chromatin, Gene regulation, 030104 developmental biology, Microsatellite, lcsh:Q, Gene expression, Generic health relevance, 030217 neurology & neurosurgery, Microsatellite Repeats, Genome-Wide Association Study
Abstract

Structural variants (SVs) and short tandem repeats (STRs) comprise a broad group of diverse DNA variants which vastly differ in their sizes and distributions across the genome. Here, we identify genomic features of SV classes and STRs that are associated with gene expression and complex traits, including their locations relative to eGenes, likelihood of being associated with multiple eGenes, associated eGene types (e.g., coding, noncoding, level of evolutionary constraint), effect sizes, linkage disequilibrium with tagging single nucleotide variants used in GWAS, and likelihood of being associated with GWAS traits. We identify a set of high-impact SVs/STRs associated with the expression of three or more eGenes via chromatin loops and show that they are highly enriched for being associated with GWAS traits. Our study provides insights into the genomic properties of structural variant classes and short tandem repeats that are associated with gene expression and human traits., Genetic variation associated with gene expression changes has mostly been studied in the context of single nucleotide variants. Here, Jakubosky et al. report eQTL analysis of structural variants and short tandem repeats and find properties, such as length of variation, that affect the association.

Published
2020
Full Text
View/download PDF

22. Joint effects of prothrombotic genotypes and body height on the risk of venous thromboembolism: the Tromsø study

Author

Frits R. Rosendaal, Kelly A. Frazer, Erin N. Smith, Kristian Hindberg, Sigrid Kufaas Brækkan, John-Bjarne Hansen, Terry Solomon, and Lars D. Horvei

Subjects
Male, 0301 basic medicine, medicine.medical_specialty, venous thromboembolism, 030204 cardiovascular system & hematology, Polymorphism, Single Nucleotide, Risk Assessment, ABO Blood-Group System, Factor IX, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Internal medicine, medicine, Factor V Leiden, Humans, Genetic Predisposition to Disease, Prospective Studies, cardiovascular diseases, Aged, risk, Framingham Risk Score, Norway, business.industry, Incidence, Hazard ratio, Absolute risk reduction, Factor V, Fibrinogen, Tall Stature, cohort, Hematology, Middle Aged, equipment and supplies, medicine.disease, Obesity, Confidence interval, Surgery, Phenotype, 030104 developmental biology, Case-Control Studies, Cohort, body height, Female, Prothrombin, business, SNPs
Abstract

Essentials Body height and prothrombotic genotypes are associated with risk of venous thromboembolism (VTE). The joint effect of prothrombotic genotypes and tall stature on VTE risk is scarcely investigated. We investigated the joint effect of prothrombotic genotypes and tall stature on VTE risk. Prothrombotic genotypes did not yield excess risk of VTE in subjects with a tall stature.Background Studies have reported synergistic effects of prothrombotic single-nucleotide polymorphisms (SNPs) and obesity on the risk of venous thromboembolism (VTE). Tall stature is associated with an increased VTE risk, but the joint effect of prothrombotic genotypes and tall stature on the VTE risk is unknown. Aims To investigate the joint effects of prothrombotic genotypes and tall stature on the VTE risk. Methods Cases with incident VTE (n = 676) and a randomly selected age-weighted subcohort (n = 1842) were sampled from the Tromsø study (cohort follow-up: 1994-2012). DNA was genotyped for rs6025 (factor V Leiden), rs1799963 (FII), rs8176719 (ABO blood group), rs2066865 (fibrinogen-γ), and rs2036914 (FIX). Age-adjusted and sex-adjusted hazard ratios (HRs) of VTE were calculated by categories of risk alleles (de Haan 5-SNP score: 0-1, 2-3, and ≥ 4) and body height ( 40th, 40th-80th and 80th percentiles). Results The VTE risk increased by increasing category of body height, and subjects with height ≥ 178 cm had a two-fold higher VTE risk (HR 2.03; 95% confidence interval [CI] 1.51-2.73) than those with height ≤ 165 cm. The VTE risk also increased across categories of risk alleles. However, the combination of a tall stature and risk alleles, either individual SNPs or risk score, did not result in an excess VTE risk. Subjects with four or more risk alleles and height ≥ 178 cm had a two-fold (HR 2.08; 95% CI 1.24-3.52) higher VTE risk than subjects ≤ 165 cm with no risk allele or one risk allele. Conclusions In contrast to obesity, the presence of prothrombotic genotypes did not result in an excess VTE risk in subjects with a tall stature.

Published
2018

23. Gene-environment interaction in yeast gene expression.

Author

Erin N Smith and Leonid Kruglyak

Subjects
Biology (General), QH301-705.5
Abstract

The effects of genetic variants on phenotypic traits often depend on environmental and physiological conditions, but such gene-environment interactions are poorly understood. Recently developed approaches that treat transcript abundances of thousands of genes as quantitative traits offer the opportunity to broadly characterize the architecture of gene-environment interactions. We examined the genetic and molecular basis of variation in gene expression between two yeast strains (BY and RM) grown in two different conditions (glucose and ethanol as carbon sources). We observed that most transcripts vary by strain and condition, with 2,996, 3,448, and 2,037 transcripts showing significant strain, condition, and strain-condition interaction effects, respectively. We expression profiled over 100 segregants derived from a cross between BY and RM in both growth conditions, and identified 1,555 linkages for 1,382 transcripts that show significant gene-environment interaction. At the locus level, local linkages, which usually correspond to polymorphisms in cis-regulatory elements, tend to be more stable across conditions, such that they are more likely to show the same effect or the same direction of effect across conditions. Distant linkages, which usually correspond to polymorphisms influencing trans-acting factors, are more condition-dependent, and often show effects in different directions in the two conditions. We characterized a locus that influences expression of many growth-related transcripts, and showed that the majority of the variation is explained by polymorphism in the gene IRA2. The RM allele of IRA2 appears to inhibit Ras/PKA signaling more strongly than the BY allele, and has undergone a change in selective pressure. Our results provide a broad overview of the genetic architecture of gene-environment interactions, as well as a detailed molecular example, and lead to key insights into how the effects of different classes of regulatory variants are modulated by the environment. These observations will guide the design of studies aimed at understanding the genetic basis of complex traits.

Published
2008
Full Text
View/download PDF

24. The influence of cultural orientation on associations between Puerto Rican adolescent mothers’ parenting and toddler compliance and defiance

Author

Erin N. Smith, Lauren E. Wood, Josefina M. Grau, Petra A. Duran, and Patricia Castellanos

Subjects
Male, Adolescent, Sociology and Political Science, Social Psychology, Child Behavior, Mothers, Puerto rican, PsycINFO, Article, 050105 experimental psychology, Compliance (psychology), Developmental psychology, Surveys and Questionnaires, Humans, 0501 psychology and cognitive sciences, Toddler, Poverty, Parenting, Cultural orientation, Puerto Rico, 05 social sciences, Mother-Child Relations, Acculturation, Enculturation, Child, Preschool, Female, Psychology, 050104 developmental & child psychology
Abstract

Objectives It is imperative that individual differences in the cultural contexts of adolescent mothers, whose parenting is often linked to poor child outcomes, be better understood, especially among Puerto Rican-origin mothers who experience high rates of poverty. Behaviors that mothers use to elicit compliance from their children are important to investigate, because children's ability to engage in regulated, compliant behavior has long-term consequences for their adjustment. This study tested whether mothers' orientation to both American and Latino cultures influenced the associations between such maternal behaviors and compliant and defiant child behaviors. Method The sample included 123 young, Puerto Rican-origin mothers and their 24-month-old toddlers. Behaviors coded from a toy cleanup task measured maternal guidance and control and child compliance and defiance, and acculturation and enculturation were measured with a self-report questionnaire. Results Maternal guidance predicted more child compliance, with no significant variations by cultural orientation; however, mothers who were more enculturated had children who were more compliant. As predicted, mothers' more frequent use of control was related to more child defiance for mothers reporting high levels of acculturation, and not for less acculturated mothers. Conclusions Findings support the hypothesis that individual differences in cultural orientation influence variations in associations between certain maternal and child behaviors. (PsycINFO Database Record

Published
2017

25. iPSCORE: A Resource of 222 iPSC Lines Enabling Functional Characterization of Genetic Variation across a Variety of Cell Types

Author

Sylvia M. Evans, Frauke Drees, Naoki Nariai, Lawrence S.B. Goldstein, Chang Zhao, Neil C. Chi, Erin N. Smith, Jonathan D. Grinstein, Olivier Harismendy, Rachel Feiring, Aitor Aguirre, Agnieszka D'Antonio-Chronowska, Eric Adler, Matteo D’Antonio, Kelly A. Frazer, William W. Greenwald, Yuriko Hishida, Fangwen Rao, Juan Carlos Izpisua Belmonte, Hiroko Matsui, Bernhard M. Schuldt, Sherin Hashem, KathyJean Farnam, Victor Borja, Paola Benaglio, Melvin Garcia, Jonathan Okubo, Franz-Josef Müller, Bradley C. Nelson, Veronica Modesto, He Li, Kenneth E. Diffenderfer, Thomas J. McGarry, Roy Williams, Margaret K.R. Donovan, Carl T. Dargitz, Gene W. Yeo, David Jakubosky, Megan Cook, Kristen Jepsen, Daniel T. O'Connor, Carl A. Miller, Christopher DeBoever, Joaquin Reyna, Athanasia D. Panopoulos, Angelo Arias, Jeanne F. Loring, and W. Travis Berggren

Subjects
0301 basic medicine, Databases, Factual, Genome-wide association study, Arrhythmias, Biochemistry, 2.1 Biological and endogenous factors, GWAS, iPSC-derived cardiomyocytes, LQT2, KCNH2, Myocytes, Cardiac, Stem Cell Research - Induced Pluripotent Stem Cell - Non-Human, Aetiology, Induced pluripotent stem cell, lcsh:QH301-705.5, Oligonucleotide Array Sequence Analysis, Genetics, lcsh:R5-920, iPSC, Continental Population Groups, Stem Cell Research - Induced Pluripotent Stem Cell - Human, High-Throughput Nucleotide Sequencing, Cell Differentiation, Single Nucleotide, Cellular Reprogramming, Phenotype, molecular traits, Multigene Family, lcsh:Medicine (General), Cardiac, Biotechnology, Resource, cardiac disease, Genotype, Clinical Sciences, Induced Pluripotent Stem Cells, NHLBI Next Gen, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, Cell Line, Databases, 03 medical and health sciences, Clinical Research, Genetic variation, iPSCORE, Humans, physiological traits, Polymorphism, Allele, Genotyping, Factual, Genetic Association Studies, Genetic association, Myocytes, Stem Cell Research - Induced Pluripotent Stem Cell, Human Genome, Racial Groups, Genetic Variation, Arrhythmias, Cardiac, Cell Biology, Stem Cell Research, 030104 developmental biology, lcsh:Biology (General), Biochemistry and Cell Biology, Developmental Biology
Abstract

Summary Large-scale collections of induced pluripotent stem cells (iPSCs) could serve as powerful model systems for examining how genetic variation affects biology and disease. Here we describe the iPSCORE resource: a collection of systematically derived and characterized iPSC lines from 222 ethnically diverse individuals that allows for both familial and association-based genetic studies. iPSCORE lines are pluripotent with high genomic integrity (no or low numbers of somatic copy-number variants) as determined using high-throughput RNA-sequencing and genotyping arrays, respectively. Using iPSCs from a family of individuals, we show that iPSC-derived cardiomyocytes demonstrate gene expression patterns that cluster by genetic background, and can be used to examine variants associated with physiological and disease phenotypes. The iPSCORE collection contains representative individuals for risk and non-risk alleles for 95% of SNPs associated with human phenotypes through genome-wide association studies. Our study demonstrates the utility of iPSCORE for examining how genetic variants influence molecular and physiological traits in iPSCs and derived cell lines., Graphical Abstract, Highlights • iPSCORE: A collection of publicly available iPSCs from 222 individuals • Several multigenerational families and individuals of various ethnicities and ages • Individuals carrying risk and non-risk genotypes for 95% of GWAS SNPs • Genetic variants associated with mRNA expression in differentiated cardiomyocytes, Working as part of the NHLBI NextGen consortium, Panopoulos and colleagues report the derivation and characterization of 222 publicly available iPSCs from ethnically diverse individuals with corresponding genomic data including SNP arrays, RNA-seq, and whole-genome sequencing. This collection provides a powerful resource to investigate the function of genetic variants.

Published
2017

26. Psychological adjustment among young Puerto Rican mothers: Perceived partner support and the moderating role of Latino cultural orientation

Author

Josefina M. Grau, Erin N. Smith, Lauren E. Wood, Petra A. Duran, Patricia Castellanos, and Stephanie G. Silberman

Subjects
Cultural Studies, Multivariate analysis, Social Psychology, Cultural orientation, 05 social sciences, Stressor, Puerto rican, 050109 social psychology, Article, Acculturation, Developmental psychology, Clinical Psychology, Social support, 050902 family studies, Orientation (mental), Anthropology, Intervention (counseling), 0501 psychology and cognitive sciences, 0509 other social sciences, Psychology, Social psychology, Applied Psychology
Abstract

Adolescent mothers face multiple stressors and are at risk for experiencing high levels of depressive symptoms and parenting stress. This study examined the interplay of Latino cultural orientation and perceived support from romantic partners in protecting the adjustment of young, low-income, Puerto Rican mothers (N = 103; M age = 18.0 yrs; SD = 1.2) during the second year postpartum. In multivariate analyses, perceived partner support was uniquely and negatively associated with both maternal depressive symptoms and parenting stress. However, in the case of parenting stress, this association was moderated by mothers’ Latino cultural orientation. Perceived partner support was related to less parenting stress when mothers endorsed a relatively strong Latino cultural orientation; perceived partner support was no longer protective at low levels of Latino orientation. The implications for intervention and for the understanding of the role of culture in social support processes within close relationships are discussed.

Published
2017

27. Allele-specific NKX2-5 binding underlies multiple genetic associations with human electrocardiographic traits

Author

Kyle J. Gaulton, Paola Benaglio, Jessica van Setten, Michael G. Rosenfeld, Nona Sotoodehnia, Erin N. Smith, Agnieszka D'Antonio-Chronowska, He Li, Wubin Ma, Margaret K.R. Donovan, Christopher DeBoever, William W. Greenwald, Feng Yang, Frauke Drees, Hiroko Matsui, Sanghamitra Singhal, Kelly A. Frazer, and Matteo D’Antonio

Subjects
Male, Epigenomics, Genome-wide association study, Cardiovascular, Medical and Health Sciences, Electrocardiography, 0302 clinical medicine, Atrial Fibrillation, 80 and over, 2.1 Biological and endogenous factors, Myocytes, Cardiac, Regulatory Elements, Transcriptional, Aetiology, Induced pluripotent stem cell, Child, Aged, 80 and over, Genetics, 0303 health sciences, Genome, Single Nucleotide, Middle Aged, Biological Sciences, Phenotype, Heart Disease, cardiovascular system, Homeobox Protein Nkx-2.5, Female, Transcriptional, Cardiac, Protein Binding, Human, Adult, Adolescent, Quantitative Trait Loci, Induced Pluripotent Stem Cells, Quantitative trait locus, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Young Adult, Humans, Genetic Predisposition to Disease, Allele, Polymorphism, Gene, Alleles, 030304 developmental biology, Aged, Myocytes, Genome, Human, Human Genome, Stem Cell Research, Regulatory Elements, Expression quantitative trait loci, Transcriptome, 030217 neurology & neurosurgery, Genome-Wide Association Study, Developmental Biology
Abstract

The cardiac transcription factor (TF) gene NKX2–5 has been associated with electrocardiographic (EKG) traits through GWAS, but the extent to which differential binding of NKX2–5 at common regulatory variants contributes to these traits has not yet been studied. We analyzed transcriptomic and epigenomic data from iPSC-derived cardiomyocytes (iPSC-CMs) from seven related individuals and identified ~2,000 single nucleotide variants (SNVs) associated with allele-specific effects (ASE) on NKX2–5 binding. NKX2–5 ASE-SNVs were enriched for altered TF motifs, for heart-specific eQTLs, and for EKG GWAS signals. Using fine-mapping combined with epigenomic data from iPSC-CMs, we prioritized candidate causal variants for EKG traits, many of which were NKX2–5 ASE-SNVs. Experimentally characterizing two NKX2–5 ASE-SNVs (rs3807989 and rs590041) showed that they modulate the expression of target genes via differential protein binding in cardiac cells, indicating that they are functional variants underlying EKG GWAS signals. Our results show that differential NKX2–5 binding at numerous regulatory variants across the genome contributes to EKG phenotypes., Editorial summary: Analysis of iPSC-derived cardiomyocytes identifies variants associated with allele-specific effects on NKX2–5 binding. Fine-mapping and functional studies suggest that such variants underlie cardiac-specific expression quantitative trait loci and associations with electrocardiographic traits.

Published
2019

28. Dyadic synchrony among young Latina mothers and their toddlers: The role of maternal and child behavior

Author

Aimee Tovah Hammer, Josefina M. Grau, Erin N. Smith, and Stephanie G. Silberman

Subjects
Male, Adolescent, Population, Child Behavior, Mothers, Affect (psychology), Article, Developmental psychology, 03 medical and health sciences, 0302 clinical medicine, Child Development, Developmental and Educational Psychology, Humans, 0501 psychology and cognitive sciences, education, 030222 orthopedics, education.field_of_study, 05 social sciences, Attentional control, Infant, Hispanic or Latino, Child development, Mother-Child Relations, Maternal sensitivity, Cross-Sectional Studies, Child, Preschool, behavior and behavior mechanisms, Female, Psychology, human activities, 050104 developmental & child psychology
Abstract

Synchronous interactions are an important indicator of parent-child relationship quality with positive implications for child development. Latina adolescent mothers face several demographic challenges that place them at risk for less synchronous interactions. To identify factors that may facilitate more optimal parent-child relationships in this population, our study examined maternal sensitivity and children’s behavioral styles as joint predictors of dyadic synchrony among young Latina mothers and their toddlers. Mother-toddler dyads (N = 170) were observed interacting across different tasks, and toddlers’ behavior was observed during the administration of a developmental test. Results of multivariate regressions revealed additive effects of maternal sensitivity and child behavioral styles (i.e., dysregulation and positive attentional control). Maternal sensitivity related to higher dyadic synchrony for the entire sample. Positive attentional control was related to higher dyadic synchrony for mother-daughter dyads only. Although no gender differences in dyadic synchrony or the behavior style variables emerged, the relative contribution of maternal and child factors differed by child gender, suggesting that mothers may have responded differently to similar behavior and affect displayed by boys and girls. The findings provide insights regarding factors that contribute to dyadic synchrony in this understudied population and emphasize the need to consider child gender when studying parent-child interactions in young Latina families.

Published
2019

29. Genomic properties of structural variants and short tandem repeats that impact gene expression and complex traits in humans

Author

David Jakubosky, Greenwald Wwy, Matteo D’Antonio, Kelly A. Frazer, Agnieszka D'Antonio-Chronowska, Craig Smail, Christopher DeBoever, Margaret K.R. Donovan, Erin N. Smith, Stephen B. Montgomery, Hiroko Matsui, Marc Jan Bonder, and Oliver Stegle

Subjects
0303 health sciences, Linkage disequilibrium, Genome-wide association study, Computational biology, Dna variants, Biology, Genome, Expression (mathematics), Chromatin, 03 medical and health sciences, 0302 clinical medicine, IMPACT gene, Microsatellite, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract

Structural variants (SVs) and short tandem repeats (STRs) comprise a broad group of diverse DNA variants which vastly differ in their sizes and distributions across the genome. Here, we show that different SV classes and STRs differentially impact gene expression and complex traits. Functional differences between SV classes and STRs include their genomic locations relative to eGenes, likelihood of being associated with multiple eGenes, associated eGene types (e.g., coding, noncoding, level of evolutionary constraint), effect sizes, linkage disequilibrium with tagging single nucleotide variants used in GWAS, and likelihood of being associated with GWAS traits. We also identified a set of high-impact SVs/STRs associated with the expression of three or more eGenes via chromatin loops and showed they are highly enriched for being associated with GWAS traits. Our study provides insights into the genomic properties of structural variant classes and short tandem repeats that impact gene expression and human traits.

Published
2019
Full Text
View/download PDF

30. Discovery and Quality Analysis of a Comprehensive Set of Structural Variants and Short Tandem Repeats

Author

Oliver Stegle, Stephen B. Montgomery, William W. Greenwald, Hiroko Matsui, Matteo D’Antonio, Marc Jan Bonder, Kelly A. Frazer, Christopher DeBoever, David Jakubosky, Agnieszka D'Antonio-Chronowska, and Erin N. Smith

Subjects
Whole genome sequencing, Set (abstract data type), Genetic diversity, Sequencing data, Genotype, Microsatellite, Computational biology, Biology
Abstract

Structural variants (SVs) and short tandem repeats (STRs) are important sources of genetic diversity but are not routinely analyzed in genetic studies because they are difficult to accurately identify and genotype. Because SVs and STRs range in size and type, it is necessary to apply multiple algorithms that incorporate different types of evidence from sequencing data and employ complex filtering strategies to discover a comprehensive set of high-quality and reproducible variants. Here we assembled a set of 719 deep whole genome sequencing (WGS) samples (mean 42x) from 477 distinct individuals which we used to discover and genotype a wide spectrum of SV and STR variants using five algorithms. We used 177 unique pairs of genetic replicates to identify factors that affect variant call reproducibility and developed a systematic filtering strategy to create of one of the most complete and well characterized maps of SVs and STRs to date.

Published
2019
Full Text
View/download PDF

31. Activation of hedgehog signaling associates with early disease progression in chronic lymphocytic leukemia

Author

Kelly A. Frazer, John Douglas Mcpherson, Thomas J. Hudson, Emanuela M. Ghia, Laura Z. Rassenti, Erin N. Smith, Donna Neuberg, Fouad Yousif, Alejandro Toro Blanco, Olivier Harismendy, and Thomas J. Kipps

Subjects
Adult, Male, 0301 basic medicine, Pyridines, Chronic lymphocytic leukemia, Immunology, medicine.disease_cause, Biochemistry, Zinc Finger Protein GLI1, 03 medical and health sciences, 0302 clinical medicine, GLI1, immune system diseases, hemic and lymphatic diseases, Cytotoxic T cell, Medicine, Humans, Hedgehog Proteins, Hedgehog, Aged, Aged, 80 and over, Mutation, Lymphoid Neoplasia, biology, integumentary system, Gene Expression Regulation, Leukemic, business.industry, Cell Biology, Hematology, Middle Aged, medicine.disease, Leukemia, Lymphocytic, Chronic, B-Cell, Hedgehog signaling pathway, Leukemia, Pyrimidines, 030104 developmental biology, 030220 oncology & carcinogenesis, Cancer research, biology.protein, Disease Progression, Female, IGHV@, business, Signal Transduction
Abstract

Targeted sequencing of 103 leukemia-associated genes in leukemia cells from 841 treatment-naive patients with chronic lymphocytic leukemia (CLL) identified 89 (11%) patients as having CLL cells with mutations in genes encoding proteins that putatively are involved in hedgehog (Hh) signaling. Consistent with this finding, there was a significant association between the presence of these mutations and the expression of GLI1 (χ2 test, P < .0001), reflecting activation of the Hh pathway. However, we discovered that 38% of cases without identified mutations also were GLI1+. Patients with GLI1+ CLL cells had a shorter median treatment-free survival than patients with CLL cells lacking expression of GLI1 independent of IGHV mutation status. We found that GANT61, a small molecule that can inhibit GLI1, was highly cytotoxic for GLI1+ CLL cells relative to that of CLL cells without GLI1. Collectively, this study shows that a large proportion of patients have CLL cells with activated Hh signaling, which is associated with early disease progression and enhanced sensitivity to inhibition of GLI1.

Published
2019

32. Human iPSC gene signatures and X chromosome dosage impact response to WNT inhibition and cardiac differentiation fate

Author

Mana Parast, Margaret K.R. Donovan, Eric Adler, Francesca Soncin, Kyohei Fujita, William W. Greenwald, Agnieszka D'Antonio-Chronowska, Paola Benaglio, Erin N. Smith, Michelle C. Ward, Matteo D’Antonio, Kelly A. Frazer, Sherin Hashem, and Hiroko Matsui

Subjects
0303 health sciences, Cell type, Wnt signaling pathway, Biology, Gene dosage, Cell biology, Transcriptome, 03 medical and health sciences, 0302 clinical medicine, Progenitor cell, Induced pluripotent stem cell, Gene, 030217 neurology & neurosurgery, X chromosome, 030304 developmental biology
Abstract

Non-genetic variability in human induced pluripotent stem cell (iPSC) lines impacts their differentiation outcome, limiting their utility for genetic studies and clinical applications. Despite the importance of understanding how non-genetic molecular variability influences iPSC differentiation outcome, large-scale studies capable of addressing this question have not yet been conducted. Here, we performed 258 directed differentiations of 191 iPSC lines using established protocols to generate iPSC-derived cardiovascular progenitor cells (iPSC-CVPCs). We observed cellular heterogeneity across the iPSC-CVPC samples due to varying fractions of two cell types: cardiomyocytes (CMs) and epicardium-derived cells (EPDCs). Analyzing the transcriptomes of CM-fated and EPDC-fated iPSCs discovered that 91 signature genes and X chromosome dosage differences influence WNT inhibition response during differentiation and are associated with cardiac fate. Analysis of an independent set of 39 iPSCs differentiated to the cardiac lineage confirmed shared sex and transcriptional differences that impact cardiac fate outcome. The scale and systematic approach of our study enabled novel insights into how iPSC transcriptional and X chromosome gene dosage differences influence WNT signaling during differentiation and hence cardiac cell fate.

Published
2019
Full Text
View/download PDF

33. Fibrinogen gamma gene

Author

Benedikte, Paulsen, Hanne, Skille, Erin N, Smith, Kristian, Hveem, Maiken E, Gabrielsen, Sigrid K, Brækkan, Frits R, Rosendaal, Kelly A, Frazer, Olga V, Gran, and John-Bjarne, Hansen

Subjects
Risk Factors, Incidence, Neoplasms, Coagulation & its Disorders, Fibrinogen, Humans, cardiovascular diseases, Venous Thromboembolism, Articles, equipment and supplies, Alleles
Abstract

Venous thromboembolism (VTE) is a frequent complication in patients with cancer. Homozygous carriers of the fibrinogen gamma gene (FGG) rs2066865 have a moderately increased risk of VTE, but the effect of the FGG variant in cancer is unknown. We aimed to investigate the effect of the FGG variant and active cancer on the risk of VTE. Cases with incident VTE (n=640) and a randomly selected age-weighted sub-cohort (n=3,734) were derived from a population-based cohort (the Tromsø study). Cox-regression was used to estimate hazard ratios (HR) with 95% confidence intervals (CI) for VTE according to categories of cancer and FGG. In those without cancer, homozygosity at the FGG variant was associated with a 70% (HR 1.7, 95% CI: 1.2–2.3) increased risk of VTE compared to non-carriers. Cancer patients homozygous for the FGG variant had a two-fold (HR 2.0, 95% CI: 1.1–3.6) higher risk of VTE than cancer patients without the variant. Moreover, the six-months cumulative incidence of VTE among cancer patients was 6.4% (95% CI: 3.5–11.6) in homozygous carriers of FGG and 3.1% (95% CI: 2.3–4.7) in those without risk alleles. A synergistic effect was observed between rs2066865 and active cancer on the risk of VTE (synergy index: 1.81, 95% CI: 1.02–3.21, attributable proportion: 0.43, 95% CI: 0.11–0.74). In conclusion, homozygosity at the FGG variant and active cancer yielded a synergistic effect on the risk of VTE.

Published
2019

34. Subtle changes in chromatin loop contact propensity are associated with differential gene regulation and expression

Author

Agnieszka D'Antonio-Chronowska, Anthony D. Schmitt, William W. Greenwald, Matteo D’Antonio, Kelly A. Frazer, Paola Benaglio, Hiroko Matsui, Siddarth Selvaraj, He Li, Erin N. Smith, and David Jakubosky

Subjects
Male, 0301 basic medicine, genetic processes, General Physics and Astronomy, 02 engineering and technology, Histones, Gene expression, Myocytes, Cardiac, skin and connective tissue diseases, lcsh:Science, Regulation of gene expression, Multidisciplinary, Single Nucleotide, Middle Aged, 021001 nanoscience & nanotechnology, Chromatin, Female, Chromatin Loop, 0210 nano-technology, Cardiac, Adult, Cell type, Adolescent, Science, Induced Pluripotent Stem Cells, Quantitative Trait Loci, Biology, Polymorphism, Single Nucleotide, Article, General Biochemistry, Genetics and Molecular Biology, Cell Line, Young Adult, 03 medical and health sciences, Genetic variation, Genetics, Humans, natural sciences, Polymorphism, Aged, Myocytes, Whole Genome Sequencing, Mechanism (biology), Human Genome, Haplotype, DNA, General Chemistry, 030104 developmental biology, Gene Expression Regulation, Evolutionary biology, Nucleic Acid Conformation, lcsh:Q, sense organs
Abstract

While genetic variation at chromatin loops is relevant for human disease, the relationships between contact propensity (the probability that loci at loops physically interact), genetics, and gene regulation are unclear. We quantitatively interrogate these relationships by comparing Hi-C and molecular phenotype data across cell types and haplotypes. While chromatin loops consistently form across different cell types, they have subtle quantitative differences in contact frequency that are associated with larger changes in gene expression and H3K27ac. For the vast majority of loci with quantitative differences in contact frequency across haplotypes, the changes in magnitude are smaller than those across cell types; however, the proportional relationships between contact propensity, gene expression, and H3K27ac are consistent. These findings suggest that subtle changes in contact propensity have a biologically meaningful role in gene regulation and could be a mechanism by which regulatory genetic variants in loop anchors mediate effects on expression., It is currently unclear how quantitative changes in chromatin loop propensity contribute to differential gene regulation. Here, the authors use phased Hi-C, RNA-seq, and ChIP-seq to show that subtle changes in loop propensity associate with differential gene regulation across cell types and haplotypes.

Published
2019

35. Identification of Common and Rare Genetic Variation Associated With Plasma Protein Levels Using Whole-Exome Sequencing and Mass Spectrometry

Author

Erin N. Smith, Terry Solomon, Nadezhda Latysheva, John-Bjarne Hansen, Kelly A. Frazer, William W. Greenwald, Kristian Hindberg, Hiroko Matsui, David Gonzalez, Søren B. Jensen, John D. Lapek, and Sigrid K. Braekken

Subjects
Male, 0301 basic medicine, Proteome, Genotype, Quantitative Trait Loci, Computational biology, 030204 cardiovascular system & hematology, Biology, Quantitative trait locus, Mass spectrometry, Proteomics, Article, Mass Spectrometry, Cohort Studies, 03 medical and health sciences, Exon, proteomics, 0302 clinical medicine, Exome Sequencing, Genetic variation, Genetics, Humans, 2.1 Biological and endogenous factors, Aetiology, plasma, Exome sequencing, Human Genome, Genetic Variation, Blood Proteins, Exons, General Medicine, 030104 developmental biology, Female, Identification (biology)
Abstract

Background: Identifying genetic variation associated with plasma protein levels, and the mechanisms by which they act, could provide insight into alterable processes involved in regulation of protein levels. Although protein levels can be affected by genetic variants, their estimation can also be biased by missense variants in coding exons causing technical artifacts. Integrating genome sequence genotype data with mass spectrometry-based protein level estimation could reduce bias, thereby improving detection of variation that affects RNA or protein metabolism. Methods: Here, we integrate the blood plasma protein levels of 664 proteins from 165 participants of the Tromsø Study, measured via tandem mass tag mass spectrometry, with whole-exome sequencing data to identify common and rare genetic variation associated with peptide and protein levels (protein quantitative trait loci [pQTLs]). We additionally use literature and database searches to prioritize putative functional variants for each pQTL. Results: We identify 109 independent associations (36 protein and 73 peptide) and use genotype data to exclude 49 (4 protein and 45 peptide) as technical artifacts. We describe 2 particular cases of rare variation: 1 associated with the complement pathway and 1 with platelet degranulation. We identify putative functional variants and show that pQTLs act through diverse molecular mechanisms that affect both RNA and protein metabolism. Conclusions: We show that although the majority of pQTLs exert their effects by modulating RNA metabolism, many affect protein levels directly. Our work demonstrates the extent by which pQTL studies are affected by technical artifacts and highlights how prioritizing the functional variant in pQTL studies can lead to insights into the molecular steps by which a protein may be regulated.

Published
2018

36. Genome Analyses of >200,000 Individuals Identify 58 Loci for Chronic Inflammation and Highlight Pathways that Link Inflammation and Complex Disorders

Author

Symen Ligthart, Ahmad Vaez, Urmo Võsa, Maria G. Stathopoulou, Paul S. de Vries, Bram P. Prins, Peter J. Van der Most, Toshiko Tanaka, Elnaz Naderi, Lynda M. Rose, Ying Wu, Robert Karlsson, Maja Barbalic, Honghuang Lin, René Pool, Gu Zhu, Aurélien Macé, Carlo Sidore, Stella Trompet, Massimo Mangino, Maria Sabater-Lleal, John P. Kemp, Ali Abbasi, Tim Kacprowski, Niek Verweij, Albert V. Smith, Tao Huang, Carola Marzi, Mary F. Feitosa, Kurt K. Lohman, Marcus E. Kleber, Yuri Milaneschi, Christian Mueller, Mahmudul Huq, Efthymia Vlachopoulou, Leo-Pekka Lyytikäinen, Christopher Oldmeadow, Joris Deelen, Markus Perola, Jing Hua Zhao, Bjarke Feenstra, Marzyeh Amini, Jari Lahti, Katharina E. Schraut, Myriam Fornage, Bhoom Suktitipat, Wei-Min Chen, Xiaohui Li, Teresa Nutile, Giovanni Malerba, Jian’an Luan, Tom Bak, Nicholas Schork, Fabiola Del Greco M., Elisabeth Thiering, Anubha Mahajan, Riccardo E. Marioni, Evelin Mihailov, Joel Eriksson, Ayse Bilge Ozel, Weihua Zhang, Maria Nethander, Yu-Ching Cheng, Stella Aslibekyan, Wei Ang, Ilaria Gandin, Loïc Yengo, Laura Portas, Charles Kooperberg, Edith Hofer, Kumar B. Rajan, Claudia Schurmann, Wouter den Hollander, Tarunveer S. Ahluwalia, Jing Zhao, Harmen H.M. Draisma, Ian Ford, Nicholas Timpson, Alexander Teumer, Hongyan Huang, Simone Wahl, YongMei Liu, Jie Huang, Hae-Won Uh, Frank Geller, Peter K. Joshi, Lisa R. Yanek, Elisabetta Trabetti, Benjamin Lehne, Diego Vozzi, Marie Verbanck, Ginevra Biino, Yasaman Saba, Ingrid Meulenbelt, Jeff R. O’Connell, Markku Laakso, Franco Giulianini, Patrik K.E. Magnusson, Christie M. Ballantyne, Jouke Jan Hottenga, Grant W. Montgomery, Fernando Rivadineira, Rico Rueedi, Maristella Steri, Karl-Heinz Herzig, David J. Stott, Cristina Menni, Mattias Frånberg, Beate St. Pourcain, Stephan B. Felix, Tune H. Pers, Stephan J.L. Bakker, Peter Kraft, Annette Peters, Dhananjay Vaidya, Graciela Delgado, Johannes H. Smit, Vera Großmann, Juha Sinisalo, Ilkka Seppälä, Stephen R. Williams, Elizabeth G. Holliday, Matthijs Moed, Claudia Langenberg, Katri Räikkönen, Jingzhong Ding, Harry Campbell, Michele M. Sale, Yii-Der I. Chen, Alan L. James, Daniela Ruggiero, Nicole Soranzo, Catharina A. Hartman, Erin N. Smith, Gerald S. Berenson, Christian Fuchsberger, Dena Hernandez, Carla M.T. Tiesler, Vilmantas Giedraitis, David Liewald, Krista Fischer, Dan Mellström, Anders Larsson, Yunmei Wang, William R. Scott, Matthias Lorentzon, John Beilby, Kathleen A. Ryan, Craig E. Pennell, Dragana Vuckovic, Beverly Balkau, Maria Pina Concas, Reinhold Schmidt, Carlos F. Mendes de Leon, Erwin P. Bottinger, Margreet Kloppenburg, Lavinia Paternoster, Michael Boehnke, A.W. Musk, Gonneke Willemsen, David M. Evans, Pamela A.F. Madden, Mika Kähönen, Zoltán Kutalik, Magdalena Zoledziewska, Ville Karhunen, Stephen B. Kritchevsky, Naveed Sattar, Genevieve Lachance, Robert Clarke, Tamara B. Harris, Olli T. Raitakari, John R. Attia, Diana van Heemst, Eero Kajantie, Rossella Sorice, Giovanni Gambaro, Robert A. Scott, Andrew A. Hicks, Luigi Ferrucci, Marie Standl, Cecilia M. Lindgren, John M. Starr, Magnus Karlsson, Lars Lind, Jun Z. Li, John C. Chambers, Trevor A. Mori, Eco J.C.N. de Geus, Andrew C. Heath, Nicholas G. Martin, Juha Auvinen, Brendan M. Buckley, Anton J.M. de Craen, Melanie Waldenberger, Konstantin Strauch, Thomas Meitinger, Rodney J. Scott, Mark McEvoy, Marian Beekman, Cristina Bombieri, Paul M. Ridker, Karen L. Mohlke, Nancy L. Pedersen, Alanna C. Morrison, Dorret I. Boomsma, John B. Whitfield, David P. Strachan, Albert Hofman, Peter Vollenweider, Francesco Cucca, Marjo-Riitta Jarvelin, J. Wouter Jukema, Tim D. Spector, Anders Hamsten, Tanja Zeller, André G. Uitterlinden, Matthias Nauck, Vilmundur Gudnason, Lu Qi, Harald Grallert, Ingrid B. Borecki, Jerome I. Rotter, Winfried März, Philipp S. Wild, Marja-Liisa Lokki, Michael Boyle, Veikko Salomaa, Mads Melbye, Johan G. Eriksson, James F. Wilson, Brenda W.J.H. Penninx, Diane M. Becker, Bradford B. Worrall, Greg Gibson, Ronald M. Krauss, Marina Ciullo, Gianluigi Zaza, Nicholas J. Wareham, Albertine J. Oldehinkel, Lyle J. Palmer, Sarah S. Murray, Peter P. Pramstaller, Stefania Bandinelli, Joachim Heinrich, Erik Ingelsson, Ian J. Deary, Reedik Mägi, Liesbeth Vandenput, Pim van der Harst, Karl C. Desch, Jaspal S. Kooner, Claes Ohlsson, Caroline Hayward, Terho Lehtimäki, Alan R. Shuldiner, Donna K. Arnett, Lawrence J. Beilin, Antonietta Robino, Philippe Froguel, Mario Pirastu, Tine Jess, Wolfgang Koenig, Ruth J.F. Loos, Denis A. Evans, Helena Schmidt, George Davey Smith, P. Eline Slagboom, Gudny Eiriksdottir, Andrew P. Morris, Bruce M. Psaty, Russell P. Tracy, Ilja M. Nolte, Eric Boerwinkle, Sophie Visvikis-Siest, Alex P. Reiner, Myron Gross, Joshua C. Bis, Lude Franke, Oscar H. Franco, Emelia J. Benjamin, Daniel I. Chasman, Josée Dupuis, Harold Snieder, Abbas Dehghan, Behrooz Z. Alizadeh, H. Marike Boezen, Gerjan Navis, Marianne Rots, Morris Swertz, Bruce H.R. Wolffenbuttel, Cisca Wijmenga, Emelia Benjamin, Tarunveer Singh Ahluwalia, James Meigs, Russell Tracy, Josh Bis, Nathan Pankratz, Alex Rainer, James G. Wilson, Josee Dupuis, Bram Prins, Urmo Vaso, Maria Stathopoulou, Terho Lehtimaki, Yalda Jamshidi, Sophie Siest, Andre G. Uitterlinden, Mohammadreza Abdollahi, Renate Schnabel, Ursula M. Schick, Aldi Kraja, Yi-Hsiang Hsu, Daniel S. Tylee, Alyson Zwicker, Rudolf Uher, George Davey-Smith, Andrew Hicks, Cornelia M. van Duijn, Cavin Ward-Caviness, J. Rotter, Ken Rice, Leslie Lange, Eco de Geus, Kari Matti Makela, David Stacey, Johan Eriksson, Tim M. Frayling, Eline P. Slagboom, Erasmus University Medical Center [Rotterdam] (Erasmus MC), University Medical Center Groningen [Groningen] (UMCG), University of Isfahan, University of Tartu, Interactions Gène-Environnement en Physiopathologie Cardio-Vasculaire (IGE-PCV), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), The University of Texas Health Science Center at Houston (UTHealth), National Institute on Aging [Bethesda, USA] (NIA), National Institutes of Health [Bethesda] (NIH), Brigham and Women's Hospital [Boston], University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC), Department of Medical Epidemiology and Biostatistics (MEB), Karolinska Institutet [Stockholm], University of Split, Boston University School of Medicine (BUSM), Boston University [Boston] (BU), Process & Energy Laboratory, Delft University of Technology (TU Delft), Grand Lyon : communauté urbaine de Lyon, Interuniversity Cardiology Institute Netherlands, Department of Twin Research and Genetic Epidemiology, King's College London, London, Huazhong University of Science and Technology [Wuhan] (HUST), Division of Statistical Genomics, Washington University School of Medicine, Department of Psychiatry, VU University Medical Center [Amsterdam], Institut fuer Theoretische Physik (Institut fuer Theoretische Physik), Universität Heidelberg [Heidelberg] = Heidelberg University, Molecular Epidemiology, MRC Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Mahidol University [Bangkok], Northwest A and F University, Laboratoire d'Optimisation des Systèmes Industriels (LOSI), Institut Charles Delaunay (ICD), Université de Technologie de Troyes (UTT)-Centre National de la Recherche Scientifique (CNRS)-Université de Technologie de Troyes (UTT)-Centre National de la Recherche Scientifique (CNRS), Institute of Genetics and Biophysics, CNR, Naples, Università degli studi di Verona = University of Verona (UNIVR), Department of Molecular Medicine [Scripps Research Institute], The Scripps Research Institute [La Jolla, San Diego], Department of Physics, Indian Institute of Technology Kanpur (IIT Kanpur), Deptartment of Medical Biochemistry and Microbiology, Uppsala University, Department of Electrical and Computer Engineering [Waterloo] (ECE), University of Waterloo [Waterloo], University of Maryland School of Medicine, University of Maryland System, Institut National de l'Environnement Industriel et des Risques (INERIS), Institute of Pop. Genetics, CNR, Sassari, Interfaculty Institute for Genetics and Functional Genomics, Universität Greifswald - University of Greifswald, IT University of Copenhagen (ITU), Robertson Centre for Biostatistics, University of Glasgow, Centre for Causal Analyses in Translational Epidemiology, University of Bristol [Bristol]-Medical Research Council, King‘s College London, Jinan University [Guangzhou], Institute of Oceanology [China], School Medicine, University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE)-Pennsylvania Commonwealth System of Higher Education (PCSHE), General Internal Medicine, Johns Hopkins School of Medicine, Johns Hopkins University School of Medicine [Baltimore], Shardna life science Pula Cagliari, Section Molecular Epidemiology, Leiden University Medical Center (LUMC), Department of Medicine, University of Eastern Finland-Kuopio University Hospital, Medstar Research Institute, Department of Cardiology, Ernst-Moritz-Arndt University, Center for Biological Sequence Analysis [Lyngby], Danmarks Tekniske Universitet = Technical University of Denmark (DTU), Department of Internal Medicine, University of Groningen and University Medical Center Groningen, Department of Epidemiology, Harvard School of Public Health, German Research Center for Environmental Health - Helmholtz Center München (GmbH), Metacohorts Consortium, INEOS Technologies (SWITZERLAND), MRC Epidemiology Unit, University of Cambridge [UK] (CAM)-Institute of Metabolic Science, University of Edinburgh, School of Population Health [Crawley, Western Australia], The University of Western Australia (UWA), Institute of Genetics and Biophysics, National Research Council of Italy | Consiglio Nazionale delle Ricerche (CNR), The Scripps Translational Science Institute and Scripps Health, Tulane Center for Cardiovascular Health, Tulane University Health Sciences Center, Centre for Population Health Sciences, Genomic Research Laboratory, Service of Infectious Disease, Hôpitaux Universitaires de Genève (HUG), Infectious diseases division, Department of internal medicine, Washington University in Saint Louis (WUSTL), Luleå University of Technology (LUT), Recherche en épidémiologie et biostatistique, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), Austrian Institute of Technology [Vienna] (AIT), Icahn School of Medicine at Mount Sinai [New York] (MSSM), Department of Rheumatology and Clinical Epidemiology, Leiden University Medical Center (LUMC), Department of Rheumatology and Clinical Epidemiology [Leiden University Medical Center] (LUMC), Leiden University Medical Center (LUMC), Universiteit Leiden-Universiteit Leiden-Leiden University Medical Center (LUMC), Universiteit Leiden-Universiteit Leiden, Department of Biostatistics and Center for Statistical Genetics, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, University of Virginia, Tampere University Hospital, Department of Medical Genetics, Université de Lausanne = University of Lausanne (UNIL), Department of Pathological Biochemistry, Royal Infirmary, Oxford University, University of Oxford, University of Newcastle [Callaghan, Australia] (UoN), Department of neurology, Institute of Metabolic Science, MRC, The Wellcome Trust Centre for Human Genetics [Oxford], Uppsala Universitet [Uppsala], QIMR Berghofer Medical Research Institute, Institute of Genetic Epidemiology [Neuherberg, Germany], Institute of Human Genetics, Helmholtz Zentrum München = German Research Center for Environmental Health, Schizophrenia Research Institute [Sydney], Department of Genetics, University of North Carolina System (UNC)-University of North Carolina System (UNC), Vrije Universiteit Brussel (VUB), Population Health Sciences and Education, St George's University of London, Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Institute of Health Sciences and Biocenter Oulu, University of Oulu, Medizinische Klinik und Poliklinik, Johannes Gutenberg - Universität Mainz = Johannes Gutenberg University (JGU), Institute of Clinical Chemistry and Laboratory Medicine, Icelandic Heart Association, Heart Preventive Clinic and Research Institute, Departments of Epidemiology and Nutrition, Institute of Epidemiology [Neuherberg] (EPI), Medical University Graz, Transplantation Laboratory [Helsinki], Haartman Institute [Helsinki], Faculty of Medecine [Helsinki], Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Faculty of Medecine [Helsinki], Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Department of Chronic Disease Prevention, National Institute for Health and Welfare [Helsinki], Dept. of Epidemiology Research, Statens Serum Institut [Copenhagen], CLinical Psychology, Genetics and Pathology, Geriatric Rehabilitation Unit, Azienda Sanitaria Firenze, Center For Narcolepsy, Stanford University, Centre for Bone and Arthritis Research, University of Gothenburg (GU)-Institute of Medicine, MRC Human Gentics Unit, Inst Genet and Mol Med, Western General Hospital, Edinburgh, University of Maryland School of Medicine [Baltimore, MD, USA], Génétique des maladies multifactorielles (GMM), Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique (CNRS), Department of Physics [Stockholm], Stockholm University, University of Bristol [Bristol], Universiteit Leiden, Department of Epidemiology, University of Washington, University of Washington [Seattle], Department of Epidemiology [Rotterdam], University of Groningen [Groningen], Dutch Initiative on Crohn and Colitis (ICC), Icelandic Heart Association [Kopavogur, Iceland] (IHA), Department of Physiology and Biophysics [Jackson, MS, USA], University of Southern Mississippi (USM), Human Genetics Branch, National Institutes of Health [Bethesda] (NIH)-National Institute of Mental Health (NIMH), Faculty of Medicine and Life Sciences [Tampere], University of Tampere [Finland], German Center for Cardiovascular Research (DZHK), Berlin Institute of Health (BIH), MRC Centre for Neuropsychiatric Genetics and Genomics, Medical Research Council-Cardiff University, Department of Social Medicine, School of Medicine [Los Angeles], University of California [Los Angeles] (UCLA), University of California (UC)-University of California (UC), Department of Medicine [Aurora, CO, USA], University of Colorado [Denver], Institute for Molecular Medicine Finland [Helsinki] (FIMM), Helsinki Institute of Life Science (HiLIFE), Mathematical Institute [Oxford] (MI), Institute of Psychiatry, Psychology & Neuroscience, King's College London, LifeLines Cohort Study, CHARGE Inflammation Working Group, Ligthart, S., Vaez, A., Vosa, U., Stathopoulou, M. G., de Vries, P. S., Prins, B. P., Van der Most, P. J., Tanaka, T., Naderi, E., Rose, L. M., Wu, Y., Karlsson, R., Barbalic, M., Lin, H., Pool, R., Zhu, G., Mace, A., Sidore, C., Trompet, S., Mangino, M., Sabater-Lleal, M., Kemp, J. P., Abbasi, A., Kacprowski, T., Verweij, N., Smith, A. V., Huang, T., Marzi, C., Feitosa, M. F., Lohman, K. K., Kleber, M. E., Milaneschi, Y., Mueller, C., Huq, M., Vlachopoulou, E., Lyytikainen, L. -P., Oldmeadow, C., Deelen, J., Perola, M., Zhao, J. H., Feenstra, B., Alizadeh, B. Z., Boezen, H. M., Franke, L., van der Harst, P., Navis, G., Rots, M., Snieder, H., Swertz, M., Wolffenbuttel, B. H. R., Wijmenga, C., Amini, M., Benjamin, E., Chasman, D. I., Dehghan, A., Ahluwalia, T. S., Meigs, J., Tracy, R., Bis, J., Eiriksdottir, G., Pankratz, N., Gross, M., Rainer, A., Wilson, J. G., Psaty, B. M., Dupuis, J., Prins, B., Vaso, U., Stathopoulou, M., Lehtimaki, T., Koenig, W., Jamshidi, Y., Siest, S., Uitterlinden, A. G., Abdollahi, M., Schnabel, R., Schick, U. M., Nolte, I. M., Kraja, A., Hsu, Y. -H., Tylee, D. S., Zwicker, A., Uher, R., Davey-Smith, G., Morrison, A. C., Hicks, A., van Duijn, C. M., Ward-Caviness, C., Boerwinkle, E., Rotter, J., Rice, K., Lange, L., de Geus, E., Morris, A. P., Makela, K. M., Stacey, D., Eriksson, J., Frayling, T. M., Slagboom, E. P., Lahti, J., Schraut, K. E., Fornage, M., Suktitipat, B., Chen, W. -M., Li, X., Nutile, T., Malerba, G., Luan, J., Bak, T., Schork, N., Del Greco, M. F., Thiering, E., Mahajan, A., Marioni, R. E., Mihailov, E., Ozel, A. B., Zhang, W., Nethander, M., Cheng, Y. -C., Aslibekyan, S., Ang, W., Gandin, I., Yengo, L., Portas, L., Kooperberg, C., Hofer, E., Rajan, K. B., Schurmann, C., den Hollander, W., Zhao, J., Draisma, H. H. M., Ford, I., Timpson, N., Teumer, A., Huang, H., Wahl, S., Liu, Y., Huang, J., Uh, H. -W., Geller, F., Joshi, P. K., Yanek, L. R., Trabetti, E., Lehne, B., Vozzi, D., Verbanck, M., Biino, G., Saba, Y., Meulenbelt, I., O'Connell, J. R., Laakso, M., Giulianini, F., Magnusson, P. K. E., Ballantyne, C. M., Hottenga, J. J., Montgomery, G. W., Rivadineira, F., Rueedi, R., Steri, M., Herzig, K. -H., Stott, D. J., Menni, C., Franberg, M., S, t. Pourcain B., Felix, S. B., Pers, T. H., Bakker, S. J. L., Kraft, P., Peters, A., Vaidya, D., Delgado, G., Smit, J. H., Grossmann, V., Sinisalo, J., Seppala, I., Williams, S. R., Holliday, E. G., Moed, M., Langenberg, C., Raikkonen, K., Ding, J., Campbell, H., Sale, M. M., Chen, Y. -D. I., James, A. L., Ruggiero, D., Soranzo, N., Hartman, C. A., Smith, E. N., Berenson, G. S., Fuchsberger, C., Hernandez, D., Tiesler, C. M. T., Giedraitis, V., Liewald, D., Fischer, K., Mellstrom, D., Larsson, A., Wang, Y., Scott, W. R., Lorentzon, M., Beilby, J., Ryan, K. A., Pennell, C. E., Vuckovic, D., Balkau, B., Concas, M. P., Schmidt, R., Mendes de Leon, C. F., Bottinger, E. P., Kloppenburg, M., Paternoster, L., Boehnke, M., Musk, A. W., Willemsen, G., Evans, D. M., Madden, P. A. F., Kahonen, M., Kutalik, Z., Zoledziewska, M., Karhunen, V., Kritchevsky, S. B., Sattar, N., Lachance, G., Clarke, R., Harris, T. B., Raitakari, O. T., Attia, J. R., van Heemst, D., Kajantie, E., Sorice, R., Gambaro, G., Scott, R. A., Hicks, A. A., Ferrucci, L., Standl, M., Lindgren, C. M., Starr, J. M., Karlsson, M., Lind, L., Li, J. Z., Chambers, J. C., Mori, T. A., de Geus, E. J. C. N., Heath, A. C., Martin, N. G., Auvinen, J., Buckley, B. M., de Craen, A. J. M., Waldenberger, M., Strauch, K., Meitinger, T., Scott, R. J., Mcevoy, M., Beekman, M., Bombieri, C., Ridker, P. M., Mohlke, K. L., Pedersen, N. L., Boomsma, D. I., Whitfield, J. B., Strachan, D. P., Hofman, A., Vollenweider, P., Cucca, F., Jarvelin, M. -R., Jukema, J. W., Spector, T. D., Hamsten, A., Zeller, T., Nauck, M., Gudnason, V., Qi, L., Grallert, H., Borecki, I. B., Rotter, J. I., Marz, W., Wild, P. S., Lokki, M. -L., Boyle, M., Salomaa, V., Melbye, M., Eriksson, J. G., Wilson, J. F., Penninx, B. W. J. H., Becker, D. M., Worrall, B. B., Gibson, G., Krauss, R. M., Ciullo, M., Zaza, G., Wareham, N. J., Oldehinkel, A. J., Palmer, L. J., Murray, S. S., Pramstaller, P. P., Bandinelli, S., Heinrich, J., Ingelsson, E., Deary, I. J., Magi, R., Vandenput, L., Desch, K. C., Kooner, J. S., Ohlsson, C., Hayward, C., Shuldiner, A. R., Arnett, D. K., Beilin, L. J., Robino, A., Froguel, P., Pirastu, M., Jess, T., Loos, R. J. F., Evans, D. A., Schmidt, H., Slagboom, P. E., Tracy, R. P., Visvikis-Siest, S., Reiner, A. P., Bis, J. C., Franco, O. H., Benjamin, E. J., AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Graduate School, Epidemiology, Internal Medicine, Groningen Institute for Organ Transplantation (GIOT), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Cardiovascular Centre (CVC), Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Stem Cell Aging Leukemia and Lymphoma (SALL), Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET), VU University medical center, Psychiatry, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Mental Health, APH - Methodology, APH - Digital Health, Biological Psychology, APH - Personalized Medicine, APH - Health Behaviors & Chronic Diseases, Universität Heidelberg [Heidelberg], University of Verona (UNIVR), Department of Molecular and Experimental Medicine, The Scripps Research Institute, The Scripps Research Institute, Université Grenoble Alpes - UFR Sciences de l'Homme et de la Société (UGA UFR SHS), Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), IT University of Copenhagen, Technical University of Denmark [Lyngby] (DTU), Consiglio Nazionale delle Ricerche (CNR), University of Virginia [Charlottesville], Université de Lausanne (UNIL), University of Oxford [Oxford], University of Newcastle [Australia] (UoN), Centre d'économie industrielle i3 (CERNA i3), Centre National de la Recherche Scientifique (CNRS)-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), Helmholtz-Zentrum München (HZM), Laboratoire Interuniversitaire des Systèmes Atmosphériques (LISA (UMR_7583)), Institut national des sciences de l'Univers (INSU - CNRS)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Centre National de la Recherche Scientifique (CNRS), Universitätsmedizin der Johannes-Gutenberg Universität Mainz, University of Helsinki-University of Helsinki-Faculty of Medecine [Helsinki], University of Helsinki-University of Helsinki, Cardiff University-Medical Research Council, University of California-University of California, and DE CARVALHO, Philippe

Subjects
0301 basic medicine, Male, Netherlands Twin Register (NTR), Bipolar Disorder, LD SCORE REGRESSION, [SDV]Life Sciences [q-bio], Genome-wide association study, [SDV.GEN] Life Sciences [q-bio]/Genetics, Body Mass Index, inflammatory disorder, 80 and over, WIDE ASSOCIATION, EPIDEMIOLOGY, ta318, International HapMap Project, Child, Genetics (clinical), 2. Zero hunger, Genetics, Genetics & Heredity, Aged, 80 and over, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, C-reactive proteingenome-wide association studyinflammationMendelian randomizationinflammatory disordersDEPICTcoronary artery diseaseschizophreniasystem biology, system biology, DEPICT, Mendelian Randomization Analysis, 11 Medical And Health Sciences, Middle Aged, C-reactive protein, coronary artery disease, genome-wide association study, inflammation, inflammatory disorders, Mendelian randomization, schizophrenia, Adolescent, Adult, Aged, Biomarkers, C-Reactive Protein, Female, Genetic Loci, Genome-Wide Association Study, Humans, Inflammation, Liver, Metabolic Networks and Pathways, Schizophrenia, Young Adult, 3. Good health, [SDV] Life Sciences [q-bio], Medical genetics, Biomarker (medicine), Life Sciences & Biomedicine, Human, medicine.medical_specialty, CHARGE Inflammation Working Group, Biology, IMMUNITY, ta3111, Article, 03 medical and health sciences, SDG 3 - Good Health and Well-being, medicine, CORONARY-HEART-DISEASE, Mendelian Randomization Analysi, 1000 Genomes Project, METAANALYSIS, Genetic association, [SDV.GEN]Life Sciences [q-bio]/Genetics, Science & Technology, ta1184, Metabolic Networks and Pathway, Biomarker, INSTRUMENTS, 06 Biological Sciences, 030104 developmental biology, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, LifeLines Cohort Study
Abstract

International audience; C-reactive protein (CRP) is a sensitive biomarker of chronic low-grade inflammation and is associated with multiple complex diseases. The genetic determinants of chronic inflammation remain largely unknown, and the causal role of CRP in several clinical outcomes is debated. We performed two genome-wide association studies (GWASs), on HapMap and 1000 Genomes imputed data, of circulating amounts of CRP by using data from 88 studies comprising 204,402 European individuals. Additionally, we performed in silico functional analyses and Mendelian randomization analyses with several clinical outcomes. The GWAS meta-analyses of CRP revealed 58 distinct genetic loci (p < 5 × 10-8). After adjustment for body mass index in the regression analysis, the associations at all except three loci remained. The lead variants at the distinct loci explained up to 7.0% of the variance in circulating amounts of CRP. We identified 66 gene sets that were organized in two substantially correlated clusters, one mainly composed of immune pathways and the other characterized by metabolic pathways in the liver. Mendelian randomization analyses revealed a causal protective effect of CRP on schizophrenia and a risk-increasing effect on bipolar disorder. Our findings provide further insights into the biology of inflammation and could lead to interventions for treating inflammation and its clinical consequences.Copyright © 2018 American Society of Human Genetics. All rights reserved.

Published
2018

37. Human iPSC-derived retinal pigment epithelium: a model system for identifying and functionally characterizing causal variants at AMD risk loci

Author

Kelly A. Frazer, Radha Ayyagari, Erin N. Smith, Matteo D’Antonio, William W. Greenwald, Hiroko Matsui, Victor Borja, Robert Pogue, Shyamanga Borooah, Lana Ribeiro Aguiar, and Agnieszka D'Antonio-Chronowska

Subjects
Genetics, 0303 health sciences, Retina, Retinal pigment epithelium, Locus (genetics), Macular degeneration, Biology, medicine.disease, eye diseases, Chromatin, 03 medical and health sciences, 0302 clinical medicine, medicine.anatomical_structure, Gene expression, medicine, sense organs, Induced pluripotent stem cell, Transcription factor, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract

SummaryWe evaluate whether human induced pluripotent stem cell-derived retinal pigment epithelium (iPSC-RPE) cells can be used to prioritize and functionally characterize causal variants at age-related macular degeneration (AMD) risk loci. We generated iPSC-RPE from six subjects and show that they have morphological and molecular characteristics similar to native RPE. We generated RNA-seq, ATAC-seq, and H3K27ac ChIP-seq data and observe high similarity in gene expression and enriched transcription factor motif profiles between iPSC-RPE and human fetal-RPE. We performed fine-mapping of AMD risk loci by integrating molecular data from the iPSC-RPE, adult retina, and adult RPE, which identified rs943080 as the probable causal variant at VEGFA. We show that rs943080 is associated with altered chromatin accessibility of a distal ATAC-seq peak, decreased overall gene expression of VEGFA, and allele specific expression of a non-coding transcript. These results provide insight into the mechanism underlying the association of the VEGFA locus with AMD.

Published
2018

38. Applying polygenic risk scoring for psychiatric disorders to a large family with bipolar disorder and major depressive disorder

Author

Peter P. Zandi, Lisa Jones, Aartjan T.F. Beekman, Christine Fraser, Andreas J. Forstner, Nese Direk, Mark Lathrop, Jesper Krogh, Merete Nordentoft, Bradley T. Webb, Yihan Li, Michael Bauer, Qingqin S. Li, Daniel J. Smith, Carsten Horn, Robert C. Thompson, René Breuer, Eli A. Stahl, David A. Collier, Richard Williamson, Boomsma, Dorret, I, Céline S. Reinbold, Laura J. Scott, Manolis Kogevinas, Jacob Lawrence, Caroline Hayward, Nicholas J. Schork, Penelope A. Lind, Wade H. Berrettini, John B. Vincent, Toni-Kim Clarke, Henry Voelzke, Stacy Steinberg, Hreinn Stefansson, Dean F. MacKinnon, Thorgeir E. Thorgeirsson, Niamh Mullins, Esben Agerbo, Rudolf Uher, Christina M. Hultman, Pamela A. F. Madden, Eva C. Schulte, Matthew Flickinger, Sebastian Zöllner, Kenneth S. Kendler, Urban Ösby, Enrique Castelao, Michael John Owen, Colm O'Dushlaine, Jens Treutlein, Joanna Hauser, Markus M. Noethen, Erin N. Smith, James McKay, Sandra Van der Auwera, Erin C. Dunn, Steven P. Hamilton, Martin Schalling, Helmut Vedder, Katherine Gordon-Smith, Fabio Rivas, Matthias Nauck, James B. Potash, Morten Mattingsdal, Ling Shen, Tim B. Bigdeli, Kimberly Chambert, Volker Arolt, Daniel L. Koller, Annelie Nordin Adolfsson, Na Cai, Nicholas G. Martin, Carlos N. Pato, Georg Homuth, Jonas Bybjerg-Grauholm, Alexander Teumer, Wesley K. Thompson, Hamel Patel, Jian Yang, Margit Burmeister, Frank Bellivier, Jodie N. Painter, Enda M. Byrne, Margarita Rivera, Nicholas John Craddock, Tatiana Foroud, Shaun Purcell, Paul D. Shilling, David Craig, Vanessa Kiyomi Ota, Michael Boehnke, Devin Absher, Stéphane Jamain, Anne Farmer, Yunpeng Wang, Ole Mors, William A. Scheftner, Jack D. Barchas, Robert Maier, Stanley J. Watson, Allan H. Young, Baptiste Couvy-Duchesne, Jakob Grove, Rick Jansen, John P. Rice, Gerome Breen, Eske M. Derks, Ingrid Melle, Tiffany A. Greenwood, Manuel Mattheisen, Bernard Ng, Edward M. Scolnick, Stefan Kloiber, Lili Milani, Yuri Milaneschi, Fermín Mayoral, Engilbert Sigurdsson, Sarah E. Medland, Wolfgang Maier, Alan F. Schatzberg, Myrna M. Weissman, Jun Li, John R. Kelsoe, Eric Jorgenson, Grant C.B. Sinnamon, Preben Bo Mortensen, Jana Strohmaier, William Byerley, Michel G. Nivard, Richard M. Myers, Evelin Mihailov, Gustavo Turecki, Benjamin S. Pickard, Ian J. Deary, Bernhard T. Baune, Marian L. Hamshere, Stephanie H. Witt, Patrick F. Sullivan, Jennifer L. Moran, Farnush Farhadi Hassan Kiadeh, Cathryn M. Lewis, Srdjan Djurovic, Ian B. Hickie, Hans J. Grabe, Helena Gaspar, Francis J. McMahon, Catherine Schaefer, Guy A. Rouleau, Sandra Meier, Derek W. Morris, Tõnu Esko, Wouter J. Peyrot, Markus Schwarz, Silviu-Alin Bacanu, Adam Wright, Melvin G. McInnis, Elaine K. Green, Douglas M. Ruderfer, Danielle Posthuma, Franziska Degenhardt, Per Qvist, Henriette N. Buttenschøn, Jolanta Lissowska, Stephan Ripke, Nicholas Bass, Giorgio Pistis, Emma M. Quinn, Shantel Weinsheimer, Howard J. Edenberg, Sintia Iole Belangero, Charles Curtis, Ashley R. Winslow, Tracy M. Air, Johannes H. Smit, Isaac S. Kohane, Wei Xu, Pamela B. Mahon, Neonila Szeszenia-Dabrowska, Gonneke Willemsen, Ivan Nikolov, Sven Cichon, Gregory E. Crawford, David M. Hougaard, E.J.C. de Geus, Klaus Berger, Evaristus A. Nwulia, Fernando S. Goes, Pablo Cervantes, Udo Dannlowski, Rolf Adolfsson, Thomas G. Schulze, Bruno Etain, Mark J. Adams, Thomas Hansen, Hugh Gurling, Fan Guo Meng, Judith A. Badner, Julien Bryois, Mateus Jose Abdalla Diniz, Rodrigo A. Bressan, Radhika Kandaswamy, Josef Frank, I. Nicol Ferrier, Bertram Mueller-Myhsok, Manuel A. R. Ferreira, Marion Leboyer, Futao Zhang, Valentina Moskvina, Patrik K. E. Magnusson, Laura M. Huckins, Douglas Blackwood, Michael Gill, Jianxin Shi, Dale R. Nyholt, Nancy L. Pedersen, André G. Uitterlinden, Henning Tiemeier, Vassily Trubetskoy, Scott D. Gordon, Ian Jones, Grant W. Montgomery, Martin Preisig, Cristiana Cruceanu, Sara A. Paciga, Lena Backlund, Abdel Abdellaoui, Andres Metspalu, Gunnar Morken, Marcus Ising, Sascha B. Fischer, Lilijana Oruc, Sian Caesar, Sarah Kittel-Schneider, Thalia C. Eley, Vihra Milanova, Thomas Werge, Andrew Heath, Katherine E. Tansey, Thomas W. Muehleisen, Jane H. Christensen, Chunyu Liu, Mikael Landén, Douglas F. Levinson, Julia Kraft, Juergen Wellmann, Coleman, Jonathan R., I, Peng Zhang, Glyn Lewis, Henning Teismann, Hamdi Mbarek, Carsten Bøcker Pedersen, Szabolcs Szelinger, Alexander Viktorin, Paul Brennan, Brenda W.J.H. Penninx, Maciej Trzaskowski, Yang Wu, Katharina Domschke, John Strauss, Hilary K. Finucane, Detelina Grozeva, Peter Holmans, Saira Saeed Mirza, Ole A. Andreassen, John I. Nurnberger, Lynsey S Hall, Till F. M. Andlauer, Sara Mostafavi, Andreas Reif, Joanna M. Biernacka, Christine Søholm Hansen, Hualin S. Xi, Stephen Newhouse, William E. Bunney, Andrew M. McIntosh, Anna Maaser, Enrico Domenici, Shyn, Stanley, I, Gail Davies, Warren W. Kretzschmar, Simone de Jong, Lucía Colodro-Conde, Pippa A. Thomson, Francis M. Mondimore, Martin Hautzinger, Cinnamon S. Bloss, Fabian Streit, James L. Kennedy, Erik Pettersson, Peter M. Visscher, Valentina Escott-Price, Donald J. MacIntyre, Johannes Schumacher, Kevin A. McGhee, Divya Mehta, Naomi R. Wray, Robert A. Schoevers, John A. Rice, Jordan W. Smoller, Anders D. Børglum, Susanne Lucae, Jorge A. Quiroz, Daniel Umbricht, Jouke-Jan Hottenga, Kari Stefansson, Marcella Rietschel, Zoltán Kutalik, Sarah E. Bergen, Paul F. O'Reilly, Amanda Dobbyn, Michael Conlon O'Donovan, Falk W. Lohoff, Caroline M. Nievergelt, David J. Porteous, Matthew Traylor, Brien P. Riley, Roy H. Perlis, J. Raymond DePaulo, Martin Alda, James A. Knowles, Cristiano Noto, Keith Matthews, Mark A. Frye, Patrick J. McGrath, Roseann E. Peterson, David St Clair, Roel A. Ophoff, William Coryell, Peter McGuffin, Andiara Calado Saloma Rodrigues, Elliot S. Gershon, Conor V. Dolan, Janice M. Fullerton, Weihua Guan, Niklas Långström, Pamela Sklar, Paul Lichtenstein, Per Hoffmann, Ary Gadelha, Alan W. McLean, Andrew McQuillin, Philip B. Mitchell, Huda Akil, Piotr M. Czerski, Michael Steffens, Hogni Oskarsson, Soumya Raychaudhuri, Marcos L. Santoro, Elisabeth B. Binder, Christel M. Middeldorp, Jose G. Para, Jurgen Del-Favero, Vishwajit L. Nimgaonkar, Peter R. Schofield, Stefan Herms, Marie Bækvad-Hansen, Andrea Pfennig, Albert M. van Hemert, Jutta Kammerer-Ciernioch, Adebayo Anjorin, Sara Paciga, William Lawson, George Kirov, Aiden Corvin, Maria Grigoroiu-Serbanescu, Marianne Giørtz Pedersen, Jonathan Marchini, Markus Leber, Maria Hipolito, Louise Frisén, Margitta Borrmann-Hassenbach, Amanda Elkin, Major Depressive Disorder and Bipolar Disorder Working Groups of the Psychiatric Genomics Consortium, Wray, N.R., Ripke, S., Mattheisen, M., Trzaskowski, M., Byrne, E.M., Abdellaoui, A., Adams, M.J., Agerbo, E., Air, T.M., Andlauer, TFM, Bacanu, S.A., Bækvad-Hansen, M., Beekman, ATF, Bigdeli, T.B., Binder, E.B., Blackwood, DHR, Bryois, J., Buttenschøn, H.N., Bybjerg-Grauholm, J., Cai, N., Castelao, E., Christensen, J.H., Clarke, T.K., Coleman, JRI, Colodro-Conde, L., Couvy-Duchesne, B., Craddock, N., Crawford, G.E., Davies, G., Deary, I.J., Degenhardt, F., Derks, E.M., Direk, N., Dolan, C.V., Dunn, E.C., Eley, T.C., Escott-Price, V., Kiadeh, FFH, Finucane, H.K., Forstner, A.J., Frank, J., Gaspar, H.A., Gill, M., Goes, F.S., Gordon, S.D., Grove, J., Hansen, C.S., Hansen, T.F., Herms, S., Hickie, I.B., Hoffmann, P., Homuth, G., Horn, C., Hottenga, J.J., Hougaard, D.M., Ising, M., Jansen, R., Jones, I., Jones, L.A., Jorgenson, E., Knowles, J.A., Kohane, I.S., Kraft, J., Kretzschmar, W.W., Krogh, J., Kutalik, Z., Li, Y., Lind, P.A., MacIntyre, D.J., MacKinnon, D.F., Maier, R.M., Maier, W., Marchini, J., Mbarek, H., McGrath, P., McGuffin, P., Medland, S.E., Mehta, D., Middeldorp, C.M., Mihailov, E., Milaneschi, Y., Milani, L., Mondimore, F.M., Montgomery, G.W., Mostafavi, S., Mullins, N., Nauck, M., Ng, B., Nivard, M.G., Nyholt, D.R., Oskarsson, H., Owen, M.J., Painter, J.N., Pedersen, C.B., Pedersen, M.G., Peterson, R.E., Pettersson, E., Peyrot, W.J., Pistis, G., Posthuma, D., Quiroz, J.A., Qvist, P., Rice, J.P., Riley, B.P., Rivera, M., Mirza, S.S., Schoevers, R., Schulte, E.C., Shen, L., Shyn, S.I., Sigurdsson, E., Sinnamon, GCB, Smit, J.H., Smith, D.J., Stefansson, H., Steinberg, S., Streit, F., Strohmaier, J., Tansey, K.E., Teismann, H., Teumer, A., Thompson, W., Thomson, P.A., Thorgeirsson, T.E., Traylor, M., Treutlein, J., Trubetskoy, V., Uitterlinden, A.G., Umbricht, D., Van der Auwera, S., van Hemert, A.M., Viktorin, A., Visscher, P.M., Wang, Y., Webb, B.T., Weinsheimer, S.M., Wellmann, J., Willemsen, G., Witt, S.H., Wu, Y., Xi, H.S., Yang, J., Zhang, F., Arolt, V., Baune, B.T., Berger, K., Boomsma, D.I., Cichon, S., Dannlowski, U., de Geus, EJC, DePaulo, J.R., Domenici, E., Domschke, K., Esko, T., Grabe, H.J., Hamilton, S.P., Hayward, C., Heath, A.C., Kendler, K.S., Kloiber, S., Lewis, G., Li, Q.S., Lucae, S., Madden, PAF, Magnusson, P.K., Martin, N.G., McIntosh, A.M., Metspalu, A., Mors, O., Mortensen, P.B., Müller-Myhsok, B., Nordentoft, M., Nöthen, M.M., O'Donovan, M.C., Paciga, S.A., Pedersen, N.L., Penninx, BWJH, Perlis, R.H., Porteous, D.J., Potash, J.B., Preisig, M., Rietschel, M., Schaefer, C., Schulze, T.G., Smoller, J.W., Stefansson, K., Tiemeier, H., Uher, R., Völzke, H., Weissman, M.M., Werge, T., Lewis, C.M., Levinson, D.F., Børglum, A.D., Sullivan, P.F., Meier, S., Strauss, J., Xu, W., Vincent, J.B., Matthews, K., Ferreira, M., O'Dushlaine, C., Purcell, S., Raychaudhuri, S., Ruderfer, D.M., Sklar, P., Scott, L.J., Flickinger, M., Burmeister, M., Li, J., Guan, W., Absher, D., Thompson, R.C., Meng, F.G., Schatzberg, A.F., Bunney, W.E., Barchas, J.D., Watson, S.J., Myers, R.M., Akil, H., Boehnke, M., Chambert, K., Moran, J., Scolnick, E., Djurovic, S., Melle, I., Morken, G., Corvin, A., Anjorin, A., Kandaswamy, R., Lawrence, J., McLean, A.W., Pickard, B.S., Bergen, S.E., Nimgaonkar, V., Landén, M., Schalling, M., Osby, U., Backlund, L., Frisén, L., Langstrom, N., Stahl, E., Dobbyn, A., Jamain, S., Etain, B., Bellivier, F., Leber, M., Maaser, A., Fischer, S.B., Reinbold, C.S., Kittel-Schneider, S., Fullerton, J.M., Oruč, L., Para, J.G., Mayoral, F., Rivas, F., Czerski, P.M., Kammerer-Ciernioch, J., Vedder, H., Borrmann-Hassenbach, M., Pfennig, A., Brennan, P., McKay, J.D., Kogevinas, M., Schwarz, M., Schofield, P.R., Mühleisen, T.W., Schumacher, J., Bauer, M., Wright, A., Mitchell, P.B., Hautzinger, M., Kelsoe, J.R., Greenwood, T.A., Nievergelt, C.M., Shilling, P.D., Smith, E.N., Bloss, C.S., Edenberg, H.J., Koller, D.L., Gershon, E.S., Liu, C., Badner, J.A., Scheftner, W.A., Lawson, W.B., Nwulia, E.A., Hipolito, M., Coryell, W., Rice, J., Byerley, W., McMahon, F.J., Lohoff, F.W., Zandi, P.P., Mahon, P.B., McInnis, M.G., Zöllner, S., Zhang, P., Szelinger, S., St Clair, D., Caesar, S., Gordon-Smith, K., Fraser, C., Green, E.K., Grozeva, D., Hamshere, M.L., Kirov, G., Nikolov, I., Collier, D.A., Elkin, A., Williamson, R., Young, A.H., Ferrier, I.N., Milanova, V., Alda, M., Cervantes, P., Cruceanu, C., Rouleau, G.A., Turecki, G., Paciga, S., Winslow, A.R., Grigoroiu-Serbanescu, M., Ophoff, R., Adolfsson, R., Adolfsson, A.N., Del-Favero, J., Pato, C., Biernacka, J.M., Frye, M.A., Morris, D., Schork, N.J., Reif, A., Lissowska, J., Hauser, J., Szeszenia-Dabrowska, N., McGhee, K., Quinn, E., Moskvina, V., Holmans, P.A., Farmer, A., Kennedy, J.L., Andreassen, O.A., Mattingsdal, M., Bass, N.J., Gurling, H., McQuillin, A., Breuer, R., Hultman, C., Lichtenstein, P., Huckins, L.M., Leboyer, M., Lathrop, M., Nurnberger, J., Steffens, M., Foroud, T.M., Berrettini, W.H., Craig, D.W., Shi, J., Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Perceptual and Cognitive Neuroscience (PCN), Clinical Cognitive Neuropsychiatry Research Program (CCNP), Major Depressive Disorder Bipolar, Biological Psychology, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Methodology, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, Complex Trait Genetics, Amsterdam Neuroscience - Complex Trait Genetics, APH - Mental Health, Pediatric Surgery, Epidemiology, Child and Adolescent Psychiatry / Psychology, Psychiatry, and Internal Medicine

Subjects
Netherlands Twin Register (NTR), 0301 basic medicine, Major Depressive Disorder and Bipolar Disorder Working Groups of the Psychiatric Genomics Consortium, Bipolar Disorder, SAMPLE, Medicine (miscellaneous), Pedigree chart, Disease, 0302 clinical medicine, SCHIZOPHRENIA, 2.1 Biological and endogenous factors, Medicine, Aetiology, ANTICIPATION, lcsh:QH301-705.5, Psychiatry, 0303 health sciences, Depression, ASSOCIATION, Serious Mental Illness, Mental Health, Schizophrenia, Major depressive disorder, General Agricultural and Biological Sciences, Engineering sciences. Technology, medicine.medical_specialty, Context (language use), Article, Psykiatri, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, AGE, SDG 3 - Good Health and Well-being, ddc:570, Behavioral and Social Science, Genetics, PLINK, Genetic Testing, Bipolar disorder, Biology, 030304 developmental biology, business.industry, Prevention, Human Genome, Assortative mating, medicine.disease, Brain Disorders, 030104 developmental biology, Mood, lcsh:Biology (General), Mood disorders, Anticipation (genetics), ONSET, Human medicine, business, 030217 neurology & neurosurgery
Abstract

Psychiatric disorders are thought to have a complex genetic pathology consisting of interplay of common and rare variation. Traditionally, pedigrees are used to shed light on the latter only, while here we discuss the application of polygenic risk scores to also highlight patterns of common genetic risk. We analyze polygenic risk scores for psychiatric disorders in a large pedigree (n ~ 260) in which 30% of family members suffer from major depressive disorder or bipolar disorder. Studying patterns of assortative mating and anticipation, it appears increased polygenic risk is contributed by affected individuals who married into the family, resulting in an increasing genetic risk over generations. This may explain the observation of anticipation in mood disorders, whereby onset is earlier and the severity increases over the generations of a family. Joint analyses of rare and common variation may be a powerful way to understand the familial genetics of psychiatric disorders., Simone de Jong et al. examine the balance of common and rare risk for psychiatric disorders in a large family with high incidence of Bipolar Disorder and Major Depressive Disorder. They find that increased polygenic risk over generations could be partially due to assortative mating, which may explain the observation of anticipation in mood disorders.

Published
2018

39. Discovery of novel plasma biomarkers for future incident venous thromboembolism by untargeted synchronous precursor selection mass spectrometry proteomics

Author

Sigrid Kufaas Brækkan, Søren B. Jensen, Erin N. Smith, John-Bjarne Hansen, D. J. Gonzalez, Kristian Hindberg, Nadezhda Latysheva, Kelly A. Frazer, Terry Solomon, and John D. Lapek

Subjects
0301 basic medicine, Oncology, Male, Proteomics, Cardiorespiratory Medicine and Haematology, 030204 cardiovascular system & hematology, Body Mass Index, 0302 clinical medicine, Tandem Mass Spectrometry, Neoplasms, 80 and over, Prospective Studies, Prospective cohort study, mass spectrometry, Aged, 80 and over, Venous Thrombosis, screening and diagnosis, education.field_of_study, Hematology, Blood Proteins, Venous Thromboembolism, Middle Aged, Prognosis, Detection, Proteome, Biomarker (medicine), Female, Risk assessment, Biotechnology, Adult, medicine.medical_specialty, venous thromboembolism, Clinical Sciences, Population, Risk Assessment, Article, 03 medical and health sciences, Internal medicine, medicine, Humans, education, Aged, business.industry, Proteomic Profiling, Prevention, Case-control study, biomarkers, 4.1 Discovery and preclinical testing of markers and technologies, Good Health and Well Being, 030104 developmental biology, Cardiovascular System & Hematology, Case-Control Studies, business, Pulmonary Embolism, Biomarkers
Abstract

Essentials Discovery of predictive biomarkers of venous thromboembolism (VTE) may aid risk stratification. A case-control study where plasma was sampled before the occurrence of VTE was established. We generated untargeted plasma proteomic profiles of 200 individuals by use of mass spectrometry. Assessment of the biomarker potential of 501 proteins yielded 46 biomarker candidates. Abstract Background Prophylactic anticoagulant treatment may substantially reduce the incidence of venous thromboembolism (VTE) but entails considerable risk of severe bleeding. Identification of individuals at high risk of VTE through the use of predictive biomarkers is desirable in order to achieve a favorable benefit-to-harm ratio. Objective We aimed to identify predictive protein biomarker candidates of VTE. Methods We performed a case-control study of 200 individuals that participated in the Tromso Study, a population-based cohort, where blood samples were collected before the VTE events occurred. Untargeted tandem mass tag-synchronous precursor selection-mass spectrometry (TMT-SPS-MS3)-based proteomic profiling was used to study the plasma proteomes of each individual. Results Of the 501 proteins detected in a sufficient number of samples to allow multivariate analysis, 46 proteins were associated with VTE case-control status with P-values below the 0.05 significance threshold. The strongest predictive biomarker candidates, assessed by statistical significance, were transthyretin, vitamin K-dependent protein Z and protein/nucleic acid deglycase DJ-1. Conclusions Our untargeted approach of plasma proteome profiling revealed novel predictive biomarker candidates of VTE and confirmed previously reported candidates, thereby providing conceptual support for the validity of the study. A larger nested case-control study will be conducted to validate our findings.

Published
2018

40. Efficient region-based test strategy uncovers genetic risk factors for functional outcome in bipolar disorder

Author

Sebastian Zöllner, Jared C. Roach, William Lawson, Howard J. Edenberg, Melvin G. McInnis, Dörthe Malzahn, Seth A. Ament, Sandra Meier, Heike Bickeböller, Jana Strohmaier, Peter Falkai, John R. Kelsoe, Evaristus A. Nwulia, William Byerley, Danjuma Quarless, Ney Alliey-Rodriguez, John I. Nurnberger, Paul D. Shilling, Marcella Rietschel, Stefanie Friedrichs, Monika Budde, Tatyana Shekhtman, Jens Treutlein, David Craig, Thomas G. Schulze, William Coryell, Judith A. Badner, Leroy Hood, Sarah S. Murray, Wade H. Berrettini, Peter P. Zandi, Chunyu Liu, Nicholas J. Schork, Erin N. Smith, Szabolcs Szelinger, Tiffany A. Greenwood, Tatiana Foroud, Markus M. Nöthen, Andreas J. Forstner, Francis J. McMahon, Elliot S. Gershon, Peng Zhang, Caroline M. Nievergelt, Maria Hipolito, Fabian Streit, Ashley L. Comes, Thomas W. Mühleisen, Daniel L. Koller, Franziska Degenhardt, Stephanie H. Witt, William A. Scheftner, Pamela B. Mahon, Cinnamon S. Bloss, Yiran Guo, John P. Rice, Sven Cichon, Brendan J. Keating, Josef Frank, Fernando S. Goes, and James B. Potash

Subjects
Adult, Male, Linkage disequilibrium, Bipolar Disorder, Adolescent, Genotype, Locus (genetics), Single-nucleotide polymorphism, Computational biology, Biology, Polymorphism, Single Nucleotide, Linkage Disequilibrium, White People, 03 medical and health sciences, Functional annotation, Global Assessment of Functioning, Hypothesis-driven GWAS, Kernel score test, Psychiatric disorder, Young Adult, 0302 clinical medicine, SNP, Humans, Pharmacology (medical), Genetic Predisposition to Disease, ddc:610, Gene, Biological Psychiatry, Genetic association, Aged, Pharmacology, Psychiatric Status Rating Scales, Models, Statistical, Haplotype, Middle Aged, Prognosis, 3. Good health, 030227 psychiatry, Psychiatry and Mental health, Neurology, Haplotypes, CTCF, Case-Control Studies, Female, Neurology (clinical), 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Genome-wide association studies of case-control status have advanced the understanding of the genetic basis of psychiatric disorders. Further progress may be gained by increasing sample size but also by new analysis strategies that advance the exploitation of existing data, especially for clinically important quantitative phenotypes. The functionally-informed efficient region-based test strategy (FIERS) introduced herein uses prior knowledge on biological function and dependence of genotypes within a powerful statistical framework with improved sensitivity and specificity for detecting consistent genetic effects across studies. As proof of concept, FIERS was used for the first genome-wide single nucleotide polymorphism (SNP)-based investigation on bipolar disorder (BD) that focuses on an important aspect of disease course, the functional outcome. FIERS identified a significantly associated locus on chromosome 15 (hg38: chr15:48965004 - 49464789 bp) with consistent effect strength between two independent studies (GAIN/TGen: European Americans, BOMA: Germans; n = 1592 BD patients in total). Protective and risk haplotypes were found on the most strongly associated SNPs. They contain a CTCF binding site (rs586758); CTCF sites are known to regulate sets of genes within a chromatin domain. The rs586758 - rs2086256 - rs1904317 haplotype is located in the promoter flanking region of the COPS2 gene, close to microRNA4716, and the EID1, SHC4, DTWD1 genes as plausible biological candidates. While implication with BD is novel, COPS2, EID1, and SHC4 are known to be relevant for neuronal differentiation and function and DTWD1 for psychopharmacological side effects. The test strategy FIERS that enabled this discovery is equally applicable for tag SNPs and sequence data. peerReviewed

Published
2018

41. Allele-specific NKX2-5 binding underlies multiple genetic associations with human EKG traits

Author

Paola Benaglio, Matteo D’Antonio, Kelly A. Frazer, William W. Greenwald, Sanghamitra Singhal, Erin N. Smith, He Li, Agnieszka D'Antonio-Chronowska, Frauke Drees, Christopher DeBoever, and Hiroko Matsui

Subjects
Genetics, 0303 health sciences, Genome-wide association study, Genomics, Biology, 03 medical and health sciences, 0302 clinical medicine, Genetic variation, Enhancer, Transcription factor, Gene, 030217 neurology & neurosurgery, 030304 developmental biology, Epigenomics, Genetic association
Abstract

Genetic variation affecting the binding of transcription factors (TFs) has been proposed as a major mechanism underlying susceptibility to common disease. NKX2-5, a key cardiac development TF, has been associated with electrocardiographic (EKG) traits through GWAS, but the extent to which differential binding of NKX2-5 contributes to these traits has not yet been studied. Here, we analyzed transcriptomic and epigenomic data generated from iPSC-derived cardiomyocyte lines (iPSC-CMs) from seven whole-genome sequenced individuals in a three-generational family. We identified ~2,000 single nucleotide variants (SNVs) associated with allele-specific effects (ASE) on NKX2-5 binding. These ASE-SNVs were enriched for altered TF motifs (both cognate and other cardiac TFs), and were positively correlated with changes in H3K27ac in iPSC-CMs, suggesting they impact cardiac enhancer activity. We found that NKX2-ASE-SNVs were significantly enriched for being heart-specific eQTLs and EKG GWAS variants, suggesting that altered NKX2-5 binding at multiple sites across the genome influences EKG traits. We used a fine-mapping approach to integrate iPSC-CM molecular phenotype data with a GWAS for heart rate, and determined that NKX2-5 ASE variants are likely causal for numerous known, as well as previously unidentified, heart rate loci. Analyzing Hi-C and gene expression data from iPSC-CMs at these heart rate loci, we identified several genes likely to be causally involved in heart rate variability. Our study demonstrates that differential binding of NKX2-5 is a common mechanism underlying genetic association with EKG traits, and shows that characterizing variants associated with differential binding of development TFs in iPSC-derived cell lines can identify novel loci and mechanisms influencing complex traits.

Published
2018
Full Text
View/download PDF

42. Integration of phased Hi-C and molecular phenotype data to study genetic and epigenetic effects on chromatin looping

Author

Erin N. Smith, David Jakubosky, Matteo D’Antonio, Paola Benaglio, Kelly A. Frazer, Hiroko Matsui, He Li, Siddarth Selvaraj, Agnieszka D'Antonio-Chronowska, Anthony D. Schmitt, and William W. Greenwald

Subjects
0303 health sciences, Genomics, Biology, Phenotype, Chromatin, 03 medical and health sciences, 0302 clinical medicine, Evolutionary biology, Genetic variation, Gene expression, Chromatin Loop, Copy-number variation, Epigenetics, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract

SummaryWhile genetic variation at chromatin loops is relevant for human disease, the relationships between loop strength, genetics, gene expression, and epigenetics are unclear. Here, we quantitatively interrogate this relationship using Hi-C and molecular phenotype data across cell types and haplotypes. We find that chromatin loops consistently form across multiple cell types and quantitatively vary in strength, instead of exclusively forming within only one cell type. We show that large haplotype loop imbalance is primarily associated with imprinting and copy number variation, rather than genetically driven traits such as allele-specific expression. Finally, across cell types and haplotypes, we show that subtle changes in chromatin loop strength are associated with large differences in other molecular phenotypes, with a 2-fold change in looping corresponding to a 100-fold change in gene expression. Our study suggests that regulatory genetic variation could mediate its effects on gene expression through subtle modification of chromatin loop strength.

Published
2018
Full Text
View/download PDF

43. Insights into the mutational burden of human induced pluripotent stem cells using an integrative omics approach

Author

Paola Benaglio, Margaret K.R. Donovan, Kelly A. Frazer, David Jakubosky, He Li, Erin N. Smith, Agnieszka D'Antonio-Chronowska, Matteo D’Antonio, William W. Greenwald, and Hiroko Matsui

Subjects
Genetics, 0303 health sciences, Mutation rate, Point mutation, Genomics, Epigenome, Biology, Genome, Transplantation, Transcriptome, 03 medical and health sciences, 0302 clinical medicine, Induced pluripotent stem cell, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract

SummaryTo understand the mutational burden of human induced pluripotent stem cells (iPSCs), we whole genome sequenced 18 fibroblast-derived iPSC lines and identified different classes of somatic mutations based on structure, origin and frequency. Copy number alterations affected 295 kb in each sample and strongly impacted gene expression. UV-damage mutations were present in ~45% of the iPSCs and accounted for most of the observed heterogeneity in mutation rates across lines. Subclonal mutations (not present in all iPSCs within a line) composed 10% of point mutations, and compared with clonal variants, showed an enrichment in active promoters and increased association with altered gene expression. Our study shows that, by combining WGS, transcriptome and epigenome data, we can understand the mutational burden of each iPSC line on an individual basis and suggests that this information could be used to prioritize iPSC lines for models of specific human diseases and/or transplantation therapy.

Published
2018
Full Text
View/download PDF

44. Insights into the Mutational Burden of Human Induced Pluripotent Stem Cells from an Integrative Multi-Omics Approach

Author

Paola Benaglio, Matteo D’Antonio, Kelly A. Frazer, Erin N. Smith, He Li, David Jakubosky, William W. Greenwald, Margaret K.R. Donovan, Hiroko Matsui, and Agnieszka D'Antonio-Chronowska

Subjects
0301 basic medicine, Mutation rate, Cells, Medical Physiology, Induced Pluripotent Stem Cells, epigenome, iPSCs, RNA-Seq, Computational biology, Biology, Regenerative Medicine, General Biochemistry, Genetics and Molecular Biology, Article, Transcriptome, 03 medical and health sciences, Mutation Rate, stem cells, Genetics, 2.1 Biological and endogenous factors, Humans, Stem Cell Research - Induced Pluripotent Stem Cell - Non-Human, Aetiology, Induced pluripotent stem cell, Cells, Cultured, whole genome sequencing, Cultured, UV damage, Stem Cell Research - Induced Pluripotent Stem Cell, Stem Cell Research - Induced Pluripotent Stem Cell - Human, Point mutation, Human Genome, Cell Differentiation, Epigenome, Stem Cell Research, Cellular Reprogramming, Transplantation, Good Health and Well Being, 030104 developmental biology, Mutation, somatic mutations, Generic health relevance, Biochemistry and Cell Biology, RNA-seq, Stem cell, sublonal mutations, Biotechnology
Abstract

Summary To understand the mutational burden of human induced pluripotent stem cells (iPSCs), we sequenced genomes of 18 fibroblast-derived iPSC lines and identified different classes of somatic mutations based on structure, origin, and frequency. Copy-number alterations affected 295 kb in each sample and strongly impacted gene expression. UV-damage mutations were present in ∼45% of the iPSCs and accounted for most of the observed heterogeneity in mutation rates across lines. Subclonal mutations (not present in all iPSCs within a line) composed 10% of point mutations and, compared with clonal variants, showed an enrichment in active promoters and increased association with altered gene expression. Our study shows that, by combining WGS, transcriptome, and epigenome data, we can understand the mutational burden of each iPSC line on an individual basis and suggests that this information could be used to prioritize iPSC lines for models of specific human diseases and/or transplantation therapy.

Published
2018

45. Developmental outcomes of toddlers of young Latina mothers: Cultural, family, and parenting factors

Author

Patricia Castellanos, Petra A. Duran, Erin N. Smith, Lauren E. Wood, Josefina M. Grau, and Stephanie G. Silberman

Subjects
Male, Adolescent, Culture, Mothers, Language Development, Article, Developmental psychology, Fathers, Young Adult, Child Development, Cognition, Developmental and Educational Psychology, Humans, Expressed emotion, Family, Prospective Studies, Cognitive skill, Young adult, Maternal Behavior, Parenting, Infant, Hispanic or Latino, Child development, Mother-Child Relations, Acculturation, Expressed Emotion, Language development, Socioeconomic Factors, Enculturation, Educational Status, Female, Psychology
Abstract

Children of adolescent mothers are at risk for poor developmental outcomes. This study is among the first to examine how cultural, family, and parenting factors prospectively predict the cognitive and language development of children of young Latina mothers (N=170; Mage = 17.9 years). Mothers were interviewed and observed interacting with their children at 18 months (W1). Children were tested at 18 (W1) and 24 (W2) months. Mothers’ cultural orientation (W1) was related to aspects of the childrearing environment (W1), which in turn had implications for the children's development (W2). Specifically, a stronger orientation toward American culture was related to higher mother-reported engagement in parenting by their own mothers (grandmothers), which in turn predicted stronger gains in cognitive and expressive language functioning from W1 to W2. A stronger Latino orientation related to the display of more directiveness and greater mother-reported engagement by the children's biological fathers; directiveness, in turn, predicted fewer gains in cognitive functioning only when father engagement was low and did not predict expressive language development. Finally, mothers’ display of more positive affect, a stronger American orientation, and higher grandmother engagement uniquely predicted gains in W2 expressive language functioning. Implications for intervention are discussed.

Published
2015

46. Assessing the causal relationship between obesity and venous thromboembolism through a Mendelian Randomization study

Author

Erin N. Smith, Immaculata DeVivo, Paul M. Ridker, Marta Crous-Bou, Weihong Tang, Marine Germain, Hugoline G. de Haan, Jennifer A. Brody, Sara Lindström, Christopher Kabrhel, Francine Grodstein, Nicholas L. Smith, Mariza de Andrade, Astrid van Hylckama Vlieg, Daniel I. Chasman, Pierre-Emmanuel Morange, John A. Heit, David-Alexandre Trégouët, ALESSI, Marie-Christine, Program in Genetic Epidemiology and Statistical Genetics (PGESG - BOSTON), Harvard School of Public Health, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), The Scripps Translational Science Institute and Scripps Health, Fibrinolyse et Pathologie Vasculaire, Université de la Méditerranée - Aix-Marseille 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Nutrition, obésité et risque thrombotique (NORT), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Thrombosis and Hemostasis (LEIDEN - DTH), Leiden University Medical Center (LUMC), Department of Thrombosis and Haemostasis, Brigham and Women's Hospital [Boston], Department of Health Sciences Research [Mayo Clinic] (HSR), Mayo Clinic, Division of Cardiovascular Diseases, Mayo Clinic College of Medicine, University of Minnesota [Twin Cities] (UMN), University of Minnesota System, Department of Epidemiology, Génétique épidémiologique et moléculaire des pathologies cardiovasculaires, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR14-Institut National de la Santé et de la Recherche Médicale (INSERM), Massachusetts General Hospital [Boston], Program in Genetic Epidemiology and Statistical Genetics ( PGESG - BOSTON ), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition ( ICAN ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -CHU Pitié-Salpêtrière [APHP], Nutrition, obésité et risque thrombotique ( NORT ), Institut National de la Recherche Agronomique ( INRA ) -Aix Marseille Université ( AMU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Department of Thrombosis and Hemostasis ( LEIDEN - DTH ), Department of Health Sciences Research [Mayo Clinic] ( HSR ), Massachusetts General Hospital [Boston] ( MGH ), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP], Aix Marseille Université (AMU)-Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Minnesota [Twin Cities], and Universiteit Leiden-Universiteit Leiden

Subjects
Male, Genome-wide association study, 030204 cardiovascular system & hematology, Body Mass Index, 0302 clinical medicine, 030212 general & internal medicine, Genetics (clinical), 2. Zero hunger, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Incidence, Confounding, [ SDV.SPEE ] Life Sciences [q-bio]/Santé publique et épidémiologie, [ SDV.MHEP.CSC ] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, [ SDV.MHEP.EM ] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 3. Good health, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Female, Adult, medicine.medical_specialty, venous thromboembolism, SNP, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, Article, White People, 03 medical and health sciences, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Internal medicine, Mendelian randomization, Genetics, medicine, Humans, cardiovascular diseases, Obesity, Proportional Hazards Models, association, nutritional and metabolic diseases, Mendelian Randomization Analysis, medicine.disease, equipment and supplies, Logistic Models, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Case-Control Studies, Observational study, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Body mass index, Genome-Wide Association Study
Abstract

International audience; Observational studies have shown an association between obesity and venous thromboembolism (VTE) but it is not known if observed associations are causal, due to reverse causation or confounding bias. We conducted a Mendelian Randomization study of body mass index (BMI) and VTE. We identified 95 single nucleotide polymorphisms (SNPs) that have been previously associated with BMI and assessed the association between genetically predicted high BMI and VTE leveraging data from a previously conducted GWAS within the INVENT consortium comprising a total of 7507 VTE cases and 52,632 controls of European ancestry. Five BMI SNPs were associated with VTE at P < 0.05, with the strongest association seen for the FTO SNP rs1558902 (OR 1.07, 95% CI 1.02–1.12, P = 0.005). In addition, we observed a significant association between genetically predicted BMI and VTE (OR = 1.59, 95% CI 1.30–1.93 per standard deviation increase in BMI, P = 5.8 × 10−6). Our study provides evidence for a causal relationship between high BMI and risk of VTE. Reducing obesity levels will likely result in lower incidence in VTE.

Published
2017

47. Gene-centric meta-analyses for central adiposity traits in up to 57 412 individuals of European descent confirm known loci and reveal several novel associations

Author

Sandosh Padmanabhan, Susan Kirkland, Patricia B. Munroe, Salim Yusuf, Brian E. Cade, Marten H. Hofker, Jose M. Ordovas, Jeffrey R. O'Connell, Liz Speilotes, Fridtjof Thomas, Caroline S. Fox, Brendan J. Keating, Gerald S. Berenson, Toby Johnson, Alan R. Shuldiner, Leslie A. Lange, Jeanne M. McCaffery, Thomas Illig, Christopher P. Nelson, Muredach P. Reilly, Wolfgang König, Keri L. Monda, Yan Gong, Olle Melander, Caitrin W. McDonough, Annette Peters, Sachiko Yoneyama, Nancy L. Heard-Costa, Cisca Wijmenga, Alexander P. Reiner, Mathias Gorski, Anna F. Dominiczak, Jens Baumert, Florianne Bauer, Karina W. Davidson, Erin N. Smith, Jonathan A. Shaffer, Konrad J. Karczewski, Clara C. Elbers, Kari E. North, Nicholas J. Schork, Sarah S. Murray, Christian Gieger, Iris M. Heid, Tom R. Gaunt, Julie A. Johnson, N. Charlotte Onland-Moret, Yvonne T. van der Schouw, Nilesh J. Samani, Ellen W. Demerath, Rhonda M. Cooper-DeHoff, Gordon S. Huggins, George J. Papanicolaou, Hakon Hakonarson, Sonia S. Anand, Daichi Shimbo, Kira C. Taylor, Jolanda M. A. Boer, Susan Redline, Martin D. Tobin, Yiran Guo, Robert A. Hegele, Michael J. LaMonte, Haiqinq Shen, Barbara Thorand, Amber L. Beitelshees, Inga Peter, Braxton D. Mitchell, Wei Chen, Matthew B. Lanktree, Michael R. Barnes, W. M. Monique Verschuren, Gregory L. Burke, Taimour Y. Langaee, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Center for Liver, Digestive and Metabolic Diseases (CLDM), and Vascular Ageing Programme (VAP)

Subjects
Adult, Male, DRUGGABLE GENOME, Candidate gene, Single-nucleotide polymorphism, Genome-wide association study, BLOOD-PRESSURE, Biology, Population stratification, White People, Body Mass Index, Young Adult, Waist–hip ratio, Genetics, Humans, GENOME-WIDE ASSOCIATION, Molecular Biology, IDENTIFIES 13, Genetics (clinical), Adiposity, Aged, METABOLIC SYNDROME, Aged, 80 and over, INSULIN-RESISTANCE, Association Studies Articles, CARDIOVASCULAR-DISEASE RISK, General Medicine, Middle Aged, BODY-MASS INDEX, ABDOMINAL OBESITY, Expression quantitative trait loci, Population study, Female, Waist Circumference, WAIST-HIP RATIO, Body mass index, Genome-Wide Association Study
Abstract

Waist circumference (WC) and waist-to-hip ratio (WHR) are surrogate measures of central adiposity that are associated with adverse cardiovascular events, type 2 diabetes and cancer independent of body mass index (BMI). WC and WHR are highly heritable with multiple susceptibility loci identified to date. We assessed the association between SNPs and BMI-adjusted WC and WHR and unadjusted WC in up to 57 412 individuals of European descent from 22 cohorts collaborating with the NHLBI's Candidate Gene Association Resource (CARe) project. The study population consisted of women and men aged 20-80 years. Study participants were genotyped using the ITMAT/Broad/CARE array, which includes ∼50 000 cosmopolitan tagged SNPs across ∼2100 cardiovascular-related genes. Each trait was modeled as a function of age, study site and principal components to control for population stratification, and we conducted a fixed-effects meta-analysis. No new loci for WC were observed. For WHR analyses, three novel loci were significantly associated (P < 2.4 × 10(-6)). Previously unreported rs2811337-G near TMCC1 was associated with increased WHR (β ± SE, 0.048 ± 0.008, P = 7.7 × 10(-9)) as was rs7302703-G in HOXC10 (β = 0.044 ± 0.008, P = 2.9 × 10(-7)) and rs936108-C in PEMT (β = 0.035 ± 0.007, P = 1.9 × 10(-6)). Sex-stratified analyses revealed two additional novel signals among females only, rs12076073-A in SHC1 (β = 0.10 ± 0.02, P = 1.9 × 10(-6)) and rs1037575-A in ATBDB4 (β = 0.046 ± 0.01, P = 2.2 × 10(-6)), supporting an already established sexual dimorphism of central adiposity-related genetic variants. Functional analysis using ENCODE and eQTL databases revealed that several of these loci are in regulatory regions or regions with differential expression in adipose tissue.

Published
2014

48. Gene-centric meta-analysis in 87,736 individuals of European ancestry identifies multiple blood-pressure-related loci

Author

Nora Franceschini, Yen Pei C. Chang, Susan Kirkland, Aravinda Chakravarti, Alice Stanton, Erik P A Van Iperen, Ilja M. Nolte, Jonathan A. Shaffer, Christopher P. Nelson, Aeilko H. Zwinderman, G. Kees Hovingh, Paul I.W. de Bakker, Christian Gieger, Shen Haiqing, John M. C. Connell, Xiaofeng Zhu, Patricia B. Munroe, Thomas S. Price, Eric Boerwinkle, Deepak L. Bhatt, Santhi K. Ganesh, Anna F. Dominiczak, Caitrin W. McDonough, Harold Snieder, Vinicius Tragante, Albertine J. Oldehinkel, Eoin O'Brien, Barbara E.K. Klein, Alexander P. Reiner, Mary E. Fischer, N. Charlotte Onland-Moret, Kate Witkowska, Christopher Newton-Cheh, Andrew D. Johnson, Laura Steele, Lynda M. Rose, Li Zhang, Erin N. Smith, Mark J. Caulfield, Sharon B. Wyatt, Morris Brown, Martin D. Tobin, Christian Delles, Gail P. Jarvik, Tom R. Gaunt, Hans L. Hillege, Steffi Maiwald, Nilesh J. Samani, Wolfgang Koenig, Konrad J. Karczewski, Julie A. Johnson, Brenda W.J.H. Penninx, Matthijs F.L. Meijs, Judith M. Vonk, Yvonne T. van der Schouw, Daniel I. Chasman, John Barnard, J. Hunter Young, Paul M. Ridker, Sean P. Curtis, Marten H. Hofker, Yan Gong, Jeffrey R. O'Connell, Barbara Thorand, Garret A. FitzGerald, Daichi Shimbo, Sonia Shah, Martin Farrall, Ronald P. Stolk, John G. Gums, Amber L. Beitelshees, Juan P. Casas, Pim van der Harst, Daniel Seung Kim, Peter S. Sever, André G. Uitterlinden, Michael Snyder, Brendan J. Keating, Susan Redline, Muredach P. Reilly, Michael V. Holmes, Maciej Tomaszewski, Daniel J. Rader, Sarah S. Murray, Myriam Fornage, Walter Palmas, Karina W. Davidson, Connie R. Bezzina, Gerald S. Berenson, Toby Johnson, Afshin Parsa, Cornelia M. van Duijn, Kandice Kottke-Marchant, Winfried März, Thomas Illig, W M Monique Verschuren, Aaron Isaacs, Matthew B. Lanktree, Amber A. Burt, Hugh Watkins, Daniel Levy, Hakon Hakonarson, Ramachandran S. Vasan, Johannes M.I.H. Gho, Nathan Pankratz, Sandosh Padmanabhan, Michael R. Barnes, Anuj Goel, Berta Almoguera, Xiuqing Guo, Peter J. van der Most, Ronald Klein, Mieke D. Trip, James S. Pankow, George Davey-Smith, Eric E. Schadt, Indrani Halder, Irene Mateo Leach, Meena Kumari, Claire E. Hastie, John J.P. Kastelein, Caroline O. L. Wong, Clara C. Elbers, Folkert W. Asselbergs, Wei Guo, Marcus E. Kleber, Karen J. Cruickshanks, Pieter A. Doevendans, Jane E. Ranchalis, Yun Li, Olle Melander, Jens Baumert, Ron T. Gansevoort, Rhonda M. Cooper-DeHoff, Mary Pettinger, Cisca Wijmenga, Epidemiology, Public Health, Clinical Genetics, Child and Adolescent Psychiatry / Psychology, Internal Medicine, EMGO+ - Mental Health, APH - Amsterdam Public Health, Epidemiology and Data Science, Graduate School, ACS - Amsterdam Cardiovascular Sciences, Vascular Medicine, Other departments, Cardiology, Psychiatry, EMGO - Mental health, Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Center for Liver, Digestive and Metabolic Diseases (CLDM), Cardiovascular Centre (CVC), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Groningen Research Institute for Asthma and COPD (GRIAC), and Vascular Ageing Programme (VAP)

Subjects
Quality Control, Candidate gene, Genotype, Systole, Population, European Continental Ancestry Group, Quantitative Trait Loci, Single-nucleotide polymorphism, Genome-wide association study, Blood Pressure, 030204 cardiovascular system & hematology, Biology, Quantitative trait locus, Essential hypertension, Polymorphism, Single Nucleotide, White People, Article, 03 medical and health sciences, 0302 clinical medicine, SDG 3 - Good Health and Well-being, Polymorphism (computer science), Diastole, Risk Factors, medicine, Genetics, Humans, Genetics(clinical), Arterial Pressure, European Continental Ancestry Group/genetics, Polymorphism, education, Genetics (clinical), 030304 developmental biology, 0303 health sciences, education.field_of_study, Computational Biology, Single Nucleotide, Computational Biology/methods, medicine.disease, 3. Good health, Europe, Genetics, Population, Blood pressure, Phenotype, Genetic Loci, Genome-Wide Association Study
Abstract

Blood pressure (BP) is a heritable risk factor for cardiovascular disease. To investigate genetic associations with systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP), and pulse pressure (PP), we genotyped ∼50,000 SNPs in up to 87,736 individuals of European ancestry and combined these in a meta-analysis. We replicated findings in an independent set of 68,368 individuals of European ancestry. Our analyses identified 11 previously undescribed associations in independent loci containing 31 genes including PDE1A, HLA-DQB1, CDK6, PRKAG2, VCL, H19, NUCB2, RELA, HOXC@ complex, FBN1, and NFAT5 at the Bonferroni-corrected array-wide significance threshold (p < 6 × 10-7) and confirmed 27 previously reported associations. Bioinformatic analysis of the 11 loci provided support for a putative role in hypertension of several genes, such as CDK6 and NUCB2. Analysis of potential pharmacological targets in databases of small molecules showed that ten of the genes are predicted to be a target for small molecules. In summary, we identified previously unknown loci associated with BP. Our findings extend our understanding of genes involved in BP regulation, which may provide new targets for therapeutic intervention or drug response stratification. © 2014 The American Society of Human Genetics.

Published
2014

49. Common genetic variation near the connexin-43 gene is associated with resting heart rate in African Americans: A genome-wide association study of 13,372 participants

Author

Christopher Newton-Cheh, Sathanur R. Srinivasan, Jerome I. Rotter, Luigi Ferrucci, Alvaro Alonso, Yongmei Liu, Renate B. Schnabel, Tandaw E. Samdarshi, Margaux F. Keller, Marian C. Limacher, Takaaki Tanaka, J. C. Bis, Ervin R. Fox, Omer T. Njajou, Dina N. Paltoo, Gerardo Heiss, Patrick T. Ellinor, Zhu Ming Zhang, AB Singleton, Christy L. Avery, Gang Li, Michele K. Evans, Dan E. Arking, Jennifer G. Robinson, Kari E. North, Mike A. Nalls, Anne M. Butler, Sarah G. Buxbaum, Gregory M. Marcus, A.B. Newman, Ermeg L. Akylbekova, Maurizio Trevisan, Alan B. Zonderman, David S. Siscovick, P. Miguel Quibrera, Wei Chen, Herman A. Taylor, Eric A. Whitsel, Jared W. Magnani, Nona Sotoodehnia, Alexander P. Reiner, Sarah S. Murray, Rajat Deo, Steven A. Lubitz, Bruce M. Psaty, Emelia J. Benjamin, Kathleen F. Kerr, Susan R. Heckbert, J. G. Smith, Lin Y. Chen, Reena Mehra, Susan Redline, Daniel S. Evans, Nicholas J. Schork, Steve Cummings, Wen-Chi Hsueh, Gerald S. Berenson, Elsayed Z. Soliman, and Erin N. Smith

Subjects
Male, Genome-wide association study, Arrhythmias, Cardiorespiratory Medicine and Haematology, Cardiovascular, Electrocardiography, Heart Rate, 2.1 Biological and endogenous factors, Medicine, Aetiology, International HapMap Project, African Americans, Genetics, education.field_of_study, Single Nucleotide, Middle Aged, Heart Disease, Female, Cardiology and Cardiovascular Medicine, Cardiac, Adult, Genotype, Rest, Heart rate, Population, Biomedical Engineering, Single-nucleotide polymorphism, Polymorphism, Single Nucleotide, Meta-Analysis as Topic, Clinical Research, Physiology (medical), Genetic variation, Humans, Singe nucleotide polymorphisms, Polymorphism, education, Aged, Genetic association, business.industry, Human Genome, Genetic Variation, Arrhythmias, Cardiac, United States, Black or African American, Minor allele frequency, Meta-analysis, Cardiovascular System & Hematology, Genetic epidemiology, Connexin 43, business, Genome-Wide Association Study
Abstract

Background Genome-wide association studies have identified several genetic loci associated with variation in resting heart rate in European and Asian populations. No study has evaluated genetic variants associated with heart rate in African Americans. Objective To identify novel genetic variants associated with resting heart rate in African Americans. Methods Ten cohort studies participating in the Candidate-gene Association Resource and Continental Origins and Genetic Epidemiology Network consortia performed genome-wide genotyping of single nucleotide polymorphisms (SNPs) and imputed 2,954,965 SNPs using HapMap YRI and CEU panels in 13,372 participants of African ancestry. Each study measured the RR interval (ms) from 10-second resting 12-lead electrocardiograms and estimated RR-SNP associations using covariate-adjusted linear regression. Random-effects meta-analysis was used to combine cohort-specific measures of association and identify genome-wide significant loci ( P ≤2.5×10 −8 ). Results Fourteen SNPs on chromosome 6q22 exceeded the genome-wide significance threshold. The most significant association was for rs9320841 (+13 ms per minor allele; P = 4.98×10 −15 ). This SNP was approximately 350 kb downstream of GJA1 , a locus previously identified as harboring SNPs associated with heart rate in Europeans. Adjustment for rs9320841 also attenuated the association between the remaining 13 SNPs in this region and heart rate. In addition, SNPs in MYH6 , which have been identified in European genome-wide association study, were associated with similar changes in the resting heart rate as this population of African Americans. Conclusions An intergenic region downstream of GJA1 (the gene encoding connexin 43, the major protein of the human myocardial gap junction) and an intragenic region within MYH6 are associated with variation in resting heart rate in African Americans as well as in populations of European and Asian origin.

Published
2013

50. Loci influencing blood pressure identified using a cardiovascular gene-centric array

Author

Braxton D. Mitchell, Wei Chen, Wei Guo, Joseph F. Polak, Wolfgang Koenig, Jonathan A. Shaffer, Christian Gieger, Thomas Illig, Abdullah Kutlar, Jessica van Setten, Matthew B. Lanktree, Pieter A. Doevendans, Nicholas J. Schork, Cisca Wijmenga, G. Kees Hovingh, Christopher Newton-Cheh, Daniel Levy, Marten H. Hofker, Eric E. Schadt, Folkert W. Asselbergs, Nicole Soranzo, Sathanur R. Srinivasan, Olle Mellander, Daniel J. Rader, Roy L. Silverstein, David Duggan, Lynda M. Rose, Ron T. Gansevoort, Cliona Molony, André G. Uitterlinden, Li Zhang, Gerald S. Berenson, John Barnard, Vasan S. Ramachandran, Paul M. Ridker, Toby Johnson, Cornelia M. van Duijn, J. Hunter Young, Martin Farrall, Willem H. Ouwehand, Muredach P. Reilly, Tom S. Price, Sean P. Curtis, Brendan J. Keating, John G. Gums, Deepak L. Bhatt, Ilja M. Nolte, Barbara Thorand, Georg Ehret, Hans L. Hillege, Julie A. Johnson, Bernhard R. Winkelmann, Andrea Z. LaCroix, Patricia B. Munroe, Vinicius Tragante, Alan R. Shuldiner, Mieke D. Trip, Karina W. Davidson, Kandice Kottke-Marchant, Hubert Scharnag, Andrew D. Johnson, Ben Burkley, Clement E. Furlong, Winfried März, Yvonne T. van der Schouw, Yen Pei C. Chang, Hakon Hakonarson, Erin N. Smith, Aaron Isaacs, Eric Boerwinkle, Albertine J. Oldehinkel, Haiqing Shen, Richard R. Fabsitz, Alice Stanton, Steffi Maiwald, Matthijs F.L. Meijs, Johannes M.I.H. Gho, Yan Gong, Herman A. Taylor, Mary E. Fischer, Jeffery R. O'Connell, Santhi K. Ganesh, Rhonda M. Cooper-DeHoff, Ervin R. Fox, Albert W. Dreisbach, Brenda W.J.H. Penninx, Susan Kirkland, Caitrin W. McDonough, Nora Franceschini, Daniel I. Chasman, Amber L. Beitelshees, Carl J. Pepine, Tom R. Gaunt, Gurunathan Murugesan, Pim van der Harst, Irene Mateo Leach, Aravinda Chakravarti, Mary Pettinger, Gail P. Jarvik, Marcus E. Kleber, Paul I.W. de Bakker, Myriam Fornage, Mark J. Caulfield, Amber A. Burt, Judith M. Vonk, Sandosh Padmanabhan, Jane E. Ranchalis, Sonia Shah, Berta Almoguera Castillo, Erik P A Van Iperen, Jolanda M. A. Boer, Kiang Liu, Ronald P. Stolk, Garret A. FitzGerald, Yun Li, Rainer Malik, Jens Baumert, Peter J. van der Most, W. M. Monique Verschuren, Bernhard O. Boehm, Clara C. Elbers, Xiaofeng Zhu, Harold Snieder, N. Charlotte Onland-Moret, Honghuang Lin, Taimour Y. Langaee, Ramakrishnan Rajagopalan, John J.P. Kastelein, Nilesh J. Samani, Daichi Shimbo, Susan Redline, Sarah S. Murray, Alexander P. Reiner, Sharon B. Wyatt, Walter Palmas, Yiran Guo, EMGO+ - Mental Health, Ehret, Georg Benedikt, APH - Amsterdam Public Health, Epidemiology and Data Science, Graduate School, ACS - Amsterdam Cardiovascular Sciences, Vascular Medicine, Other departments, Cardiology, Psychiatry, EMGO - Mental health, Faculteit Medische Wetenschappen/UMCG, Life Course Epidemiology (LCE), Groningen Research Institute for Asthma and COPD (GRIAC), Cardiovascular Centre (CVC), Groningen Kidney Center (GKC), Center for Liver, Digestive and Metabolic Diseases (CLDM), Vascular Ageing Programme (VAP), Lifestyle Medicine (LM), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Epidemiology, Public Health, Clinical Genetics, Immunology, Child and Adolescent Psychiatry / Psychology, and Internal Medicine

Subjects
Male, Candidate gene, Genome-wide association study, Blood Pressure, 030204 cardiovascular system & hematology, Bioinformatics, Cohort Studies, 0302 clinical medicine, Polymorphism (computer science), European Continental Ancestry Group/genetics, Genetics (clinical), ddc:616, Genetics, 0303 health sciences, Association Studies Articles, PULSE PRESSURE, Chromosome Mapping, General Medicine, Single Nucleotide, Middle Aged, 3. Good health, Cardiovascular Diseases, 030220 oncology & carcinogenesis, Female, Corrigendum, circulatory and respiratory physiology, EXPRESSION, Adult, Blood Pressure/genetics, Genotype, Single-nucleotide polymorphism, Quantitative trait locus, Biology, Polymorphism, Single Nucleotide, White People, Cardiovascular Diseases/genetics/physiopathology, 03 medical and health sciences, MDM2, SDG 3 - Good Health and Well-being, Cardiovascular Diseases/genetics, Humans, CORONARY-HEART-DISEASE, Genetic Predisposition to Disease, HISTAMINE-RECEPTOR H-1, cardiovascular diseases, GENOME-WIDE ASSOCIATION, Polymorphism, Molecular Biology, Gene, METAANALYSIS, 030304 developmental biology, Aged, P53, HYPERTENSION, MICE, Blood pressure, Methylenetetrahydrofolate reductase, Expression quantitative trait loci, biology.protein, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Blood pressure (BP) is a heritable determinant of risk for cardiovascular disease (CVD). To investigate genetic associations with systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP) and pulse pressure (PP), we genotyped ∼50 000 single-nucleotide polymorphisms (SNPs) that capture variation in ∼2100 candidate genes for cardiovascular phenotypes in 61 619 individuals of European ancestry from cohort studies in the USA and Europe. We identified novel associations between rs347591 and SBP (chromosome 3p25.3, in an intron of HRH1) and between rs2169137 and DBP (chromosome1q32.1 in an intron of MDM4) and between rs2014408 and SBP (chromosome 11p15 in an intron of SOX6), previously reported to be associated with MAP. We also confirmed 10 previously known loci associated with SBP, DBP, MAP or PP (ADRB1, ATP2B1, SH2B3/ATXN2, CSK, CYP17A1, FURIN, HFE, LSP1, MTHFR, SOX6) at array-wide significance (P < 2.4 × 10(-6)). We then replicated these associations in an independent set of 65 886 individuals of European ancestry. The findings from expression QTL (eQTL) analysis showed associations of SNPs in the MDM4 region with MDM4 expression. We did not find any evidence of association of the two novel SNPs in MDM4 and HRH1 with sequelae of high BP including coronary artery disease (CAD), left ventricular hypertrophy (LVH) or stroke. In summary, we identified two novel loci associated with BP and confirmed multiple previously reported associations. Our findings extend our understanding of genes involved in BP regulation, some of which may eventually provide new targets for therapeutic intervention.

Published
2013

Catalog

Books, media, physical & digital resources
See catalog results