Search

Your search keyword '"Jun Z Li"' showing total 57 results
Start Over Author "Jun Z Li"
57 results on '"Jun Z Li"'

1. Impact of between-tissue differences on pan-cancer predictions of drug sensitivity.

Author

John P Lloyd, Matthew B Soellner, Sofia D Merajver, and Jun Z Li

Subjects
Biology (General), QH301-705.5
Abstract

Increased availability of drug response and genomics data for many tumor cell lines has accelerated the development of pan-cancer prediction models of drug response. However, it is unclear how much between-tissue differences in drug response and molecular characteristics may contribute to pan-cancer predictions. Also unknown is whether the performance of pan-cancer models could vary by cancer type. Here, we built a series of pan-cancer models using two datasets containing 346 and 504 cell lines, each with MEK inhibitor (MEKi) response and mRNA expression, point mutation, and copy number variation data, and found that, while the tissue-level drug responses are accurately predicted (between-tissue ρ = 0.88-0.98), only 5 of 10 cancer types showed successful within-tissue prediction performance (within-tissue ρ = 0.11-0.64). Between-tissue differences make substantial contributions to the performance of pan-cancer MEKi response predictions, as exclusion of between-tissue signals leads to a decrease in Spearman's ρ from a range of 0.43-0.62 to 0.30-0.51. In practice, joint analysis of multiple cancer types usually has a larger sample size, hence greater power, than for one cancer type; and we observe that higher accuracy of pan-cancer prediction of MEKi response is almost entirely due to the sample size advantage. Success of pan-cancer prediction reveals how drug response in different cancers may invoke shared regulatory mechanisms despite tissue-specific routes of oncogenesis, yet predictions in different cancer types require flexible incorporation of between-cancer and within-cancer signals. As most datasets in genome sciences contain multiple levels of heterogeneity, careful parsing of group characteristics and within-group, individual variation is essential when making robust inference.

Published
2021
Full Text
View/download PDF

2. Variants in myelin regulatory factor (MYRF) cause autosomal dominant and syndromic nanophthalmos in humans and retinal degeneration in mice.

Author

Sarah J Garnai, Michelle L Brinkmeier, Ben Emery, Tomas S Aleman, Louise C Pyle, Biliana Veleva-Rotse, Robert A Sisk, Frank W Rozsa, Ayse Bilge Ozel, Jun Z Li, Sayoko E Moroi, Steven M Archer, Cheng-Mao Lin, Sarah Sheskey, Laurel Wiinikka-Buesser, James Eadie, Jill E Urquhart, Graeme C M Black, Mohammad I Othman, Michael Boehnke, Scot A Sullivan, Gregory L Skuta, Hemant S Pawar, Alexander E Katz, Laryssa A Huryn, Robert B Hufnagel, Genomic Ascertainment Cohort, Sally A Camper, Julia E Richards, and Lev Prasov

Subjects
Genetics, QH426-470
Abstract

Nanophthalmos is a rare, potentially devastating eye condition characterized by small eyes with relatively normal anatomy, a high hyperopic refractive error, and frequent association with angle closure glaucoma and vision loss. The condition constitutes the extreme of hyperopia or farsightedness, a common refractive error that is associated with strabismus and amblyopia in children. NNO1 was the first mapped nanophthalmos locus. We used combined pooled exome sequencing and strong linkage data in the large family used to map this locus to identify a canonical splice site alteration upstream of the last exon of the gene encoding myelin regulatory factor (MYRF c.3376-1G>A), a membrane bound transcription factor that undergoes autoproteolytic cleavage for nuclear localization. This variant produced a stable RNA transcript, leading to a frameshift mutation p.Gly1126Valfs*31 in the C-terminus of the protein. In addition, we identified an early truncating MYRF frameshift mutation, c.769dupC (p.S264QfsX74), in a patient with extreme axial hyperopia and syndromic features. Myrf conditional knockout mice (CKO) developed depigmentation of the retinal pigment epithelium (RPE) and retinal degeneration supporting a role of this gene in retinal and RPE development. Furthermore, we demonstrated the reduced expression of Tmem98, another known nanophthalmos gene, in Myrf CKO mice, and the physical interaction of MYRF with TMEM98. Our study establishes MYRF as a nanophthalmos gene and uncovers a new pathway for eye growth and development.

Published
2019
Full Text
View/download PDF

3. Genetic Overlap Between Alzheimer’s Disease and Bipolar Disorder Implicates the MARK2 and VAC14 Genes

Author

Ole Kristian Drange, Olav Bjerkehagen Smeland, Alexey A. Shadrin, Per Ivar Finseth, Aree Witoelar, Oleksandr Frei, Psychiatric Genomics Consortium Bipolar Disorder Working Group, Yunpeng Wang, Sahar Hassani, Srdjan Djurovic, Anders M. Dale, Ole A. Andreassen, Eli A Stahl, Gerome Breen, Andreas J Forstner, Andrew McQuillin, Stephan Ripke, Vassily Trubetskoy, Manuel Mattheisen, Jonathan R I Coleman, Heìleìna A Gaspar, Christiaan A de Leeuw, Stacy Steinberg, Jennifer M Whitehead Pavlides, Maciej Trzaskowski, Tune H Pers, Peter A Holmans, Liam Abbott, Esben Agerbo, Huda Akil, Diego Albani, Ney Alliey-Rodriguez, Thomas D Als, Adebayo Anjorin, Verneri Antilla, Swapnil Awasthi, Judith A Badner, Marie Bækvad-Hansen, Jack D Barchas, Nicholas Bass, Michael Bauer, Richard Belliveau, Sarah E Bergen, Carsten Bøcker Pedersen, Erlend Bøen, Marco Boks, James Boocock, Monika Budde, William Bunney, Margit Burmeister, Jonas Bybjerg-Grauholm, William Byerley, Miquel Casas, Felecia Cerrato, Pablo Cervantes, Kimberly Chambert, Alexander W Charney, Danfeng Chen, Claire Churchhouse, Toni-Kim Clarke, William Coryell, David W Craig, Cristiana Cruceanu, David Curtis, Piotr M Czerski, Anders M Dale, Simone de Jong, Franziska Degenhardt, Jurgen Del-Favero, J Raymond DePaulo, Amanda L Dobbyn, Ashley Dumont, Torbjørn Elvsåshagen, Valentina Escott-Price, Chun Chieh Fan, Sascha B Fischer, Matthew Flickinger, Tatiana M Foroud, Liz Forty, Josef Frank, Christine Fraser, Nelson B Freimer, Louise Friseìn, Katrin Gade, Diane Gage, Julie Garnham, Claudia Giambartolomei, Marianne Giørtz Pedersen, Jaqueline Goldstein, Scott D Gordon, Katherine Gordon-Smith, Elaine K Green, Melissa J Green, Tiffany A Greenwood, Jakob Grove, Weihua Guan, Joseì Guzman Parra, Marian L Hamshere, Martin Hautzinger, Urs Heilbronner, Stefan Herms, Maria Hipolito, Per Hoffmann, Dominic Holland, Laura Huckins, Steìphane Jamain, Jessica S Johnson, Anders Jureìus, Radhika Kandaswamy, Robert Karlsson, James L Kennedy, Sarah Kittel-Schneider, Sarah V Knott, James A Knowles, Manolis Kogevinas, Anna C Koller, Ralph Kupka, Catharina Lavebratt, Jacob Lawrence, William B Lawson, Markus Leber, Phil H Lee, Shawn E Levy, Jun Z Li, Chunyu Liu, Susanne Lucae, Anna Maaser, Donald J MacIntyre, Pamela B Mahon, Wolfgang Maier, Lina Martinsson, Steve McCarroll, Peter McGuffin, Melvin G McInnis, James D McKay, Helena Medeiros, Sarah E Medland, Fan Meng, Lili Milani, Grant W Montgomery, Derek W Morris, Thomas W Mühleisen, Niamh Mullins, Hoang Nguyen, Caroline M Nievergelt, Annelie Nordin Adolfsson, Evaristus A Nwulia, Claire O’Donovan, Loes M Olde Loohuis, Anil P S Ori, Lilijana Oruc, Urban Ösby, Roy H Perlis, Amy Perry, Andrea Pfennig, James B Potash, Shaun M Purcell, Eline J Regeer, Andreas Reif, Ceìline S Reinbold, John P Rice, Fabio Rivas, Margarita Rivera, Panos Roussos, Douglas M Ruderfer, Euijung Ryu, Cristina Saìnchez-Mora, Alan F Schatzberg, William A Scheftner, Nicholas J Schork, Cynthia Shannon Weickert, Tatyana Shehktman, Paul D Shilling, Engilbert Sigurdsson, Claire Slaney, Olav B Smeland, Janet L Sobell, Christine Søholm Hansen, Anne T Spijker, David St Clair, Michael Steffens, John S Strauss, Fabian Streit, Jana Strohmaier, Szabolcs Szelinger, Robert C Thompson, Thorgeir E Thorgeirsson, Jens Treutlein, Helmut Vedder, Weiqing Wang, Stanley J Watson, Thomas W Weickert, Stephanie H Witt, Simon Xi, Wei Xu, Allan H Young, Peter Zandi, Peng Zhang, Sebastian Zollner, Rolf Adolfsson, Ingrid Agartz, Martin Alda, Lena Backlund, Bernhard T Baune, Frank Bellivier, Wade H Berrettini, Joanna M Biernacka, Douglas H R Blackwood, Michael Boehnke, Anders D Børglum, Aiden Corvin, Nicholas Craddock, Mark J Daly, Udo Dannlowski, ToÞnu Esko, Bruno Etain, Mark Frye, Janice M Fullerton, Elliot S Gershon, Michael Gill, Fernando Goes, Maria Grigoroiu-Serbanescu, Joanna Hauser, David M Hougaard, Christina M Hultman, Ian Jones, Lisa A Jones, Reneì S Kahn, George Kirov, Mikael Landeìn, Marion Leboyer, Cathryn M Lewis, Qingqin S Li, Jolanta Lissowska, Nicholas G Martin, Fermin Mayoral, Susan L McElroy, Andrew M McIntosh, Francis J McMahon, Ingrid Melle, Andres Metspalu, Philip B Mitchell, Gunnar Morken, Ole Mors, Preben Bo Mortensen, Bertram Müller-Myhsok, Richard M Myers, Benjamin M Neale, Vishwajit Nimgaonkar, Merete Nordentoft, Markus M Nöthen, Michael C O’Donovan, Ketil J Oedegaard, Michael J Owen, Sara A Paciga, Carlos Pato, Michele T Pato, Danielle Posthuma, Josep Antoni Ramos-Quiroga, Marta Ribaseìs, Marcella Rietschel, Guy A Rouleau, Martin Schalling, Peter R Schofield, Thomas G Schulze, Alessandro Serretti, Jordan W Smoller, Hreinn Stefansson, Kari Stefansson, Eystein Stordal, Patrick F Sullivan, Gustavo Turecki, Arne E Vaaler, Eduard Vieta, John B Vincent, Thomas Werge, John I Nurnberger, Naomi R Wray, Arianna Di Florio, Howard J Edenberg, Sven Cichon, Roel A Ophoff, Laura J Scott, Ole A Andreassen, John Kelsoe, and Pamela Sklar

Subjects
Alzheimer’s disease, bipolar disorder, GWAS, pleiotropy, cognitive symptoms, affective symptoms, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Background: Alzheimer’s disease (AD) and bipolar disorder (BIP) are complex traits influenced by numerous common genetic variants, most of which remain to be detected. Clinical and epidemiological evidence suggest that AD and BIP are related. However, it is not established if this relation is of genetic origin. Here, we applied statistical methods based on the conditional false discovery rate (FDR) framework to detect genetic overlap between AD and BIP and utilized this overlap to increase the power to identify common genetic variants associated with either or both traits.Methods: We obtained genome wide association studies data from the International Genomics of Alzheimer’s Project part 1 (17,008 AD cases and 37,154 controls) and the Psychiatric Genetic Consortium Bipolar Disorder Working Group (20,352 BIP cases and 31,358 controls). We used conditional QQ-plots to assess overlap in common genetic variants between AD and BIP. We exploited the genetic overlap to re-rank test-statistics for AD and BIP and improve detection of genetic variants using the conditional FDR framework.Results: Conditional QQ-plots demonstrated a polygenic overlap between AD and BIP. Using conditional FDR, we identified one novel genomic locus associated with AD, and nine novel loci associated with BIP. Further, we identified two novel loci jointly associated with AD and BIP implicating the MARK2 gene (lead SNP rs10792421, conjunctional FDR = 0.030, same direction of effect) and the VAC14 gene (lead SNP rs11649476, conjunctional FDR = 0.022, opposite direction of effect).Conclusion: We found polygenic overlap between AD and BIP and identified novel loci for each trait and two jointly associated loci. Further studies should examine if the shared loci implicating the MARK2 and VAC14 genes could explain parts of the shared and distinct features of AD and BIP.

Published
2019
Full Text
View/download PDF

4. Inference of cell type content from human brain transcriptomic datasets illuminates the effects of age, manner of death, dissection, and psychiatric diagnosis.

Author

Megan Hastings Hagenauer, Anton Schulmann, Jun Z Li, Marquis P Vawter, David M Walsh, Robert C Thompson, Cortney A Turner, William E Bunney, Richard M Myers, Jack D Barchas, Alan F Schatzberg, Stanley J Watson, and Huda Akil

Subjects
Medicine, Science
Abstract

Psychiatric illness is unlikely to arise from pathology occurring uniformly across all cell types in affected brain regions. Despite this, transcriptomic analyses of the human brain have typically been conducted using macro-dissected tissue due to the difficulty of performing single-cell type analyses with donated post-mortem brains. To address this issue statistically, we compiled a database of several thousand transcripts that were specifically-enriched in one of 10 primary cortical cell types in previous publications. Using this database, we predicted the relative cell type content for 833 human cortical samples using microarray or RNA-Seq data from the Pritzker Consortium (GSE92538) or publicly-available databases (GSE53987, GSE21935, GSE21138, CommonMind Consortium). These predictions were generated by averaging normalized expression levels across transcripts specific to each cell type using our R-package BrainInABlender (validated and publicly-released on github). Using this method, we found that the principal components of variation in the datasets strongly correlated with the predicted neuronal/glial content of the samples. This variability was not simply due to dissection-the relative balance of brain cell types appeared to be influenced by a variety of demographic, pre- and post-mortem variables. Prolonged hypoxia around the time of death predicted increased astrocytic and endothelial gene expression, illustrating vascular upregulation. Aging was associated with decreased neuronal gene expression. Red blood cell gene expression was reduced in individuals who died following systemic blood loss. Subjects with Major Depressive Disorder had decreased astrocytic gene expression, mirroring previous morphometric observations. Subjects with Schizophrenia had reduced red blood cell gene expression, resembling the hypofrontality detected in fMRI experiments. Finally, in datasets containing samples with especially variable cell content, we found that controlling for predicted sample cell content while evaluating differential expression improved the detection of previously-identified psychiatric effects. We conclude that accounting for cell type can greatly improve the interpretability of transcriptomic data.

Published
2018
Full Text
View/download PDF

5. Mutation in ATG5 reduces autophagy and leads to ataxia with developmental delay

Author

Myungjin Kim, Erin Sandford, Damian Gatica, Yu Qiu, Xu Liu, Yumei Zheng, Brenda A Schulman, Jishu Xu, Ian Semple, Seung-Hyun Ro, Boyoung Kim, R Nehir Mavioglu, Aslıhan Tolun, Andras Jipa, Szabolcs Takats, Manuela Karpati, Jun Z Li, Zuhal Yapici, Gabor Juhasz, Jun Hee Lee, Daniel J Klionsky, and Margit Burmeister

Subjects
ataxia, next generation sequencing, autophagy, Medicine, Science, Biology (General), QH301-705.5
Abstract

Autophagy is required for the homeostasis of cellular material and is proposed to be involved in many aspects of health. Defects in the autophagy pathway have been observed in neurodegenerative disorders; however, no genetically-inherited pathogenic mutations in any of the core autophagy-related (ATG) genes have been reported in human patients to date. We identified a homozygous missense mutation, changing a conserved amino acid, in ATG5 in two siblings with congenital ataxia, mental retardation, and developmental delay. The subjects' cells display a decrease in autophagy flux and defects in conjugation of ATG12 to ATG5. The homologous mutation in yeast demonstrates a 30-50% reduction of induced autophagy. Flies in which Atg5 is substituted with the mutant human ATG5 exhibit severe movement disorder, in contrast to flies expressing the wild-type human protein. Our results demonstrate the critical role of autophagy in preventing neurological diseases and maintaining neuronal health.

Published
2016
Full Text
View/download PDF

6. G Protein-Linked Signaling Pathways in Bipolar and Major Depressive Disorders

Author

Hiroaki eTomita, Mary E Ziegler, Helen B Kim, Simon J Evans, Prabhakara V Choudary, Jun Z Li, Fan eMeng, Manhong eDai, Charles R Neal, Richard M Myers, Terry P Speed, Jack D Barchas, Alan F Schatzberg, Stanley J Watson, Huda eAkil, Edward G Jones, William E Bunney, and Marquis P Vawter

Subjects
Microarray, Effectors, postmortem brain, G-protein, G-protein coupled receptor (GPCR), G-protein linked signaling, Genetics, QH426-470
Abstract

The G-protein linked signaling system (GPLS) comprises a large number of G-proteins, G protein-coupled receptors (GPCRs), GPCR ligands, and downstream effector molecules. G-proteins interact with both GPCRs and downstream effectors such as cyclic adenosine monophosphate (cAMP), phosphatidylinositols, and ion channels. The GPLS is implicated in the pathophysiology and pharmacology of both major depressive disorder (MDD) and bipolar disorder (BPD). This study evaluated whether GPLS is altered at the transcript level. The gene expression in the dorsolateral prefrontal (DLPFC) and anterior cingulate (ACC) were compared from MDD, BPD, and control subjects using Affymetrix Gene Chips and real time quantitative PCR. High quality brain tissue was used in the study to control for confounding effects of agonal events, tissue pH, RNA integrity, gender, and age. GPLS signaling transcripts were altered especially in the ACC of BPD and MDD subjects. Transcript levels of molecules which repress cAMP activity were increased in BPD and decreased in MDD. Two orphan GPCRs, GPRC5B and GPR37, showed significantly decreased expression levels in MDD, and significantly increased expression levels in BPD. Our results suggest opposite changes in BPD and MDD in the GPLS, ‘activated’ cAMP signaling activity in BPD and ‘blunted’ cAMP signaling activity in MDD. GPRC5B and GPR37 both appear to have behavioral effects, and are also candidate genes for neurodegenerative disorders. In the context of the opposite changes observed in BPD and MDD, these GPCRs warrant further study of their brain effects.

Published
2013
Full Text
View/download PDF

7. Genetic analysis of a rat model of aerobic capacity and metabolic fitness.

Author

Yu-Yu Ren, Katherine A Overmyer, Nathan R Qi, Mary K Treutelaar, Lori Heckenkamp, Molly Kalahar, Lauren G Koch, Steven L Britton, Charles F Burant, and Jun Z Li

Subjects
Medicine, Science
Abstract

Aerobic capacity is a strong predictor of all-cause mortality and can influence many complex traits. To explore the biological basis underlying this connection, we developed via artificial selection two rat lines that diverge for intrinsic (i.e. inborn) aerobic capacity and differ in risk for complex disease traits. Here we conduct the first in-depth pedigree and molecular genetic analysis of these lines, the high capacity runners (HCR) and low capacity runners (LCR). Our results show that both HCR and LCR lines maintain considerable narrow-sense heritability (h(2)) for the running capacity phenotype over 28 generations (h(2) = 0.47 ± 0.02 and 0.43 ± 0.02, respectively). To minimize inbreeding, the lines were maintained by rotational mating. Pedigree records predict that the inbreeding coefficient increases at a rate of

Published
2013
Full Text
View/download PDF

8. Genome-wide association studies of quantitatively measured skin, hair, and eye pigmentation in four European populations.

Author

Sophie I Candille, Devin M Absher, Sandra Beleza, Marc Bauchet, Brian McEvoy, Nanibaa' A Garrison, Jun Z Li, Richard M Myers, Gregory S Barsh, Hua Tang, and Mark D Shriver

Subjects
Medicine, Science
Abstract

Pigmentation of the skin, hair, and eyes varies both within and between human populations. Identifying the genes and alleles underlying this variation has been the goal of many candidate gene and several genome-wide association studies (GWAS). Most GWAS for pigmentary traits to date have been based on subjective phenotypes using categorical scales. But skin, hair, and eye pigmentation vary continuously. Here, we seek to characterize quantitative variation in these traits objectively and accurately and to determine their genetic basis. Objective and quantitative measures of skin, hair, and eye color were made using reflectance or digital spectroscopy in Europeans from Ireland, Poland, Italy, and Portugal. A GWAS was conducted for the three quantitative pigmentation phenotypes in 176 women across 313,763 SNP loci, and replication of the most significant associations was attempted in a sample of 294 European men and women from the same countries. We find that the pigmentation phenotypes are highly stratified along axes of European genetic differentiation. The country of sampling explains approximately 35% of the variation in skin pigmentation, 31% of the variation in hair pigmentation, and 40% of the variation in eye pigmentation. All three quantitative phenotypes are correlated with each other. In our two-stage association study, we reproduce the association of rs1667394 at the OCA2/HERC2 locus with eye color but we do not identify new genetic determinants of skin and hair pigmentation supporting the lack of major genes affecting skin and hair color variation within Europe and suggesting that not only careful phenotyping but also larger cohorts are required to understand the genetic architecture of these complex quantitative traits. Interestingly, we also see that in each of these four populations, men are more lightly pigmented in the unexposed skin of the inner arm than women, a fact that is underappreciated and may vary across the world.

Published
2012
Full Text
View/download PDF

9. Intrinsic cardiorespiratory fitness modulates clinical and molecular response to caloric restriction

Author

Johanna Y. Fleischman, Nathan R. Qi, Mary K. Treutelaar, Steven L. Britton, Lauren G. Koch, Jun Z. Li, and Charles F. Burant

Subjects
Caloric restriction, Cardiorespiratory fitness, Mitochondria, Metabolism, Muscle, Internal medicine, RC31-1245
Abstract

Objective: Caloric restriction (CR) is one extrinsic intervention that can improve metabolic health, and it shares many phenotypical parallels with intrinsic high cardiorespiratory fitness (CRF), including reduced adiposity, increased cardiometabolic health, and increased longevity. CRF is a highly heritable trait in humans and has been established in a genetic rat model selectively bred for high (HCR) and low (LCR) CRF, in which the HCR live longer and have reduced body weight compared to LCR. This study addresses whether the inherited high CRF phenotype occurs through similar mechanisms by which CR promotes health and longevity. Methods: We compared HCR and LCR male rats fed ad libitum (AL) or calorically restricted (CR) for multiple physiological, metabolic, and molecular traits, including running capacity at 2, 8, and 12 months; per-hour metabolic cage activity over daily cycles at 6 and 12 months; and plasma lipidomics, liver and muscle transcriptomics, and body composition after 12 months of treatment. Results: LCR-CR developed a physiological profile that mirrors the high-CRF phenotype in HCR-AL, including reduced adiposity and increased insulin sensitivity. HCR show higher spontaneous activity than LCR. Temporal modeling of hourly energy expenditure (EE) dynamics during the day, adjusted for body weight and hourly activity levels, suggest that CR has an EE-suppressing effect, and high-CRF has an EE-enhancing effect. Pathway analysis of gene transcripts indicates that HCR and LCR both show a response to CR that is similar in the muscle and different in the liver. Conclusions: CR provides LCR a health-associated positive effect on physiological parameters that strongly resemble HCR. Analysis of whole-body EE and transcriptomics suggests that HCR and LCR show line-dependent responses to CR that may be accreditable to difference in genetic makeup. The results do not preclude the possibility that CRF and CR pathways may converge.

Published
2023
Full Text
View/download PDF

10. Presence of ovarian stromal aberrations after cessation of testosterone therapy in a transgender mouse model

Author

Hadrian M Kinnear, Prianka H Hashim, Cynthia Dela Cruz, Faith L Chang, Gillian Rubenstein, Likitha Nimmagadda, Venkateswaran Ramamoorthi Elangovan, Andrea Jones, Margaret A Brunette, D Ford Hannum, Jun Z Li, Vasantha Padmanabhan, Molly B Moravek, and Ariella Shikanov

Subjects
Reproductive Medicine, Cell Biology, General Medicine
Abstract

Some transmasculine individuals may be interested in pausing gender-affirming testosterone therapy and carrying a pregnancy. The ovarian impact of taking and pausing testosterone is not completely understood. The objective of this study was to utilize a mouse model mimicking transmasculine testosterone therapy to characterize the ovarian dynamics following testosterone cessation. We injected postpubertal 9–10-week-old female C57BL/6N mice once weekly with 0.9 mg of testosterone enanthate or a vehicle control for 6 weeks. All testosterone-treated mice stopped cycling and demonstrated persistent diestrus within 1 week of starting testosterone, while control mice cycled regularly. After 6 weeks of testosterone therapy, one group of testosterone-treated mice and age-matched vehicle-treated diestrus controls were sacrificed. Another group of testosterone-treated mice were maintained after stopping testosterone therapy and were sacrificed in diestrus four cycles after the resumption of cyclicity along with age-matched vehicle-treated controls. Ovarian histological analysis revealed stromal changes with clusters of large round cells in the post testosterone group as compared to both age-matched controls and mice at 6 weeks on testosterone. These clusters exhibited periodic acid–Schiff staining, which has been previously reported in multinucleated macrophages in aging mouse ovaries. Notably, many of these cells also demonstrated positive staining for macrophage markers CD68 and CD11b. Ovarian ribonucleic acid-sequencing found upregulation of immune pathways post testosterone as compared to age-matched controls and ovaries at 6 weeks on testosterone. Although functional significance remains unknown, further attention to the ovarian stroma may be relevant for transmasculine people interested in pausing testosterone to carry a pregnancy.

Published
2023
Full Text
View/download PDF

11. Genetic variants in ADAMTS13 as well as smoking are major determinants of plasma ADAMTS13 levels

Author

Qianyi Ma, Paula M. Jacobi, Brian T. Emmer, Colin A. Kretz, Ayse Bilge Ozel, Beth McGee, Chava Kimchi-Sarfaty, David Ginsburg, Jun Z. Li, and Karl C. Desch

Subjects
Specialties of internal medicine, RC581-951
Abstract

Abstract: The metalloprotease ADAMTS13 cleaves von Willebrand factor (VWF) in circulating blood, limiting the size of VWF multimers and regulating VWF activity. Abnormal regulation of VWF contributes to bleeding and to thrombotic disorders. ADAMTS13 levels in plasma are highly variable among healthy individuals, although the heritability and the genetic determinants of this variation are unclear. We performed genome-wide association studies of plasma ADAMTS13 concentrations in 3244 individuals from 2 independent cohorts of healthy individuals. The heritability of ADAMTS13 levels was between 59.1% (all individuals) and 83.5% (siblings only), whereas tobacco smoking was associated with a decrease in plasma ADAMTS13 levels. Meta-analysis identified common variants near the ADAMTS13 locus on chromosome 9q34.2 that were significantly associated with ADAMTS13 levels and collectively explained 20.0% of the variance. The top single nucleotide polymorphism (SNP), rs28673647, resides in an intron of ADAMTS13 (β, 6.7%; P = 1.3E-52). Conditional analysis revealed 3 additional independent signals represented by rs3739893 (β, −22.3%; P = 1.2E-30) and rs3124762 (β, 3.5%; P = 8.9E-9) close to ADAMTS13 and rs4075970 (β, 2.4%; P = 6.8E-9) on 21q22.3. Linkage analysis also identified the region around ADAMTS13 (9q34.2) as the top signal (LOD 3.5), consistent with our SNP association analyses. Two nonsynonymous ADAMTS13 variants in the top 2 independent linkage disequilibrium blocks (Q448E and A732V) were identified and characterized in vitro. This study uncovered specific common genetic polymorphisms that are key genetic determinants of the variation in plasma ADAMTS13 levels in healthy individuals.

Published
2017
Full Text
View/download PDF

12. A revamped rat reference genome improves the discovery of genetic diversity in laboratory rats

Author

Tristan V de Jong, Yanchao Pan, Pasi Rastas, Daniel Munro, Monika Tutaj, Huda Akil, Chris Benner, Apurva S Chitre, William Chow, Vincenza Colonna, Clifton L Dalgard, Wendy M Demos, Peter A Doris, Erik Garrison, Aron Geurts, Hakan M Gunturkun, Victor Guryev, Thibaut Hourlier, Kerstin Howe, Jun Huang, Ted Kalbfleisch, Panjun Kim, Ling Li, Spencer Mahaffey, Fergal J Martin, Pejman Mohammadi, Ayse Bilge Ozel, Oksana Polesskaya, Michal Pravenec, Pjotr Prins, Jonathan Sebat, Jennifer R Smith, Leah C Solberg Woods, Boris Tabakoff, Alan Tracey, Marcela Uliano-Silva, Flavia Villani, Hongyang Wang, Burt M Sharp, Francesca Telese, Zhihua Jiang, Laura Saba, Xusheng Wang, Terence D Murphy, Abraham A Palmer, Anne E Kwitek, Melinda (Mindy) R Dwinell, Robert W Williams, Jun Z Li, and Hao Chen

Abstract

For over a decade, a large research community has relied on a flawed reference assembly of the genome ofRattus norvegicusknown as Rnor_6.0. The seventh assembly of the rat reference genome4mRatBN7.2, based on the inbred Brown Norway rat, corrects numerous misplaced segments, reduces base-level errors by approximately 9-fold, and increases contiguity by 290-fold, despite some remaining regions of potential misassembly. Gene annotations are now more complete, significantly improving the mapping precision of genomic, transcriptomic, and proteomics data sets. SimpleLiftOverfrom Rnor_6.0 to mRatBN7.2 misses ∼12% of variants. To facilitate the transition to mRatBN7.2, we performed a joint analysis of 163 whole genomes representing 120 strains/substrains. We defined 20.0 million sequence variations, of which 18.7 thousand are predicted to potentially impact the function of 6,677 genes. Phylogenetic analysis confirmed historical records and prior results and refined the ancestral relationship of these strains. Sixteen million polymorphisms segregate in the widely studied heterogeneous stock rat population, and 11313 million variants segregate collectively in the HXB/BXH and FXLE/LEXF strain families. Some inbred strains differ by only 132 M variants, and closely related substrains segregate by even fewer variants. We generated a new rat genetic map based on data from 1,893 heterogeneous stock rats and annotated transcription start sites and alternative polyadenylation sites.

Published
2023
Full Text
View/download PDF

17. Supplementary Figures 1-14 from Genomic Estimates of Aneuploid Content in Glioblastoma Multiforme and Improved Classification

Author

Jun Z. Li, Jishu Xu, Min-Lee Yang, Weiping Peng, Yasin Senbabaoglu, and Bo Li

Abstract

PDF file, 6233K, S1: Inference of Aneuploid Genome Proportion and its goodness-of-fit measures; Figure S2: Histolopathological estimates of tumor purities versus AGP; S3: Relationship between AGP and gene expression pattern in ovarian cancer (OV); S4: PCA plots for CNA and CNA-MicroRNA joint analysis; S5: Principal component analyses of gene expression and CNA data for GBM2; S6: Clustering pattern of three data types: PC1 of copy number data, PC1 of expression data, and PC2 of methylation data; S7: Classification of Non-Proneural GBM tumors; S8: Cross-correlation analysis of GBM1-GBM2 at K=3 and 4; S9: Comparison between the revised and the previous GBM classification systems; S10: Cross-correlation analysis between GBM1 and Phillips' dataset at K=2, 3 and 4; S11: PCA plots for 46 Non-Proneural GBM samples in Phillips' dataset; S12: Survival time differences between GBM subtypes, compared between the current and previous classification systems; S13: Cox proportional hazard regression analysis with GBM subtypes as covariates, along with age and Karnofsky performance scores (KPS); S14: Four clusters formed by the 38 reference samples in the Cahoy's dataset.

Published
2023
Full Text
View/download PDF

20. Data from Genomic Estimates of Aneuploid Content in Glioblastoma Multiforme and Improved Classification

Author

Jun Z. Li, Jishu Xu, Min-Lee Yang, Weiping Peng, Yasin Senbabaoglu, and Bo Li

Abstract

Purpose: Accurate classification of glioblastoma multiforme (GBM) is crucial for understanding its biologic diversity and informing diagnosis and treatment. The Cancer Genome Atlas (TCGA) project identified four GBM classes using gene expression data and separately identified three classes using methylation data. We sought to integrate multiple data types in GBM classification, understand biologic features of the newly defined subtypes, and reconcile with prior studies.Experimental Design: We used allele-specific copy number data to estimate the aneuploid content of each tumor and incorporated this measure of intratumor heterogeneity in class discovery. We estimated the potential cell of origin of individual subtypes and the euploid and aneuploid fractions using reference datasets of known neuronal cell types.Results: There exists an unexpected correlation between aneuploid content and the observed among-tumor diversity of expression patterns. Joint use of DNA and mRNA data in ab initio class discovery revealed a distinct group that resembles the Proneural subtype described in a separate study and the glioma-CpG island methylator phenotype (G-CIMP+) class based on methylation data. Three additional subtypes, Classical, Proliferative, and Mesenchymal, were also identified and revised the assignment for many samples. The revision showed stronger differences in patient outcome and clearer cell type–specific signatures. Mesenchymal GBMs had higher euploid content, potentially contributed by microglia/macrophage infiltration.Conclusion: We clarified the confusion about the “Proneural” subtype that was defined differently in different prior studies. The ability to infer within-tumor heterogeneity improved class discovery, leading to new subtypes that are closer to the fundamental biology of GBM. Clin Cancer Res; 18(20); 5595–605. ©2012 AACR.

Published
2023
Full Text
View/download PDF

21. The Legacy of Infectious Disease Exposure on the Genomic Diversity of Indigenous Southern Mexicans

Author

Obed A Garcia, Kendall Arslanian, Daniel Whorf, Serena Thariath, Mark Shriver, Jun Z Li, and Abigail W Bigham

Subjects
Genetics, Ecology, Evolution, Behavior and Systematics
Abstract

To characterize host risk factors for infectious disease in Mesoamerican populations, we interrogated 857,481 SNPs assayed using the Affymetrix 6.0 genotyping array for signatures of natural selection in immune response genes. We applied three statistical tests to identify signatures of natural selection: locus-specific branch length (LSBL), the cross-population extended haplotype homozygosity (XP-EHH), and the integrated haplotype score (iHS). Each of the haplotype tests (XP-EHH and iHS) were paired with LSBL and significance was determined at the 1% level. For the paired analyses, we identified 95 statistically significant windows for XP-EHH/LSBL and 63 statistically significant windows for iHS/LSBL. Among our top immune response loci, we found evidence of recent directional selection associated with the major histocompatibility complex (MHC) and the peroxisome proliferator-activated receptor gamma (PPAR-γ) signaling pathway. These findings illustrate that Mesoamerican populations' immunity has been shaped by exposure to infectious disease. As targets of selection, these variants are likely to encode phenotypes that manifest themselves physiologically and therefore may contribute to population-level variation in immune response. Our results shed light on past selective events influencing the host response to modern diseases, both pathogenic infection as well as autoimmune disorders.

Published
2023
Full Text
View/download PDF

22. Decoding the Spermatogenesis Program: New Insights from Transcriptomic Analyses

Author

Mashiat Rabbani, Xianing Zheng, Gabe L. Manske, Alexander Vargo, Adrienne N. Shami, Jun Z. Li, and Saher Sue Hammoud

Subjects
Male, Gene Expression Profiling, Testis, Genetics, Humans, Cell Differentiation, Transcriptome, Spermatogenesis
Abstract

Spermatogenesis is a complex differentiation process coordinated spatiotemporally across and along seminiferous tubules. Cellular heterogeneity has made it challenging to obtain stage-specific molecular profiles of germ and somatic cells using bulk transcriptomic analyses. This has limited our ability to understand regulation of spermatogenesis and to integrate knowledge from model organisms to humans. The recent advancement of single-cell RNA-sequencing (scRNA-seq) technologies provides insights into the cell type diversity and molecular signatures in the testis. Fine-grained cell atlases of the testis contain both known and novel cell types and define the functional states along the germ cell developmental trajectory in many species. These atlases provide a reference system for integrated interspecies comparisons to discover mechanistic parallels and to enable future studies. Despite recent advances, we currently lack high-resolution data to probe germ cell–somatic cell interactions in the tissue environment, but the use of highly multiplexed spatial analysis technologies has begun to resolve this problem. Taken together, recent single-cell studies provide an improvedunderstanding of gametogenesis to examine underlying causes of infertility and enable the development of new therapeutic interventions.

Published
2022

24. Cellular heterogeneity of human fallopian tubes in normal and hydrosalpinx disease states identified by scRNA-seq

Author

Nicole D. Ulrich, Yu-chi Shen, Qianyi Ma, Kun Yang, D. Ford Hannum, Andrea Jones, Jordan Machlin, John F. Randolph, Yolanda R. Smith, Samantha B. Schon, Ariella Shikanov, Erica E. Marsh, Richard Lieberman, Stephen J. Gurczynski, Bethany B. Moore, Jun Z. Li, and Sue Hammoud

Subjects
Ovarian Neoplasms, Humans, Epithelial Cells, Female, Cell Biology, Single-Cell Analysis, Molecular Biology, General Biochemistry, Genetics and Molecular Biology, Article, Fallopian Tubes, Developmental Biology
Abstract

Fallopian tube (FT) homeostasis requires dynamic regulation of heterogeneous cell populations and is disrupted in infertility and ovarian cancer. Here, we applied single-cell RNA-seq to profile 59,738 FT cells from four healthy, pre-menopausal subjects. The resulting cell atlas contains 12 major cell types representing epithelial, stromal, and immune compartments. Re-clustering of epithelial cells identified four ciliated and six non-ciliated secretory epithelial subtypes, two of which represent potential progenitor pools: one leading to mature secretory cells and the other contributing to either ciliated cells or one of the stromal cell types. To understand how FT cell numbers and states change in a disease state, we analyzed 17,798 cells from two hydrosalpinx samples and observed shifts in epithelial and stromal populations and cell-type-specific changes in extracellular matrix and TGF-β signaling; this underscores fibrosis pathophysiology. This resource is expected to facilitate future studies aimed at expanding understanding of fallopian tube homeostasis in normal development and disease.

Published
2022

25. Self-organizing Single-Rosette Brain Organoids from Human Pluripotent Stem Cells

Author

Andrew M. Tidball, Wei Niu, Qianyi Ma, Taylor N. Takla, J. Clayton Walker, Joshua L. Margolis, Sandra P. Mojica-Perez, Roksolana Sudyk, Shannon J. Moore, Ravi Chopra, Vikram G. Shakkottai, Geoffrey G. Murphy, Jun Z. Li, and Jack M. Parent

Abstract

The field of brain organoid research is complicated by morphological variability with multiple neural rosette structures per organoid. We have developed a new human brain organoid technique that generates self-organizing, single-rosette spheroids (SOSRS) with reproducible size, cortical-like lamination, and cell diversity. Rather than patterning a 3-dimensional embryoid body, we initiate brain organoid formation from a 2-dimensional monolayer of human pluripotent stem cells (hPSCs) that is patterned with small molecules into neuroepithelium and differentiated to cells of the developing dorsal cerebral cortex. This approach recapitulates the 2D to 3D transition from neural plate to neural tube that occurs during neurodevelopment. The vast majority of monolayer fragments form spheres with a single central lumen and consistent growth rates. Over time, the SOSRS develop appropriately ordered lamination consistent with six cortical layers by immunocytochemistry and single cell RNA-sequencing. The reproducibility of this method has allowed us to demonstrate robust structural phenotypes arising from chemical teratogen exposure or when modeling a genetic neurodevelopmental epileptic disorder. This platform should advance studies of human cortical development, brain disorder mechanisms, and precision therapies.SUMMARY STATEMENTSimple procedure for generating reproducible single rosette cortical brain organoids used to identify robust structural phenotypes with neuroteratogen exposure and in a genetic neurodevelopmental disease model.

Published
2022
Full Text
View/download PDF

26. Sex-Dependent Shared and Nonshared Genetic Architecture Across Mood and Psychotic Disorders

Author

Gabriëlla A.M. Blokland, Jakob Grove, Chia-Yen Chen, Chris Cotsapas, Stuart Tobet, Robert Handa, David St Clair, Todd Lencz, Bryan J. Mowry, Sathish Periyasamy, Murray J. Cairns, Paul A. Tooney, Jing Qin Wu, Brian Kelly, George Kirov, Patrick F. Sullivan, Aiden Corvin, Brien P. Riley, Tõnu Esko, Lili Milani, Erik G. Jönsson, Aarno Palotie, Hannelore Ehrenreich, Martin Begemann, Agnes Steixner-Kumar, Pak C. Sham, Nakao Iwata, Daniel R. Weinberger, Pablo V. Gejman, Alan R. Sanders, Joseph D. Buxbaum, Dan Rujescu, Ina Giegling, Bettina Konte, Annette M. Hartmann, Elvira Bramon, Robin M. Murray, Michele T. Pato, Jimmy Lee, Ingrid Melle, Espen Molden, Roel A. Ophoff, Andrew McQuillin, Nicholas J. Bass, Rolf Adolfsson, Anil K. Malhotra, Nicholas G. Martin, Janice M. Fullerton, Philip B. Mitchell, Peter R. Schofield, Andreas J. Forstner, Franziska Degenhardt, Sabrina Schaupp, Ashley L. Comes, Manolis Kogevinas, José Guzman-Parra, Andreas Reif, Fabian Streit, Lea Sirignano, Sven Cichon, Maria Grigoroiu-Serbanescu, Joanna Hauser, Jolanta Lissowska, Fermin Mayoral, Bertram Müller-Myhsok, Beata Świątkowska, Thomas G. Schulze, Markus M. Nöthen, Marcella Rietschel, John Kelsoe, Marion Leboyer, Stéphane Jamain, Bruno Etain, Frank Bellivier, John B. Vincent, Martin Alda, Claire O’Donovan, Pablo Cervantes, Joanna M. Biernacka, Mark Frye, Susan L. McElroy, Laura J. Scott, Eli A. Stahl, Mikael Landén, Marian L. Hamshere, Olav B. Smeland, Srdjan Djurovic, Arne E. Vaaler, Ole A. Andreassen, Bernhard T. Baune, Tracy Air, Martin Preisig, Rudolf Uher, Douglas F. Levinson, Myrna M. Weissman, James B. Potash, Jianxin Shi, James A. Knowles, Roy H. Perlis, Susanne Lucae, Dorret I. Boomsma, Brenda W.J.H. Penninx, Jouke-Jan Hottenga, Eco J.C. de Geus, Gonneke Willemsen, Yuri Milaneschi, Henning Tiemeier, Hans J. Grabe, Alexander Teumer, Sandra Van der Auwera, Uwe Völker, Steven P. Hamilton, Patrik K.E. Magnusson, Alexander Viktorin, Divya Mehta, Niamh Mullins, Mark J. Adams, Gerome Breen, Andrew M. McIntosh, Cathryn M. Lewis, David M. Hougaard, Merete Nordentoft, Ole Mors, Preben B. Mortensen, Thomas Werge, Thomas D. Als, Anders D. Børglum, Tracey L. Petryshen, Jordan W. Smoller, Jill M. Goldstein, Stephan Ripke, Benjamin M. Neale, James T.R. Walters, Kai-How Farh, Peter A. Holmans, Phil Lee, Brendan Bulik-Sullivan, David A. Collier, Hailiang Huang, Tune H. Pers, Ingrid Agartz, Esben Agerbo, Margot Albus, Madeline Alexander, Farooq Amin, Silviu A. Bacanu, Richard A. Belliveau, Judit Bene, Sarah E. Bergen, Elizabeth Bevilacqua, Tim B. Bigdeli, Donald W. Black, Richard Bruggeman, Nancy G. Buccola, Randy L. Buckner, William Byerley, Wiepke Cahn, Guiqing Cai, Dominique Campion, Rita M. Cantor, Vaughan J. Carr, Noa Carrera, Stanley V. Catts, Kimberly D. Chambert, Raymond C.K. Chan, Ronald Y.L. Chen, Eric Y.H. Chen, Wei Cheng, Eric F.C. Cheung, Siow Ann Chong, C. Robert Cloninger, David Cohen, Nadine Cohen, Paul Cormican, Nick Craddock, James J. Crowley, David Curtis, Michael Davidson, Kenneth L. Davis, Jurgen Del Favero, Ditte Demontis, Dimitris Dikeos, Timothy Dinan, Gary Donohoe, Elodie Drapeau, Jubao Duan, Frank Dudbridge, Naser Durmishi, Peter Eichhammer, Johan Eriksson, Valentina Escott-Price, Laurent Essioux, Ayman H. Fanous, Martilias S. Farrell, Josef Frank, Lude Franke, Robert Freedman, Nelson B. Freimer, Marion Friedl, Joseph I. Friedman, Menachem Fromer, Giulio Genovese, Lyudmila Georgieva, Paola Giusti-Rodríguez, Stephanie Godard, Jacqueline I. Goldstein, Vera Golimbet, Srihari Gopal, Jacob Gratten, Lieuwe de Haan, Christian Hammer, Mark Hansen, Thomas Hansen, Vahram Haroutunian, Frans A. Henskens, Stefan Herms, Joel N. Hirschhorn, Per Hoffmann, Andrea Hofman, Mads V. Hollegaard, Masashi Ikeda, Inge Joa, Antonio Julià, René S. Kahn, Luba Kalaydjieva, Sena Karachanak-Yankova, Juha Karjalainen, David Kavanagh, Matthew C. Keller, James L. Kennedy, Andrey Khrunin, Yunjung Kim, Janis Klovins, Vaidutis Kucinskas, Zita Ausrele Kucinskiene, Hana Kuzelova-Ptackova, Anna K. Kähler, Claudine Laurent, Jimmy Lee Chee Keong, S. Hong Lee, Sophie E. Legge, Bernard Lerer, Miaoxin Li, Tao Li, Kung-Yee Liang, Jeffrey Lieberman, Svetlana Limborska, Carmel M. Loughland, Jan Lubinski, Jouko Lönnqvist, Milan Macek, Brion S. Maher, Wolfgang Maier, Jacques Mallet, Sara Marsal, Manuel Mattheisen, Morten Mattingsdal, Robert W. McCarley, Colm McDonald, Sandra Meier, Carin J. Meijer, Bela Melegh, Raquelle I. Mesholam-Gately, Andres Metspalu, Patricia T. Michie, Vihra Milanova, Younes Mokrab, Derek W. Morris, Kieran C. Murphy, Inez Myin-Germeys, Mari Nelis, Igor Nenadic, Deborah A. Nertney, Gerald Nestadt, Kristin K. Nicodemus, Liene Nikitina-Zake, Laura Nisenbaum, Annelie Nordin, Eadbhard O’Callaghan, Colm O’Dushlaine, F. Anthony O’Neill, Sang-Yun Oh, Ann Olincy, Line Olsen, Jim Van Os, Christos Pantelis, George N. Papadimitriou, Sergi Papiol, Elena Parkhomenko, Tiina Paunio, Milica Pejovic-Milovancevic, Diana O. Perkins, Olli Pietiläinen, Jonathan Pimm, Andrew J. Pocklington, John Powell, Alkes Price, Ann E. Pulver, Shaun M. Purcell, Digby Quested, Henrik B. Rasmussen, Abraham Reichenberg, Mark A. Reimers, Alexander L. Richards, Joshua L. Roffman, Panos Roussos, Douglas M. Ruderfer, Veikko Salomaa, Ulrich Schall, Christian R. Schubert, Sibylle G. Schwab, Edward M. Scolnick, Rodney J. Scott, Larry J. Seidman, Engilbert Sigurdsson, Teimuraz Silagadze, Jeremy M. Silverman, Kang Sim, Petr Slominsky, Hon-Cheong So, Chris C.A. Spencer, Hreinn Stefansson, Stacy Steinberg, Elisabeth Stogmann, Richard E. Straub, Eric Strengman, Jana Strohmaier, T. Scott Stroup, Mythily Subramaniam, Jaana Suvisaari, Dragan M. Svrakic, Jin P. Szatkiewicz, Erik Söderman, Srinivas Thirumalai, Draga Toncheva, Sarah Tosato, Juha Veijola, John Waddington, Dermot Walsh, Dai Wang, Qiang Wang, Bradley T. Webb, Mark Weiser, Dieter B. Wildenauer, Nigel M. Williams, Stephanie Williams, Stephanie H. Witt, Aaron R. Wolen, Emily H.M. Wong, Brandon K. Wormley, Hualin Simon Xi, Clement C. Zai, Xuebin Zheng, Fritz Zimprich, Naomi R. Wray, Kari Stefansson, Peter M. Visscher, Douglas H.R. Blackwood, Ariel Darvasi, Enrico Domenici, Michael Gill, Hugh Gurling, Christina M. Hultman, Assen V. Jablensky, Kenneth S. Kendler, Jo Knight, Qingqin S. Li, Jianjun Liu, Steven A. McCarroll, Jennifer L. Moran, Michael J. Owen, Carlos N. Pato, Danielle Posthuma, Pamela Sklar, Jens R. Wendland, Mark J. Daly, Michael C. O’Donovan, Peter Donnelly, Ines Barroso, Jenefer M. Blackwell, Matthew A. Brown, Juan P. Casas, Panos Deloukas, Audrey Duncanson, Janusz Jankowski, Hugh S. Markus, Christopher G. Mathew, Colin N.A. Palmer, Robert Plomin, Anna Rautanen, Stephen J. Sawcer, Richard C. Trembath, Ananth C. Viswanathan, Nicholas W. Wood, Gavin Band, Céline Bellenguez, Colin Freeman, Eleni Giannoulatou, Garrett Hellenthal, Richard Pearson, Matti Pirinen, Amy Strange, Zhan Su, Damjan Vukcevic, Cordelia Langford, Hannah Blackburn, Suzannah J. Bumpstead, Serge Dronov, Sarah Edkins, Matthew Gillman, Emma Gray, Rhian Gwilliam, Naomi Hammond, Sarah E. Hunt, Alagurevathi Jayakumar, Jennifer Liddle, Owen T. McCann, Simon C. Potter, Radhi Ravindrarajah, Michelle Ricketts, Avazeh Tashakkori-Ghanbaria, Matthew Waller, Paul Weston, Pamela Whittaker, Sara Widaa, Mark I. McCarthy, Maria J. Arranz, Steven Bakker, Stephan Bender, Benedicto Crespo-Facorro, Jeremy Hall, Conrad Iyegbe, Stephen Lawrie, Kuang Lin, Don H. Linszen, Ignacio Mata, Muriel Walshe, Matthias Weisbrod, Durk Wiersma, Vassily Trubetskoy, Yunpeng Wang, Jonathan R.I. Coleman, Héléna A. Gaspar, Christiaan A. de Leeuw, Jennifer M. Whitehead Pavlides, Maciej Trzaskowski, Enda M. Byrne, Liam Abbott, Huda Akil, Diego Albani, Ney Alliey-Rodriguez, Adebayo Anjorin, Verneri Antilla, Swapnil Awasthi, Judith A. Badner, Marie Bækvad-Hansen, Jack D. Barchas, Nicholas Bass, Michael Bauer, Richard Belliveau, Carsten Bøcker Pedersen, Erlend Bøen, Marco P. Boks, James Boocock, Monika Budde, William Bunney, Margit Burmeister, Jonas Bybjerg-Grauholm, Miquel Casas, Felecia Cerrato, Kimberly Chambert, Alexander W. Charney, Danfeng Chen, Claire Churchhouse, Toni-Kim Clarke, William Coryell, David W. Craig, Cristiana Cruceanu, Piotr M. Czerski, Anders M. Dale, Simone de Jong, Jurgen Del-Favero, J. Raymond DePaulo, Amanda L. Dobbyn, Ashley Dumont, Torbjørn Elvsåshagen, Chun Chieh Fan, Sascha B. Fischer, Matthew Flickinger, Tatiana M. Foroud, Liz Forty, Christine Fraser, Katrin Gade, Diane Gage, Julie Garnham, Claudia Giambartolomei, Marianne Giørtz Pedersen, Jaqueline Goldstein, Scott D. Gordon, Katherine Gordon-Smith, Elaine K. Green, Melissa J. Green, Tiffany A. Greenwood, Weihua Guan, Martin Hautzinger, Urs Heilbronner, Maria Hipolito, Dominic Holland, Laura Huckins, Jessica S. Johnson, Radhika Kandaswamy, Robert Karlsson, Sarah Kittel-Schneider, Anna C. Koller, Ralph Kupka, Catharina Lavebratt, Jacob Lawrence, William B. Lawson, Markus Leber, Phil H. Lee, Shawn E. Levy, Jun Z. Li, Chunyu Liu, Anna Maaser, Donald J. MacIntyre, Pamela B. Mahon, Lina Martinsson, Steve McCarroll, Peter McGuffin, Melvin G. McInnis, James D. McKay, Helena Medeiros, Sarah E. Medland, Fan Meng, Grant W. Montgomery, Thomas W. Mühleisen, Hoang Nguyen, Caroline M. Nievergelt, Annelie Nordin Adolfsson, Evaristus A. Nwulia, Claire O'Donovan, Loes M. Olde Loohuis, Anil P.S. Ori, Lilijana Oruc, Urban Ösby, Amy Perry, Andrea Pfennig, Eline J. Regeer, Céline S. Reinbold, John P. Rice, Fabio Rivas, Margarita Rivera, Euijung Ryu, Cristina Sánchez-Mora, Alan F. Schatzberg, William A. Scheftner, Nicholas J. Schork, Cynthia Shannon Weickert, Tatyana Shehktman, Paul D. Shilling, Claire Slaney, Janet L. Sobell, Christine Søholm Hansen, Anne T. Spijker, Michael Steffens, John S. Strauss, Szabolcs Szelinger, Robert C. Thompson, Thorgeir E. Thorgeirsson, Jens Treutlein, Helmut Vedder, Weiqing Wang, Stanley J. Watson, Thomas W. Weickert, Simon Xi, Wei Xu, Allan H. Young, Peter Zandi, Peng Zhang, Sebastian Zöllner, Abdel Abdellaoui, Tracy M. Air, Till F.M. Andlauer, Silviu-Alin Bacanu, Aartjan T.F. Beekman, Elisabeth B. Binder, Julien Bryois, Henriette N. Buttenschøn, Na Cai, Enrique Castelao, Jane Hvarregaard Christensen, Lucía Colodro-Conde, Baptiste Couvy-Duchesne, Gregory E. Crawford, Gail Davies, Ian J. Deary, Eske M. Derks, Nese Direk, Conor V. Dolan, Erin C. Dunn, Thalia C. Eley, Farnush Farhadi Hassan Kiadeh, Hilary K. Finucane, Jerome C. Foo, Fernando S. Goes, Lynsey S. Hall, Thomas F. Hansen, Ian B. Hickie, Georg Homuth, Carsten Horn, David M. Howard, Marcus Ising, Rick Jansen, Ian Jones, Lisa A. Jones, Eric Jorgenson, Isaac S. Kohane, Julia Kraft, Warren W. Kretzschmar, Zoltán Kutalik, Yihan Li, Penelope A. Lind, Dean F. MacKinnon, Robert M. Maier, Jonathan Marchini, Hamdi Mbarek, Patrick McGrath, Christel M. Middeldorp, Evelin Mihailov, Francis M. Mondimore, Sara Mostafavi, Matthias Nauck, Bernard Ng, Michel G. Nivard, Dale R. Nyholt, Paul F. O'Reilly, Hogni Oskarsson, Jodie N. Painter, Roseann E. Peterson, Wouter J. Peyrot, Giorgio Pistis, Jorge A. Quiroz, Per Qvist, Saira Saeed Mirza, Robert Schoevers, Eva C. Schulte, Ling Shen, Stanley I. Shyn, Grant C.B. Sinnamon, Johannes H. Smit, Daniel J. Smith, Katherine E. Tansey, Henning Teismann, Wesley Thompson, Pippa A. Thomson, Matthew Traylor, André G. Uitterlinden, Daniel Umbricht, Albert M. van Hemert, Shantel Marie Weinsheimer, Jürgen Wellmann, Yang Wu, Hualin S. Xi, Jian Yang, Futao Zhang, Volker Arolt, Klaus Berger, Udo Dannlowski, Katharina Domschke, Caroline Hayward, Andrew C. Heath, Stefan Kloiber, Glyn Lewis, Pamela AF. Madden, Patrik K. Magnusson, Preben Bo Mortensen, Michael C. O'Donovan, Sara A. Paciga, Nancy L. Pedersen, David J. Porteous, Catherine Schaefer, Henry Völzke, Marco Bortolato, Janita Bralten, Cynthia M. Bulik, Christie L. Burton, Caitlin E. Carey, Lea K. Davis, Laramie E. Duncan, Howard J. Edenberg, Lauren Erdman, Stephen V. Faraone, Slavina B. Goleva, Wei Guo, Christopher Hübel, Laura M. Huckins, Ekaterina A. Khramtsova, Joanna Martin, Carol A. Mathews, Elise Robinson, Eli Stahl, Barbara E. Stranger, Michela Traglia, Raymond K. Walters, Lauren A. Weiss, Stacey J. Winham, Yin Yao, Kristjar Skajaa, Markus Nöthen, Michael Owen, Robert H. Yolken, Niels Plath, Jonathan Mill, Daniel Geschwind, Psychiatry 1, RS: MHeNs - R2 - Mental Health, Psychiatrie & Neuropsychologie, Centre of Excellence in Complex Disease Genetics, Research Programme of Molecular Medicine, Research Programs Unit, Aarno Palotie / Principal Investigator, Institute for Molecular Medicine Finland, Genomics of Neurological and Neuropsychiatric Disorders, Functional Genomics, Biological Psychology, APH - Mental Health, APH - Methodology, Sociology and Social Gerontology, APH - Personalized Medicine, APH - Health Behaviors & Chronic Diseases, Blokland, Gabriella AM, Grove, Jakob, Chen, Chia Yen, Cotsapas, Chris, Tobet, Stuart, Handa, Robert, Lee, Sang Hong, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Bipolar Disorder Working Group of the Psychiatric Genomics Consortium, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Sex Differences Cross-Disorder Analysis Group of the Psychiatric Genomics Consortium, iPSYCH, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Human genetics, Amsterdam Neuroscience - Compulsivity, Impulsivity & Attention, Amsterdam Reproduction & Development (AR&D), Child and Adolescent Psychiatry / Psychology, Adult Psychiatry, ANS - Complex Trait Genetics, and ANS - Mood, Anxiety, Psychosis, Stress & Sleep

Subjects
0301 basic medicine, Male, Bipolar Disorder, Schizophrenia/genetics, LD SCORE REGRESSION, Genome-wide association study, 0302 clinical medicine, Receptors, SCHIZOPHRENIA, Psychotic Disorders/genetics, KYNURENINE PATHWAY METABOLISM, Genetics, RISK, Sex Characteristics, Vascular Endothelial Growth Factor, Bipolar Disorder/genetics, Major/genetics, Single Nucleotide, AFFECTIVE STIMULI IMPACT, Schizophrenia, Sulfurtransferases, Major depressive disorder, Female, Depressive Disorder, Major/genetics, Bipolar disorder, Locus (genetics), Genomics, Biology, Polymorphism, Single Nucleotide, Article, DYSPHORIC MOOD, 03 medical and health sciences, Sex differences, medicine, Humans, Genetic Predisposition to Disease, ddc:610, Polymorphism, GENOME-WIDE ASSOCIATION, Genotype-by-sex interaction, Biological Psychiatry, Depressive Disorder, Major, Depressive Disorder, GENDER-DIFFERENCES, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], PARAVENTRICULAR NUCLEUS, 3112 Neurosciences, Endothelial Cells, MAJOR DEPRESSION, medicine.disease, Genetic architecture, 030104 developmental biology, Mood, Receptors, Vascular Endothelial Growth Factor, Psychotic Disorders, 3111 Biomedicine, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Contains fulltext : 248656.pdf (Publisher’s version ) (Closed access) BACKGROUND: Sex differences in incidence and/or presentation of schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP) are pervasive. Previous evidence for shared genetic risk and sex differences in brain abnormalities across disorders suggest possible shared sex-dependent genetic risk. METHODS: We conducted the largest to date genome-wide genotype-by-sex (G×S) interaction of risk for these disorders using 85,735 cases (33,403 SCZ, 19,924 BIP, and 32,408 MDD) and 109,946 controls from the PGC (Psychiatric Genomics Consortium) and iPSYCH. RESULTS: Across disorders, genome-wide significant single nucleotide polymorphism-by-sex interaction was detected for a locus encompassing NKAIN2 (rs117780815, p = 3.2 × 10(-8)), which interacts with sodium/potassium-transporting ATPase (adenosine triphosphatase) enzymes, implicating neuronal excitability. Three additional loci showed evidence (p < 1 × 10(-6)) for cross-disorder G×S interaction (rs7302529, p = 1.6 × 10(-7); rs73033497, p = 8.8 × 10(-7); rs7914279, p = 6.4 × 10(-7)), implicating various functions. Gene-based analyses identified G×S interaction across disorders (p = 8.97 × 10(-7)) with transcriptional inhibitor SLTM. Most significant in SCZ was a MOCOS gene locus (rs11665282, p = 1.5 × 10(-7)), implicating vascular endothelial cells. Secondary analysis of the PGC-SCZ dataset detected an interaction (rs13265509, p = 1.1 × 10(-7)) in a locus containing IDO2, a kynurenine pathway enzyme with immunoregulatory functions implicated in SCZ, BIP, and MDD. Pathway enrichment analysis detected significant G×S interaction of genes regulating vascular endothelial growth factor receptor signaling in MDD (false discovery rate-corrected p < .05). CONCLUSIONS: In the largest genome-wide G×S analysis of mood and psychotic disorders to date, there was substantial genetic overlap between the sexes. However, significant sex-dependent effects were enriched for genes related to neuronal development and immune and vascular functions across and within SCZ, BIP, and MDD at the variant, gene, and pathway levels.

Published
2022
Full Text
View/download PDF

27. Burden of Rare Genetic Variants in Spontaneous Coronary Artery Dissection With High-risk Features

Author

Yu, Wang, Andrew, Starovoytov, Andrea M, Murad, Kristina L, Hunker, Liam R, Brunham, Jun Z, Li, Jacqueline, Saw, and Santhi K, Ganesh

Subjects
Canada, Coronary Vessel Anomalies, Receptor, Transforming Growth Factor-beta Type II, Humans, Female, Genetic Testing, Vascular Diseases, Cardiology and Cardiovascular Medicine, Coronary Vessels, Genome-Wide Association Study
Abstract

ImportanceThe emerging genetic basis of spontaneous coronary artery dissection (SCAD) has been defined as both partially complex and monogenic in some patients, involving variants predominantly in genes known to underlie vascular connective tissue diseases (CTDs). The effect of these genetic influences has not been defined in high-risk SCAD phenotypes, and the identification of a high-risk subgroup of individuals may help to guide clinical genetic evaluations of SCAD.ObjectiveTo identify and quantify the burden of rare genetic variation in individuals with SCAD with high-risk clinical features.Design, Setting, and ParticipantsWhole-exome sequencing (WES) was performed for subsequent case-control association analyses and individual variant annotation among individuals with high-risk SCAD. Genetic variants were annotated for pathogenicity by in-silico analysis of genes previously defined by sequencing for vascular CTDs and/or SCAD, as well as genes prioritized by genome-wide association study (GWAS) and colocalization of arterial expression quantitative trait loci. Unbiased genome-wide association analysis of the WES data was performed by comparing aggregated variants in individuals with SCAD to healthy matched controls or the Genome Aggregation Database (gnomAD). This study was conducted at a tertiary care center. Individuals in the Canadian SCAD Registry genetics study with a high-risk SCAD phenotype were selected and defined as peripartum SCAD, recurrent SCAD, or SCAD in an individual with family history of arteriopathy.Main Outcomes and MeasuresBurden of genetic variants defined by DNA sequencing in individuals with high-risk SCAD.ResultsThis study included a total of 336 participants (mean [SD] age, 53.0 [9.5] years; 301 female participants [90%]). Variants in vascular CTD genes were identified in 17.0% of individuals (16 of 94) with high-risk SCAD and were enriched (OR, 2.6; 95% CI, 1.6-4.2; P = 7.8 × 10−4) as compared with gnomAD, with leading significant signals in COL3A1 (OR, 13.4; 95% CI, 4.9-36.2; P = 2.8 × 10−4) and Loeys-Dietz syndrome genes (OR, 7.9; 95% CI, 2.9-21.2; P = 2.0 × 10−3). Variants in GWAS-prioritized genes, observed in 6.4% of individuals (6 of 94) with high-risk SCAD, were also enriched (OR, 3.6; 95% CI, 1.6-8.2; P = 7.4 × 10−3). Variants annotated as likely pathogenic or pathogenic occurred in 4 individuals, in the COL3A1, TGFBR2, and ADAMTSL4 genes. Genome-wide aggregated variant testing identified novel associations with peripartum SCAD.Conclusions and RelevanceIn this genetic study, approximately 1 in 5 individuals with a high-risk SCAD phenotype harbored a rare genetic variant in genes currently implicated for SCAD. Genetic screening in this subgroup of individuals presenting with SCAD may be considered.

Published
2022
Full Text
View/download PDF

28. Inference of unexpected genetic relatedness among individuals in HapMap phase III

Author

Pemberton, Trevor J., Chaolong Wang, Jun Z. Li, and Rosenberg, Noah A.

Subjects
Haplotypes -- Research, Human genome -- Research, Population genetics -- Analysis, Single nucleotide polymorphisms -- Analysis, Biological sciences
Abstract

A systematic analysis of genetic relatedness is undertaken among individuals studied in the International Haplotype Project (HapMap) phase III. Results confirm the already known genetic relationships among some phase III individuals, while also enabling the inference of several unexpected, previously unknown relative pairs in the sample.

Published
2010

29. A Novel Recurrent

Author

Julie, Richer, Hannah L, Hill, Yu, Wang, Min-Lee, Yang, Kristina L, Hunker, Jamie, Lane, Susan, Blackburn, Dawn M, Coleman, Jonathan, Eliason, Guillaume, Sillon, Maria-Daniela, D'Agostino, Prasad, Jetty, François-Pierre, Mongeon, Anne-Marie, Laberge, Stephen E, Ryan, Natalia, Fendrikova-Mahlay, Thais, Coutinho, Michael R, Mathis, Matthew, Zawistowski, Stanley L, Hazen, Alexander E, Katz, Heather L, Gornik, Chad M, Brummett, Goncalo, Abecasis, Ingrid L, Bergin, James C, Stanley, Jun Z, Li, and Santhi K, Ganesh

Subjects
Adult, Male, Arteries, Middle Aged, Polymorphism, Single Nucleotide, Article, Aortic Dissection, Young Adult, Phenotype, Haplotypes, Fibromuscular Dysplasia, Humans, Ehlers-Danlos Syndrome, Female, Genetic Predisposition to Disease, Collagen Type V
Abstract

OBJECTIVE: While rare variants in the COL5A1 gene have been associated with classical Ehlers-Danlos Syndrome (EDS) and rarely with arterial dissections, recurrent variants in COL5A1 underlying a systemic arteriopathy have not been described. Monogenic forms of multifocal fibromuscular dysplasia (mFMD) have not been previously defined. APPROACH AND RESULTS: We studied four independent probands with the COL5A1 pathogenic variant c.1540G>A, p.(Gly514Ser) who presented with arterial aneurysms, dissections, tortuosity, and mFMD affecting multiple arteries. Arterial medial fibroplasia and smooth muscle cell disorganization were confirmed histologically. The COL5A1 c.1540G>A variant is predicted to be pathogenic in silico and absent in gnomAD. The c.1540G>A variant is on a shared 160.1kb haplotype with 0.4% frequency in Europeans. Further, exome sequencing data from a cohort of 264 individuals with mFMD were examined for COL5A1 variants. In this mFMD cohort, COL5A1 c.1540G>A and six additional relatively rare COL5A1 variants predicted to be deleterious in silico were identified and were associated with arterial dissections (p=0.005). CONCLUSIONS: COL5A1 c.1540G>A is the first recurring variant recognized to be associated with arterial dissections and mFMD. This variant presents with a phenotype reminiscent of vascular EDS. A shared haplotype among probands supports the existence of a common founder. Relatively rare COL5A1 genetic variants predicted to be deleterious by in silico analysis were identified in ~2.7% of mFMD cases, and as they were enriched in patients with arterial dissections, may act as disease modifiers. Molecular testing for COL5A1 should be considered in patients with a phenotype overlapping with vascular EDS and mFMD.

Published
2020

30. The Genetics of the Mood Disorder Spectrum: Genome-wide Association Analyses of More Than 185,000 Cases and 439,000 Controls

Author

Jonathan R.I. Coleman, Héléna A. Gaspar, Julien Bryois, Gerome Breen, Enda M. Byrne, Andreas J. Forstner, Peter A. Holmans, Christiaan A. de Leeuw, Manuel Mattheisen, Andrew McQuillin, Jennifer M. Whitehead Pavlides, Tune H. Pers, Stephan Ripke, Eli A. Stahl, Stacy Steinberg, Vassily Trubetskoy, Maciej Trzaskowski, Yunpeng Wang, Liam Abbott, Abdel Abdellaoui, Mark J. Adams, Annelie Nordin Adolfsson, Esben Agerbo, Huda Akil, Diego Albani, Ney Alliey-Rodriguez, Thomas D. Als, Till F.M. Andlauer, Adebayo Anjorin, Verneri Antilla, Sandra Van der Auwera, Swapnil Awasthi, Silviu-Alin Bacanu, Judith A. Badner, Marie Bækvad-Hansen, Jack D. Barchas, Nicholas Bass, Michael Bauer, Aartjan T.F. Beekman, Richard Belliveau, Sarah E. Bergen, Tim B. Bigdeli, Elisabeth B. Binder, Erlend Bøen, Marco Boks, James Boocock, Monika Budde, William Bunney, Margit Burmeister, Henriette N. Buttenschøn, Jonas Bybjerg-Grauholm, William Byerley, Na Cai, Miquel Casas, Enrique Castelao, Felecia Cerrato, Pablo Cervantes, Kimberly Chambert, Alexander W. Charney, Danfeng Chen, Jane Hvarregaard Christensen, Claire Churchhouse, David St Clair, Toni-Kim Clarke, Lucía Colodro-Conde, William Coryell, Baptiste Couvy-Duchesne, David W. Craig, Gregory E. Crawford, Cristiana Cruceanu, Piotr M. Czerski, Anders M. Dale, Gail Davies, Ian J. Deary, Franziska Degenhardt, Jurgen Del-Favero, J Raymond DePaulo, Eske M. Derks, Nese Direk, Srdjan Djurovic, Amanda L. Dobbyn, Conor V. Dolan, Ashley Dumont, Erin C. Dunn, Thalia C. Eley, Torbjørn Elvsåshagen, Valentina Escott-Price, Chun Chieh Fan, Hilary K. Finucane, Sascha B. Fischer, Matthew Flickinger, Jerome C. Foo, Tatiana M. Foroud, Liz Forty, Josef Frank, Christine Fraser, Nelson B. Freimer, Louise Frisén, Katrin Gade, Diane Gage, Julie Garnham, Claudia Giambartolomei, Fernando S. Goes, Jaqueline Goldstein, Scott D. Gordon, Katherine Gordon-Smith, Elaine K. Green, Melissa J. Green, Tiffany A. Greenwood, Jakob Grove, Weihua Guan, Lynsey S. Hall, Marian L. Hamshere, Christine Søholm Hansen, Thomas F. Hansen, Martin Hautzinger, Urs Heilbronner, Albert M. van Hemert, Stefan Herms, Ian B. Hickie, Maria Hipolito, Per Hoffmann, Dominic Holland, Georg Homuth, Carsten Horn, Jouke-Jan Hottenga, Laura Huckins, Marcus Ising, Stéphane Jamain, Rick Jansen, Jessica S. Johnson, Simone de Jong, Eric Jorgenson, Anders Juréus, Radhika Kandaswamy, Robert Karlsson, James L. Kennedy, Farnush Farhadi Hassan Kiadeh, Sarah Kittel-Schneider, James A. Knowles, Manolis Kogevinas, Isaac S. Kohane, Anna C. Koller, Julia Kraft, Warren W. Kretzschmar, Jesper Krogh, Ralph Kupka, Zoltán Kutalik, Catharina Lavebratt, Jacob Lawrence, William B. Lawson, Markus Leber, Phil H. Lee, Shawn E. Levy, Jun Z. Li, Yihan Li, Penelope A. Lind, Chunyu Liu, Loes M. Olde Loohuis, Anna Maaser, Donald J. MacIntyre, Dean F. MacKinnon, Pamela B. Mahon, Wolfgang Maier, Robert M. Maier, Jonathan Marchini, Lina Martinsson, Hamdi Mbarek, Steve McCarroll, Patrick McGrath, Peter McGuffin, Melvin G. McInnis, James D. McKay, Helena Medeiros, Sarah E. Medland, Divya Mehta, Fan Meng, Christel M. Middeldorp, Evelin Mihailov, Yuri Milaneschi, Lili Milani, Saira Saeed Mirza, Francis M. Mondimore, Grant W. Montgomery, Derek W. Morris, Sara Mostafavi, Thomas W. Mühleisen, Niamh Mullins, Matthias Nauck, Bernard Ng, Hoang Nguyen, Caroline M. Nievergelt, Michel G. Nivard, Evaristus A. Nwulia, Dale R. Nyholt, Claire O'Donovan, Paul F. O'Reilly, Anil P.S. Ori, Lilijana Oruc, Urban Ösby, Hogni Oskarsson, Jodie N. Painter, José Guzman Parra, Carsten Bøcker Pedersen, Marianne Giørtz Pedersen, Amy Perry, Roseann E. Peterson, Erik Pettersson, Wouter J. Peyrot, Andrea Pfennig, Giorgio Pistis, Shaun M. Purcell, Jorge A. Quiroz, Per Qvist, Eline J. Regeer, Andreas Reif, Céline S. Reinbold, John P. Rice, Brien P. Riley, Fabio Rivas, Margarita Rivera, Panos Roussos, Douglas M. Ruderfer, Euijung Ryu, Cristina Sánchez-Mora, Alan F. Schatzberg, William A. Scheftner, Robert Schoevers, Nicholas J. Schork, Eva C. Schulte, Tatyana Shehktman, Ling Shen, Jianxin Shi, Paul D. Shilling, Stanley I. Shyn, Engilbert Sigurdsson, Claire Slaney, Olav B. Smeland, Johannes H. Smit, Daniel J. Smith, Janet L. Sobell, Anne T. Spijker, Michael Steffens, John S. Strauss, Fabian Streit, Jana Strohmaier, Szabolcs Szelinger, Katherine E. Tansey, Henning Teismann, Alexander Teumer, Robert C. Thompson, Wesley Thompson, Pippa A. Thomson, Thorgeir E. Thorgeirsson, Matthew Traylor, Jens Treutlein, André G. Uitterlinden, Daniel Umbricht, Helmut Vedder, Alexander Viktorin, Peter M. Visscher, Weiqing Wang, Stanley J. Watson, Bradley T. Webb, Cynthia Shannon Weickert, Thomas W. Weickert, Shantel Marie Weinsheimer, Jürgen Wellmann, Gonneke Willemsen, Stephanie H. Witt, Yang Wu, Hualin S. Xi, Wei Xu, Jian Yang, Allan H. Young, Peter Zandi, Peng Zhang, Futao Zhang, Sebastian Zollner, Rolf Adolfsson, Ingrid Agartz, Martin Alda, Volker Arolt, Lena Backlund, Bernhard T. Baune, Frank Bellivier, Klaus Berger, Wade H. Berrettini, Joanna M. Biernacka, Douglas H.R. Blackwood, Michael Boehnke, Dorret I. Boomsma, Aiden Corvin, Nicholas Craddock, Mark J. Daly, Udo Dannlowski, Enrico Domenici, Katharina Domschke, Tõnu Esko, Bruno Etain, Mark Frye, Janice M. Fullerton, Elliot S. Gershon, E.J.C. de Geus, Michael Gill, Fernando Goes, Hans J. Grabe, Maria Grigoroiu-Serbanescu, Steven P. Hamilton, Joanna Hauser, Caroline Hayward, Andrew C. Heath, David M. Hougaard, Christina M. Hultman, Ian Jones, Lisa A. Jones, René S. Kahn, Kenneth S. Kendler, George Kirov, Stefan Kloiber, Mikael Landén, Marion Leboyer, Glyn Lewis, Qingqin S. Li, Jolanta Lissowska, Susanne Lucae, Pamela A.F. Madden, Patrik K. Magnusson, Nicholas G. Martin, Fermin Mayoral, Susan L. McElroy, Andrew M. McIntosh, Francis J. McMahon, Ingrid Melle, Andres Metspalu, Philip B. Mitchell, Gunnar Morken, Ole Mors, Preben Bo Mortensen, Bertram Müller-Myhsok, Richard M. Myers, Benjamin M. Neale, Vishwajit Nimgaonkar, Merete Nordentoft, Markus M. Nöthen, Michael C. O'Donovan, Ketil J. Oedegaard, Michael J. Owen, Sara A. Paciga, Carlos Pato, Michele T. Pato, Nancy L. Pedersen, Brenda W.J. H. Penninx, Roy H. Perlis, David J. Porteous, Danielle Posthuma, James B. Potash, Martin Preisig, Josep Antoni Ramos-Quiroga, Marta Ribasés, Marcella Rietschel, Guy A. Rouleau, Catherine Schaefer, Martin Schalling, Peter R. Schofield, Thomas G. Schulze, Alessandro Serretti, Jordan W. Smoller, Hreinn Stefansson, Kari Stefansson, Eystein Stordal, Henning Tiemeier, Gustavo Turecki, Rudolf Uher, Arne E. Vaaler, Eduard Vieta, John B. Vincent, Henry Völzke, Myrna M. Weissman, Thomas Werge, Ole A. Andreassen, Anders D. Børglum, Sven Cichon, Howard J. Edenberg, Arianna Di Florio, John Kelsoe, Douglas F. Levinson, Cathryn M. Lewis, John I. Nurnberger, Roel A. Ophoff, Laura J. Scott, Pamela Sklar, Patrick F. Sullivan, Naomi R. Wray, APH - Methodology, Biological Psychology, APH - Personalized Medicine, APH - Health Behaviors & Chronic Diseases, APH - Mental Health, Amsterdam Neuroscience - Complex Trait Genetics, Complex Trait Genetics, Epidemiology, Erasmus MC other, Urology, Psychiatry, Internal Medicine, Medical Informatics, Immunology, Child and Adolescent Psychiatry / Psychology, Adult Psychiatry, Coleman J.R.I., Gaspar H.A., Bryois J., Byrne E.M., Forstner A.J., Holmans P.A., de Leeuw C.A., Mattheisen M., McQuillin A., Whitehead Pavlides J.M., Pers T.H., Ripke S., Stahl E.A., Steinberg S., Trubetskoy V., Trzaskowski M., Wang Y., Abbott L., Abdellaoui A., Adams M.J., Adolfsson A.N., Agerbo E., Akil H., Albani D., Alliey-Rodriguez N., Als T.D., Andlauer T.F.M., Anjorin A., Antilla V., Van der Auwera S., Awasthi S., Bacanu S.-A., Badner J.A., Baekvad-Hansen M., Barchas J.D., Bass N., Bauer M., Beekman A.T.F., Belliveau R., Bergen S.E., Bigdeli T.B., Binder E.B., Boen E., Boks M., Boocock J., Budde M., Bunney W., Burmeister M., Buttenschon H.N., Bybjerg-Grauholm J., Byerley W., Cai N., Casas M., Castelao E., Cerrato F., Cervantes P., Chambert K., Charney A.W., Chen D., Christensen J.H., Churchhouse C., St Clair D., Clarke T.-K., Colodro-Conde L., Coryell W., Couvy-Duchesne B., Craig D.W., Crawford G.E., Cruceanu C., Czerski P.M., Dale A.M., Davies G., Deary I.J., Degenhardt F., Del-Favero J., DePaulo J.R., Derks E.M., Direk N., Djurovic S., Dobbyn A.L., Dolan C.V., Dumont A., Dunn E.C., Eley T.C., Elvsashagen T., Escott-Price V., Fan C.C., Finucane H.K., Fischer S.B., Flickinger M., Foo J.C., Foroud T.M., Forty L., Frank J., Fraser C., Freimer N.B., Frisen L., Gade K., Gage D., Garnham J., Giambartolomei C., Goes F.S., Goldstein J., Gordon S.D., Gordon-Smith K., Green E.K., Green M.J., Greenwood T.A., Grove J., Guan W., Hall L.S., Hamshere M.L., Hansen C.S., Hansen T.F., Hautzinger M., Heilbronner U., van Hemert A.M., Herms S., Hickie I.B., Hipolito M., Hoffmann P., Holland D., Homuth G., Horn C., Hottenga J.-J., Huckins L., Ising M., Jamain S., Jansen R., Johnson J.S., de Jong S., Jorgenson E., Jureus A., Kandaswamy R., Karlsson R., Kennedy J.L., Hassan Kiadeh F.F., Kittel-Schneider S., Knowles J.A., Kogevinas M., Kohane I.S., Koller A.C., Kraft J., Kretzschmar W.W., Krogh J., Kupka R., Kutalik Z., Lavebratt C., Lawrence J., Lawson W.B., Leber M., Lee P.H., Levy S.E., Li J.Z., Li Y., Lind P.A., Liu C., Olde Loohuis L.M., Maaser A., MacIntyre D.J., MacKinnon D.F., Mahon P.B., Maier W., Maier R.M., Marchini J., Martinsson L., Mbarek H., McCarroll S., McGrath P., McGuffin P., McInnis M.G., McKay J.D., Medeiros H., Medland S.E., Mehta D., Meng F., Middeldorp C.M., Mihailov E., Milaneschi Y., Milani L., Mirza S.S., Mondimore F.M., Montgomery G.W., Morris D.W., Mostafavi S., Muhleisen T.W., Mullins N., Nauck M., Ng B., Nguyen H., Nievergelt C.M., Nivard M.G., Nwulia E.A., Nyholt D.R., O'Donovan C., O'Reilly P.F., Ori A.P.S., Oruc L., Osby U., Oskarsson H., Painter J.N., Parra J.G., Pedersen C.B., Pedersen M.G., Perry A., Peterson R.E., Pettersson E., Peyrot W.J., Pfennig A., Pistis G., Purcell S.M., Quiroz J.A., Qvist P., Regeer E.J., Reif A., Reinbold C.S., Rice J.P., Riley B.P., Rivas F., Rivera M., Roussos P., Ruderfer D.M., Ryu E., Sanchez-Mora C., Schatzberg A.F., Scheftner W.A., Schoevers R., Schork N.J., Schulte E.C., Shehktman T., Shen L., Shi J., Shilling P.D., Shyn S.I., Sigurdsson E., Slaney C., Smeland O.B., Smit J.H., Smith D.J., Sobell J.L., Spijker A.T., Steffens M., Strauss J.S., Streit F., Strohmaier J., Szelinger S., Tansey K.E., Teismann H., Teumer A., Thompson R.C., Thompson W., Thomson P.A., Thorgeirsson T.E., Traylor M., Treutlein J., Uitterlinden A.G., Umbricht D., Vedder H., Viktorin A., Visscher P.M., Wang W., Watson S.J., Webb B.T., Weickert C.S., Weickert T.W., Weinsheimer S.M., Wellmann J., Willemsen G., Witt S.H., Wu Y., Xi H.S., Xu W., Yang J., Young A.H., Zandi P., Zhang P., Zhang F., Zollner S., Adolfsson R., Agartz I., Alda M., Arolt V., Backlund L., Baune B.T., Bellivier F., Berger K., Berrettini W.H., Biernacka J.M., Blackwood D.H.R., Boehnke M., Boomsma D.I., Corvin A., Craddock N., Daly M.J., Dannlowski U., Domenici E., Domschke K., Esko T., Etain B., Frye M., Fullerton J.M., Gershon E.S., de Geus E.J.C., Gill M., Goes F., Grabe H.J., Grigoroiu-Serbanescu M., Hamilton S.P., Hauser J., Hayward C., Heath A.C., Hougaard D.M., Hultman C.M., Jones I., Jones L.A., Kahn R.S., Kendler K.S., Kirov G., Kloiber S., Landen M., Leboyer M., Lewis G., Li Q.S., Lissowska J., Lucae S., Madden P.A.F., Magnusson P.K., Martin N.G., Mayoral F., McElroy S.L., McIntosh A.M., McMahon F.J., Melle I., Metspalu A., Mitchell P.B., Morken G., Mors O., Mortensen P.B., Muller-Myhsok B., Myers R.M., Neale B.M., Nimgaonkar V., Nordentoft M., Nothen M.M., O'Donovan M.C., Oedegaard K.J., Owen M.J., Paciga S.A., Pato C., Pato M.T., Pedersen N.L., Penninx B.W.J.H., Perlis R.H., Porteous D.J., Posthuma D., Potash J.B., Preisig M., Ramos-Quiroga J.A., Ribases M., Rietschel M., Rouleau G.A., Schaefer C., Schalling M., Schofield P.R., Schulze T.G., Serretti A., Smoller J.W., Stefansson H., Stefansson K., Stordal E., Tiemeier H., Turecki G., Uher R., Vaaler A.E., Vieta E., Vincent J.B., Volzke H., Weissman M.M., Werge T., Andreassen O.A., Borglum A.D., Cichon S., Edenberg H.J., Di Florio A., Kelsoe J., Levinson D.F., Lewis C.M., Nurnberger J.I., Ophoff R.A., Scott L.J., Sklar P., Sullivan P.F., Wray N.R., and Breen G.

Subjects
0301 basic medicine, Netherlands Twin Register (NTR), Genetic correlation, Genome-wide association study, Mood Disorder, Bipolar disorder, Population, BF, Genomics, Major depressive disorder, Affective disorder, Article, Mice, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, mental disorders, medicine, Animals, ddc:610, education, Depression (differential diagnoses), Biological Psychiatry, 030304 developmental biology, Genetic association, Genetics, Depressive Disorder, Major, 0303 health sciences, education.field_of_study, Animal, business.industry, Risk Factor, medicine.disease, 3. Good health, Affective disorders, 030104 developmental biology, Mood, Mood disorders, RC0321, Biological psychiatry, business, 030217 neurology & neurosurgery, Clinical psychology
Abstract

BackgroundMood disorders (including major depressive disorder and bipolar disorder) affect 10-20% of the population. They range from brief, mild episodes to severe, incapacitating conditions that markedly impact lives. Despite their diagnostic distinction, multiple approaches have shown considerable sharing of risk factors across the mood disorders.MethodsTo clarify their shared molecular genetic basis, and to highlight disorder-specific associations, we meta-analysed data from the latest Psychiatric Genomics Consortium (PGC) genome-wide association studies of major depression (including data from 23andMe) and bipolar disorder, and an additional major depressive disorder cohort from UK Biobank (total: 185,285 cases, 439,741 controls; non-overlapping N = 609,424).ResultsSeventy-three loci reached genome-wide significance in the meta-analysis, including 15 that are novel for mood disorders. More genome-wide significant loci from the PGC analysis of major depression than bipolar disorder reached genome-wide significance. Genetic correlations revealed that type 2 bipolar disorder correlates strongly with recurrent and single episode major depressive disorder. Systems biology analyses highlight both similarities and differences between the mood disorders, particularly in the mouse brain cell types implicated by the expression patterns of associated genes. The mood disorders also differ in their genetic correlation with educational attainment – positive in bipolar disorder but negative in major depressive disorder.ConclusionsThe mood disorders share several genetic associations, and can be combined effectively to increase variant discovery. However, we demonstrate several differences between these disorders. Analysing subtypes of major depressive disorder and bipolar disorder provides evidence for a genetic mood disorders spectrum.

Published
2020
Full Text
View/download PDF

31. Molecular Transducers of Physical Activity Consortium (MoTrPAC): Mapping the Dynamic Responses to Exercise

Author

James A. Sanford, Christopher D. Nogiec, Malene E. Lindholm, Joshua N. Adkins, David Amar, Surendra Dasari, Jonelle K. Drugan, Facundo M. Fernández, Shlomit Radom-Aizik, Simon Schenk, Michael P. Snyder, Russell P. Tracy, Patrick Vanderboom, Scott Trappe, Martin J. Walsh, Charles R. Evans, Facundo M. Fernandez, Yafeng Li, Lyl Tomlinson, D. Lee Alekel, Iddil Bekirov, Amanda T. Boyce, Josephine Boyington, Jerome L. Fleg, Lyndon J.O. Joseph, Maren R. Laughlin, Padma Maruvada, Stephanie A. Morris, Joan A. McGowan, Concepcion Nierras, Vinay Pai, Charlotte Peterson, Ed Ramos, Mary C. Roary, John P. Williams, Ashley Xia, Elaine Cornell, Jessica Rooney, Michael E. Miller, Walter T. Ambrosius, Scott Rushing, Cynthia L. Stowe, W. Jack Rejeski, Barbara J. Nicklas, Marco Pahor, Ching-ju Lu, Todd Trappe, Toby Chambers, Ulrika Raue, Bridget Lester, Bryan C. Bergman, David H. Bessesen, Catherine M. Jankowski, Wendy M. Kohrt, Edward L. Melanson, Kerrie L. Moreau, Irene E. Schauer, Robert S. Schwartz, William E. Kraus, Cris A. Slentz, Kim M. Huffman, Johanna L. Johnson, Leslie H. Willis, Leslie Kelly, Joseph A. Houmard, Gabriel Dubis, Nick Broskey, Bret H. Goodpaster, Lauren M. Sparks, Paul M. Coen, Dan M. Cooper, Fadia Haddad, Tuomo Rankinen, Eric Ravussin, Neil Johannsen, Melissa Harris, John M. Jakicic, Anne B. Newman, Daniel D. Forman, Erin Kershaw, Renee J. Rogers, Bradley C. Nindl, Lindsay C. Page, Maja Stefanovic-Racic, Susan L. Barr, Blake B. Rasmussen, Tatiana Moro, Doug Paddon-Jones, Elena Volpi, Heidi Spratt, Nicolas Musi, Sara Espinoza, Darpan Patel, Monica Serra, Jonathan Gelfond, Aisling Burns, Marcas M. Bamman, Thomas W. Buford, Gary R. Cutter, Sue C. Bodine, Karyn Esser, Rodger P. Farrar, Laurie J. Goodyear, Michael F. Hirshman, Brent G. Albertson, Wei-Jun Qian, Paul Piehowski, Marina A. Gritsenko, Matthew E. Monore, Vladislav A. Petyuk, Jason E. McDermott, Joshua N. Hansen, Chelsea Hutchison, Samuel Moore, David A. Gaul, Clary B. Clish, Julian Avila-Pacheco, Courtney Dennis, Manolis Kellis, Steve Carr, Pierre M. Jean-Beltran, Hasmik Keshishian, D.R. Mani, Karl Clauser, Karsten Krug, Charlie Mundorff, Cadence Pearce, Anna A. Ivanova, Eric A. Ortlund, Kristal Maner-Smith, Karan Uppal, Tiantian Zhang, Stuart C. Sealfon, Elena Zaslavsky, Venugopalan Nair, SiDe Li, Nimisha Jain, YongChao Ge, Yifei Sun, German Nudelman, Frederique Ruf-zamojski, Gregory Smith, Nhanna Pincas, Aliza Rubenstein, Mary Anne Amper, Nitish Seenarine, Tuuli Lappalainen, Ian R. Lanza, K. Sreekumaran Nair, Katherine Klaus, Stephen B. Montgomery, Kevin S. Smith, Nicole R. Gay, Bingqing Zhao, Chia-Jiu Hung, Navid Zebarjadi, Brunilda Balliu, Laure Fresard, Charles F. Burant, Jun Z. Li, Maureen Kachman, Tanu Soni, Alexander B. Raskind, Robert Gerszten, Jeremy Robbins, Olga Ilkayeva, Michael J. Muehlbauer, Christopher B. Newgard, Euan A. Ashley, Matthew T. Wheeler, David Jimenez-Morales, Archana Raja, Karen P. Dalton, Jimmy Zhen, Young Suk Kim, Jeffrey W. Christle, Shruti Marwaha, Elizabeth T. Chin, Steven G. Hershman, Trevor Hastie, Robert Tibshirani, and Manuel A. Rivas

Subjects
Adult, Male, medicine.medical_specialty, Adolescent, Physical activity, Disease, Health benefits, Biology, Animals, Child, Exercise, Female, Humans, Middle Aged, Oxygen Consumption, Physical Endurance, Research Design, Young Adult, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, 0302 clinical medicine, Physical medicine and rehabilitation, medicine, Exercise physiology, Organ system, 030304 developmental biology, 0303 health sciences, Extramural, Resistance training, 030217 neurology & neurosurgery
Abstract

Exercise provides a robust physiological stimulus that evokes cross-talk among multiple tissues that when repeated regularly (i.e., training) improves physiological capacity, benefits numerous organ systems, and decreases the risk for premature mortality. However, a gap remains in identifying the detailed molecular signals induced by exercise that benefits health and prevents disease. The Molecular Transducers of Physical Activity Consortium (MoTrPAC) was established to address this gap and generate a molecular map of exercise. Preclinical and clinical studies will examine the systemic effects of endurance and resistance exercise across a range of ages and fitness levels by molecular probing of multiple tissues before and after acute and chronic exercise. From this multi-omic and bioinformatic analysis, a molecular map of exercise will be established. Altogether, MoTrPAC will provide a public database that is expected to enhance our understanding of the health benefits of exercise and to provide insight into how physical activity mitigates disease.

Published
2020

32. Landscape of Intercellular Crosstalk in Healthy and NASH Liver Revealed by Single-Cell Secretome Gene Analysis

Author

Robert H. Lyons, Aldons J. Lusis, Jun Z. Li, Linkang Zhou, Sahar Ansari, Jiandie D. Lin, Carey N. Lumeng, Francisco Campos-Pérez, Adriana Huertas-Vazquez, Hugo Villamil-Ramírez, Judy S. Opp, Katsuo Kurabayashi, Siming Li, Yewei Ji, Henry Kuang, Samuel Canizales-Quinteros, Ling Qi, Chuan Li, X.Z. Shawn Xu, Paola León-Mimila, Beiyan Zhou, Liang Guo, Zhimin Chen, Meng Ting Chung, Jianke Gong, Shuai Wang, Xu-Yun Zhao, Yonghao Yu, Tongyu Liu, and Xuelian Xiong

Subjects
Cell, Cell Communication, Biology, Ligands, Article, 03 medical and health sciences, Mice, 0302 clinical medicine, Non-alcoholic Fatty Liver Disease, medicine, Hepatic Stellate Cells, Animals, Humans, Receptor, Molecular Biology, Gene, 030304 developmental biology, 0303 health sciences, TREM2, Sequence Analysis, RNA, Macrophages, RNA, Cell Biology, Cellular Reprogramming, Cell biology, Crosstalk (biology), Disease Models, Animal, medicine.anatomical_structure, Liver, Hepatic stellate cell, Single-Cell Analysis, Reprogramming, 030217 neurology & neurosurgery, Signal Transduction
Abstract

Cell-cell communication via ligand-receptor signaling is a fundamental feature of complex organs. Despite this, the global landscape of intercellular signaling in mammalian liver has not been elucidated. Here we perform single-cell RNA sequencing on non-parenchymal cells isolated from healthy and NASH mouse livers. Secretome gene analysis revealed a highly connected network of intrahepatic signaling and disruption of vascular signaling in NASH. We uncovered the emergence of NASH-associated macrophages (NAMs), which are marked by high expression of triggering receptors expressed on myeloid cells 2 (Trem2), as a feature of mouse and human NASH that is linked to disease severity and highly responsive to pharmacological and dietary interventions. Finally, hepatic stellate cells (HSCs) serve as a hub of intrahepatic signaling via HSC-derived stellakines and their responsiveness to vasoactive hormones. These results provide unprecedented insights into the landscape of intercellular crosstalk and reprogramming of liver cells in health and disease.

Published
2018

33. 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
Full Text
View/download PDF

34. Extremely rare variants reveal patterns of germline mutation rate heterogeneity in humans

Author

Jedidiah Carlson, Adam E. Locke, Matthew Flickinger, Matthew Zawistowski, Shawn Levy, Richard M. Myers, Michael Boehnke, Hyun Min Kang, Laura J. Scott, Jun Z. Li, Sebastian Zöllner, and The BRIDGES Consortium

Subjects
0301 basic medicine, Mutation rate, Guanine, Science, General Physics and Astronomy, Genomics, Context (language use), Biology, Polymorphism, Single Nucleotide, Genome, General Biochemistry, Genetics and Molecular Biology, Evolution, Molecular, Cytosine, 03 medical and health sciences, 0302 clinical medicine, Germline mutation, Mutation Rate, Humans, Histone code, lcsh:Science, Germ-Line Mutation, 030304 developmental biology, Genetics, Base Composition, 0303 health sciences, Replication timing, Deoxyribonucleases, Multidisciplinary, Genome, Human, Genetic Variation, General Chemistry, DNA Methylation, Histone Code, 030104 developmental biology, CpG site, Mutation (genetic algorithm), CpG Islands, lcsh:Q, Human genome, Hypersensitive site, 030217 neurology & neurosurgery
Abstract

Precise estimates of the single-nucleotide mutation rate and its variability are essential to the study of human genome evolution and genetic diseases. Here we use ~36 million singleton variants observed in 3,716 whole-genome sequences to characterize the heterogeneity of germline mutation rates across the genome. Adjacent-nucleotide context is the strongest predictor of mutability, with mutation rates varying by >650-fold depending on the identity of three bases upstream or downstream of the mutated site. Histone modifications, replication timing, recombination rate, and other local genomic features further modify mutability; magnitude and direction of this modification varies with the sequence context. Compared to estimates based on common variants used in previous approaches, singleton-based estimates provide a more accurate prediction of the mutation patterns seen in an independent dataset of ~46,000 de novo mutations; and incorporating the effects of genomic features further improves the prediction. The effects of sequence contexts, genomic features, and their interactions reported here capture the most refined portrait to date of the germline mutation patterns in humans.

Published
2018
Full Text
View/download PDF

35. Genome-wide association study identifies 30 Loci Associated with Bipolar Disorder

Author

Eli A Stahl, Gerome Breen, Andreas J Forstner, Andrew McQuillin, Stephan Ripke, Vassily Trubetskoy, Manuel Mattheisen, Yunpeng Wang, Jonathan R I Coleman, Héléna A Gaspar, Christiaan A de Leeuw, Stacy Steinberg, Jennifer M Whitehead Pavlides, Maciej Trzaskowski, Tune H Pers, Peter A Holmans, Liam Abbott, Esben Agerbo, Huda Akil, Diego Albani, Ney Alliey-Rodriguez, Thomas D Als, Adebayo Anjorin, Verneri Antilla, Swapnil Awasthi, Judith A Badner, Marie Bækvad-Hansen, Jack D Barchas, Nicholas Bass, Michael Bauer, Richard Belliveau, Sarah E Bergen, Carsten Bøcker Pedersen, Erlend Bøen, Marco Boks, James Boocock, Monika Budde, William Bunney, Margit Burmeister, Jonas Bybjerg-Grauholm, William Byerley, Miquel Casas, Felecia Cerrato, Pablo Cervantes, Kimberly Chambert, Alexander W Charney, Danfeng Chen, Claire Churchhouse, Toni-Kim Clarke, William Coryell, David W Craig, Cristiana Cruceanu, David Curtis, Piotr M Czerski, Anders M Dale, Simone de Jong, Franziska Degenhardt, Jurgen Del-Favero, J Raymond DePaulo, Srdjan Djurovic, Amanda L Dobbyn, Ashley Dumont, Torbjørn Elvsåshagen, Valentina Escott-Price, Chun Chieh Fan, Sascha B Fischer, Matthew Flickinger, Tatiana M Foroud, Liz Forty, Josef Frank, Christine Fraser, Nelson B Freimer, Louise Frisén, Katrin Gade, Diane Gage, Julie Garnham, Claudia Giambartolomei, Marianne Giørtz Pedersen, Jaqueline Goldstein, Scott D Gordon, Katherine Gordon-Smith, Elaine K Green, Melissa J Green, Tiffany A Greenwood, Jakob Grove, Weihua Guan, JoséGuzman Parra, Marian L Hamshere, Martin Hautzinger, Urs Heilbronner, Stefan Herms, Maria Hipolito, Per Hoffmann, Dominic Holland, Laura Huckins, Stéphane Jamain, Jessica S Johnson, Anders Juréus, Radhika Kandaswamy, Robert Karlsson, James L Kennedy, Sarah Kittel-Schneider, Sarah V Knott, James A Knowles, Manolis Kogevinas, Anna C Koller, Ralph Kupka, Catharina Lavebratt, Jacob Lawrence, William B Lawson, Markus Leber, Phil H Lee, Shawn E Levy, Jun Z Li, Chunyu Liu, Susanne Lucae, Anna Maaser, Donald J MacIntyre, Pamela B Mahon, Wolfgang Maier, Lina Martinsson, Steve McCarroll, Peter McGuffin, Melvin G McInnis, James D McKay, Helena Medeiros, Sarah E Medland, Fan Meng, Lili Milani, Grant W Montgomery, Derek W Morris, Thomas W Mühleisen, Niamh Mullins, Hoang Nguyen, Caroline M Nievergelt, Annelie Nordin Adolfsson, Evaristus A Nwulia, Claire O’Donovan, Loes M Olde Loohuis, Anil P S Ori, Lilijana Oruc, Urban Ösby, Roy H Perlis, Amy Perry, Andrea Pfennig, James B Potash, Shaun M Purcell, Eline J Regeer, Andreas Reif, Céline S Reinbold, John P Rice, Fabio Rivas, Margarita Rivera, Panos Roussos, Douglas M Ruderfer, Euijung Ryu, Cristina Sánchez-Mora, Alan F Schatzberg, William A Scheftner, Nicholas J Schork, Cynthia Shannon Weickert, Tatyana Shehktman, Paul D Shilling, Engilbert Sigurdsson, Claire Slaney, Olav B Smeland, Janet L Sobell, Christine Søholm Hansen, Anne T Spijker, David St Clair, Michael Steffens, John S Strauss, Fabian Streit, Jana Strohmaier, Szabolcs Szelinger, Robert C Thompson, Thorgeir E Thorgeirsson, Jens Treutlein, Helmut Vedder, Weiqing Wang, Stanley J Watson, Thomas W Weickert, Stephanie H Witt, Simon Xi, Wei Xu, Allan H Young, Peter Zandi, Peng Zhang, Sebastian Zollner, Rolf Adolfsson, Ingrid Agartz, Martin Alda, Lena Backlund, Bernhard T Baune, Frank Bellivier, Wade H Berrettini, Joanna M Biernacka, Douglas H R Blackwood, Michael Boehnke, Anders D Børglum, Aiden Corvin, Nicholas Craddock, Mark J Daly, Udo Dannlowski, Tõnu Esko, Bruno Etain, Mark Frye, Janice M Fullerton, Elliot S Gershon, Michael Gill, Fernando Goes, Maria Grigoroiu-Serbanescu, Joanna Hauser, David M Hougaard, Christina M Hultman, Ian Jones, Lisa A Jones, RenéS Kahn, George Kirov, Mikael Landén, Marion Leboyer, Cathryn M Lewis, Qingqin S Li, Jolanta Lissowska, Nicholas G Martin, Fermin Mayoral, Susan L McElroy, Andrew M McIntosh, Francis J McMahon, Ingrid Melle, Andres Metspalu, Philip B Mitchell, Gunnar Morken, Ole Mors, Preben Bo Mortensen, Bertram Müller-Myhsok, Richard M Myers, Benjamin M Neale, Vishwajit Nimgaonkar, Merete Nordentoft, Markus M Nöthen, Michael C O’Donovan, Ketil J Oedegaard, Michael J Owen, Sara A Paciga, Carlos Pato, Michele T Pato, Danielle Posthuma, Josep Antoni Ramos-Quiroga, Marta Ribasés, Marcella Rietschel, Guy A Rouleau, Martin Schalling, Peter R Schofield, Thomas G Schulze, Alessandro Serretti, Jordan W Smoller, Hreinn Stefansson, Kari Stefansson, Eystein Stordal, Patrick F Sullivan, Gustavo Turecki, Arne E Vaaler, Eduard Vieta, John B Vincent, Thomas Werge, John I Nurnberger, Naomi R Wray, Arianna Di Florio, Howard J Edenberg, Sven Cichon, Roel A Ophoff, Laura J Scott, Ole A Andreassen, John Kelsoe, and Pamela Sklar

Subjects
0303 health sciences, medicine.medical_specialty, business.industry, medicine.disease, European descent, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Genomewide association, medicine, Bipolar disorder, medicine.symptom, Psychiatry, business, Mania, 030217 neurology & neurosurgery, Depression (differential diagnoses), 030304 developmental biology
Abstract

Bipolar disorder is a highly heritable psychiatric disorder that features episodes of mania and depression. We performed the largest genome-wide association study to date, including 20,352 cases and 31,358 controls of European descent, with follow-up analysis of 822 sentinel variants at loci with P-4 in an independent sample of 9,412 cases and 137,760 controls. In the combined analysis, 30 loci reached genome-wide significant evidence for association, of which 20 were novel. These significant loci contain genes encoding ion channels and neurotransmitter transporters (CACNA1C, GRIN2A, SCN2A, SLC4A1), synaptic components (RIMS1, ANK3), immune and energy metabolism components. Bipolar disorder type I (depressive and manic episodes; ~73% of our cases) is strongly genetically correlated with schizophrenia whereas bipolar disorder type II (depressive and hypomanic episodes; ~17% of our cases) is more strongly correlated with major depressive disorder. These findings address key clinical questions and provide potential new biological mechanisms for bipolar disorder.

Published
2017
Full Text
View/download PDF

36. Circadian rhythms and mood: Opportunities for multi‐level analyses in genomics and neuroscience

Author

Jun Z. Li

Subjects
Neural adaptation, Flexibility (personality), medicine.disease, Affect (psychology), Network dynamics, General Biochemistry, Genetics and Molecular Biology, Mood, medicine.anatomical_structure, Mood disorders, medicine, Major depressive disorder, Circadian rhythm, Psychology, Neuroscience
Abstract

In the healthy state, both circadian rhythm and mood are stable against perturbations, yet they are capable of adjusting to altered internal cues or ongoing changes in external conditions. The dual demands of stability and flexibility are met by the collective properties of complex neural networks. Disruption of this balance underlies both circadian rhythm abnormality and mood disorders. However, we do not fully understand the network properties that govern the crosstalk between the circadian system and mood regulation. This puzzle reflects a challenge at the center of neurobiology, and its solution requires the successful integration of existing data across all levels of neural organization, from molecules, cells, circuits, network dynamics, to integrated mental function. This essay discusses several open questions confronting the cross-level synthesis, and proposes that circadian regulation, and its role in mood, stands as a uniquely tractable system to study the causal mechanisms of neural adaptation. Also watch the Video Abstract. Editor's suggested further reading in BioEssays Major depressive disorder: A loss of circadian synchrony? Abstract.

Published
2013
Full Text
View/download PDF

37. Inference of Cell Type Composition from Human Brain Transcriptomic Datasets Illuminates the Effects of Age, Manner of Death, Dissection, and Psychiatric Diagnosis

Author

Megan Hastings Hagenauer, Anton Schulmann, Jun Z. Li, Marquis P. Vawter, David M. Walsh, Robert C. Thompson, Cortney A. Turner, William E. Bunney, Richard M. Myers, Jack D. Barchas, Alan F. Schatzberg, Stanley J. Watson, and Huda Akil

Subjects
Transcriptome, Cell type, medicine.anatomical_structure, Microarray, Dentate gyrus, Brain atlas, medicine, Human brain, Neuron, Biology, Corpus callosum, Bioinformatics, Neuroscience
Abstract

Most neuroscientists would agree that psychiatric illness is unlikely to arise from pathological changes that occur uniformly across all cells in a given brain region. Despite this fact, the majority of transcriptomic analyses of the human brain to date are conducted using macro-dissected tissue due to the difficulty of conducting single-cell level analyses on donated post-mortem brains. To address this issue statistically, we compiled a database of several thousand transcripts that were specifically-enriched in one of 10 primary brain cell types identified in published single cell type transcriptomic experiments. Using this database, we predicted the relative cell type composition for 157 human dorsolateral prefrontal cortex samples using Affymetrix microarray data collected by the Pritzker Neuropsychiatric Consortium, as well as for 841 samples spanning 160 brain regions included in an Agilent microarray dataset collected by the Allen Brain Atlas. These predictions were generated by averaging normalized expression levels across the transcripts specific to each primary cell type to create a "cell type index". Using this method, we determined that the expression of cell type specific transcripts identified by different experiments, methodologies, and species clustered into three main cell type groups: neurons, oligodendrocytes, and astrocytes/support cells. Overall, the principal components of variation in the data were largely explained by the neuron to glia ratio of the samples. When comparing across brain regions, we were able to statistically identify canonical cell type signatures - increased endothelial cells and vasculature in the choroid plexus, oligodendrocytes in the corpus callosum, astrocytes in the central glial substance, neurons and immature cells in the dentate gyrus, and oligodendrocytes and interneurons in the globus pallidus. The relative balance of these cell types was influenced by a variety of demographic, pre- and post-mortem variables. Age and prolonged hypoxia around the time of death were associated with decreased neuronal content and increased astrocytic and endothelial content in the tissue, replicating the known higher vulnerability of neurons to adverse conditions and illustrating the proliferation of vasculature in a hypoxic environment. We also found that the red blood cell content was reduced in individuals who died in a manner that involved systemic blood loss. Finally, statistically accounting for cell type improved both the sensitivity and interpretability of diagnosis effects within the data. We were able to observe a decrease in astrocytic content in subjects with Major Depressive Disorder, mirroring what had been previously observed morphometrically. By including a set of "cell type indices" in a larger model examining the relationship between gene expression and neuropsychiatric illness, we were able to successfully detect almost twice as many genes with previously-identified relationships to bipolar disorder and schizophrenia than using more traditional analysis methods.

Published
2016
Full Text
View/download PDF

39. [Untitled]

Author

Zhuo Chen, Jun Z. Li, Xiao H. Yuan, Yanna Liu, and Karen Adler-Storthz

Subjects
Point mutation, General Medicine, Biology, medicine.disease_cause, Molecular biology, Cell culture, Transcription (biology), Virology, Genetics, medicine, Luciferase, Binding site, Carcinogenesis, Molecular Biology, Transcription factor, Carcinogen
Abstract

Expression of the human papillomavirus (HPV) E6 and E7 oncoproteins is responsible for the transforming ability of the virus. The HPV long control region (LCR) and E6/E7 promoter regulate transcription of the E6 and E7 viral oncogenes. However, factors involved in the stimulation of E6/E7 promoter activity in carcinogenesis are unclear. We previously identified a point mutation in an HPV-16 immortalized human oral keratinocyte cell line subsequently exposed to a tobacco-specific carcinogen. This mutation was located in the LCR at nucleotide 7633 and contains binding sites for the transcription activator, AP-1, overlapping with putative binding regions for the transcription factor, C/EBP, which represses the E6/E7 promoter. In this study, this mutation was analyzed by both electrophoretic mobility shift analysis and luciferase assays. We found that the point mutation enhanced the binding affinity of AP-1 to the LCR, thus stimulating the E6/E7 promoter activity. Our results suggest that mutations in binding sites for crucial regulators may be the result of exposure to carcinogens and could induce expression of the E6 and E7 oncogenes.

Published
2002
Full Text
View/download PDF

40. Signals of recent positive selection in a worldwide sample of human populations

Author

Pickrell, Joseph K., Coop, Graham, Novembre, John, Kudaravalli, Sridhar, Jun Z. Li, Absher, Devin, Srinivasan, Balaji S., Barsh, Gregory S., Myers, Richard M., Feldman, Marcus W., and Pritchard, Jonathan K.

Subjects
Population genetics -- Research, Biological diversity -- Research, Natural selection -- Research, Health
Published
2009

41. Sensitized mutagenesis screen in Factor V Leiden mice identifies thrombosis suppressor loci.

Author

Westrick, Randal J., Tomberg, Kärt, Siebert, Amy E., Guojing Zhu, Winn, Mary E., Dobies, Sarah L., Manning, Sara L., Brake, Marisa A., Cleuren, Audrey C., Hobbs, Linzi M., Mishack, Lena M., Johnston, Alexander J., Kotnik, Emilee, Siemieniak, David R., Jishu Xu, Jun Z. Li, Saunders, Thomas L., and Ginsburg, David

Subjects
VENOUS thrombosis, FACTOR V Leiden, MUTAGENESIS, GENETIC mutation, THROMBOEMBOLISM
Abstract

Factor V Leiden (F5L) is a common genetic risk factor for venous thromboembolism in humans. We conducted a sensitized N-ethyl-N-nitrosourea (ENU) mutagenesis screen for dominant thrombosuppressor genes based on perinatal lethal thrombosis in mice homozygous for F5L (F5L/L) and haploinsufficient for tissue factor pathway inhibitor (Tfpi+/-). F8 deficiency enhanced the survival of F5L/L Tfpi+/- mice, demonstrating that F5L/L Tfpi+/- lethality is genetically suppressible. ENU-mutagenized F5L/L males and F5L/+ Tfpi+/- females were crossed to generate 6,729 progeny, with 98 F5L/L Tfpi+/- offspring surviving until weaning. Sixteen lines, referred to as "modifier of Factor 5 Leiden (MF5L1-16)," exhibited transmission of a putative thrombosuppressor to subsequent generations. Linkage analysis in MF5L6 identified a chromosome 3 locus containing the tissue factor gene (F3). Although no ENU-induced F3 mutation was identified, haploinsufficiency for F3 (F3+/-) suppressed F5L/L Tfpi+/- lethality. Whole-exome sequencing in MF5L12 identified an Actr2 gene point mutation (p.R258G) as the sole candidate. Inheritance of this variant is associated with suppression of F5L/L Tfpi+/- lethality (P = 1.7 x 10-6), suggesting that Actr2p.R258G is thrombosuppressive. CRISPR/Cas9 experiments to generate an independent Actr2 knockin/knockout demonstrated that Actr2 haploinsufficiency is lethal, supporting a hypomorphic or gain-of-function mechanism of action for Actr2p.R258G. Our findings identify F8 and the Tfpi/F3 axis as key regulators in determining thrombosis balance in the setting of F5L and also suggest a role for Actr2 in this process. [ABSTRACT FROM AUTHOR]

Published
2017
Full Text
View/download PDF

42. An AP-1 binding site mutation in HPV-16 LCR enhances E6/E7 promoter activity in human oral epithelial cells

Author

Yanna, Liu, Jun Z, Li, Xiao H, Yuan, Karen, Adler-Storthz, and Zhuo, Che

Subjects
Binding Sites, Papillomavirus E7 Proteins, Gene Expression, Oncogene Proteins, Viral, Regulatory Sequences, Nucleic Acid, Repressor Proteins, Transcription Factor AP-1, Gene Expression Regulation, Mutation, Humans, Point Mutation, Promoter Regions, Genetic, Papillomaviridae, Cell Line, Transformed
Abstract

Expression of the human papillomavirus (HPV) E6 and E7 oncoproteins is responsible for the transforming ability of the virus. The HPV long control region (LCR) and E6/E7 promoter regulate transcription of the E6 and E7 viral oncogenes. However, factors involved in the stimulation of E6/E7 promoter activity in carcinogenesis are unclear. We previously identified a point mutation in an HPV-16 immortalized human oral keratinocyte cell line subsequently exposed to a tobacco-specific carcinogen. This mutation was located in the LCR at nucleotide 7633 and contains binding sites for the transcription activator, AP-1, overlapping with putative binding regions for the transcription factor, C/EBP, which represses the E6/E7 promoter. In this study, this mutation was analyzed by both electrophoretic mobility shift analysis and luciferase assays. We found that the point mutation enhanced the binding affinity of AP-1 to the LCR, thus stimulating the E6/E7 promoter activity. Our results suggest that mutations in binding sites for crucial regulators may be the result of exposure to carcinogens and could induce expression of the E6 and E7 oncogenes.

Published
2002

43. Genetic investigation of fibromuscular dysplasia identifies risk loci and shared genetics with common cardiovascular diseases

Author

Adrien Georges, Min-Lee Yang, Takiy-Eddine Berrandou, Mark K. Bakker, Ozan Dikilitas, Soto Romuald Kiando, Lijiang Ma, Benjamin A. Satterfield, Sebanti Sengupta, Mengyao Yu, Jean-François Deleuze, Delia Dupré, Kristina L. Hunker, Sergiy Kyryachenko, Lu Liu, Ines Sayoud-Sadeg, Laurence Amar, Chad M. Brummett, Dawn M. Coleman, Valentina d’Escamard, Peter de Leeuw, Natalia Fendrikova-Mahlay, Daniella Kadian-Dodov, Jun Z. Li, Aurélien Lorthioir, Marco Pappaccogli, Aleksander Prejbisz, Witold Smigielski, James C. Stanley, Matthew Zawistowski, Xiang Zhou, Sebastian Zöllner, FEIRI investigators, International Stroke Genetics Consortium (ISGC) Intracranial Aneurysm Working Group, MEGASTROKE, Philippe Amouyel, Marc L. De Buyzere, Stéphanie Debette, Piotr Dobrowolski, Wojciech Drygas, Heather L. Gornik, Jeffrey W. Olin, Jerzy Piwonski, Ernst R. Rietzschel, Ynte M. Ruigrok, Miikka Vikkula, Ewa Warchol Celinska, Andrzej Januszewicz, Iftikhar J. Kullo, Michel Azizi, Xavier Jeunemaitre, Alexandre Persu, Jason C. Kovacic, Santhi K. Ganesh, and Nabila Bouatia-Naji

Subjects
Science
Abstract

Fibromuscular dysplasia is a cardiovascular disease affecting mostly women with a mostly unknown genetic basis. Here the authors have performed a genome-wide association meta-analysis of Fibromuscular dysplasia to identify genetic loci, some of which are shared with common cardiovascular disease and traits.

Published
2021
Full Text
View/download PDF

44. TCF21+ mesenchymal cells contribute to testis somatic cell development, homeostasis, and regeneration in mice

Author

Yu-chi Shen, Adrienne Niederriter Shami, Lindsay Moritz, Hailey Larose, Gabriel L. Manske, Qianyi Ma, Xianing Zheng, Meena Sukhwani, Michael Czerwinski, Caleb Sultan, Haolin Chen, Stephen J. Gurczynski, Jason R. Spence, Kyle E. Orwig, Michelle Tallquist, Jun Z. Li, and Saher Sue Hammoud

Subjects
Science
Abstract

Whether the adult testis harbours a somatic progenitor population is unknown. Here, the authors provide evidence that the testis interstitial cells expressing the transcription factor Tcf21 maintain adult testis homeostasis during aging, and act as potential reserve somatic progenitors following injury.

Published
2021
Full Text
View/download PDF

45. Chromosome 1q21.2 and additional loci influence risk of spontaneous coronary artery dissection and myocardial infarction

Author

Jacqueline Saw, Min-Lee Yang, Mark Trinder, Catherine Tcheandjieu, Chang Xu, Andrew Starovoytov, Isabelle Birt, Michael R. Mathis, Kristina L. Hunker, Ellen M. Schmidt, Linda Jackson, Natalia Fendrikova-Mahlay, Matthew Zawistowski, Chad M. Brummett, Sebastian Zoellner, Alexander Katz, Dawn M. Coleman, Kirby Swan, Christopher J. O’Donnell, Million Veteran Program, Xiang Zhou, Jun Z. Li, Heather L. Gornik, Themistocles L. Assimes, James C. Stanley, Liam R. Brunham, and Santhi K. Ganesh

Subjects
Science
Abstract

Spontaneous coronary artery dissection (SCAD) is a cause of myocardial infarction Here, the authors present a genome-wide association study of SCAD, finding an association at 1q21.2 which potentially affects expression of ADAMTSL4.

Published
2020
Full Text
View/download PDF

46. Murine models of IDH-wild-type glioblastoma exhibit spatial segregation of tumor initiation and manifestation during evolution

Author

Yinghua Li, Bo Li, Wei Li, Yuan Wang, Seçkin Akgül, Daniel M. Treisman, Kevin A. Heist, Brianna R. Pierce, Benjamin Hoff, Cheng-Ying Ho, David O. Ferguson, Alnawaz Rehemtulla, Siyuan Zheng, Brian D. Ross, Jun Z. Li, and Yuan Zhu

Subjects
Science
Abstract

Recent studies suggest spatial segregation of tumor initiation and manifestation in IDH-WT glioblastomas. Here, the authors use serial MRI/3D-reconstruction, whole-genome sequencing and spectral karyotyping-based single-cell phylogenetic tree building to establish this unique evolutionary mode in a murine model.

Published
2020
Full Text
View/download PDF

47. Author Correction: Genetic investigation of fibromuscular dysplasia identifies risk loci and shared genetics with common cardiovascular diseases

Author

Adrien Georges, Min-Lee Yang, Takiy-Eddine Berrandou, Mark K. Bakker, Ozan Dikilitas, Soto Romuald Kiando, Lijiang Ma, Benjamin A. Satterfield, Sebanti Sengupta, Mengyao Yu, Jean-François Deleuze, Delia Dupré, Kristina L. Hunker, Sergiy Kyryachenko, Lu Liu, Ines Sayoud-Sadeg, Laurence Amar, Chad M. Brummett, Dawn M. Coleman, Valentina d’Escamard, Peter de Leeuw, Natalia Fendrikova-Mahlay, Daniella Kadian-Dodov, Jun Z. Li, Aurélien Lorthioir, Marco Pappaccogli, Aleksander Prejbisz, Witold Smigielski, James C. Stanley, Matthew Zawistowski, Xiang Zhou, Sebastian Zöllner, FEIRI investigators, International Stroke Genetics Consortium (ISGC) Intracranial Aneurysm Working Group, MEGASTROKE, Philippe Amouyel, Marc L. De Buyzere, Stéphanie Debette, Piotr Dobrowolski, Wojciech Drygas, Heather L. Gornik, Jeffrey W. Olin, Jerzy Piwonski, Ernst R. Rietzschel, Ynte M. Ruigrok, Miikka Vikkula, Ewa Warchol Celinska, Andrzej Januszewicz, Iftikhar J. Kullo, Michel Azizi, ARCADIA Investigators, Xavier Jeunemaitre, Alexandre Persu, Jason C. Kovacic, Santhi K. Ganesh, and Nabila Bouatia-Naji

Subjects
Science
Published
2022
Full Text
View/download PDF

48. Helmsman: fast and efficient mutation signature analysis for massive sequencing datasets

Author

Jedidiah Carlson, Jun Z. Li, and Sebastian Zöllner

Subjects
Mutational signatures, Cancer genomics, Python, Single nucleotide variants, Biotechnology, TP248.13-248.65, Genetics, QH426-470
Abstract

Abstract Background The spectrum of somatic single-nucleotide variants in cancer genomes often reflects the signatures of multiple distinct mutational processes, which can provide clinically actionable insights into cancer etiology. Existing software tools for identifying and evaluating these mutational signatures do not scale to analyze large datasets containing thousands of individuals or millions of variants. Results We introduce Helmsman, a program designed to perform mutation signature analysis on arbitrarily large sequencing datasets. Helmsman is up to 300 times faster than existing software. Helmsman’s memory usage is independent of the number of variants, resulting in a small enough memory footprint to analyze datasets that would otherwise exceed the memory limitations of other programs. Conclusions Helmsman is a computationally efficient tool that enables users to evaluate mutational signatures in massive sequencing datasets that are otherwise intractable with existing software. Helmsman is freely available at https://github.com/carjed/helmsman.

Published
2018
Full Text
View/download PDF

49. Post-mortem molecular profiling of three psychiatric disorders

Author

Ryne C. Ramaker, Kevin M. Bowling, Brittany N. Lasseigne, Megan H. Hagenauer, Andrew A. Hardigan, Nicholas S. Davis, Jason Gertz, Preston M. Cartagena, David M. Walsh, Marquis P. Vawter, Edward G. Jones, Alan F. Schatzberg, Jack D. Barchas, Stanley J. Watson, Blynn G. Bunney, Huda Akil, William E. Bunney, Jun Z. Li, Sara J. Cooper, and Richard M. Myers

Subjects
Schizophrenia, Bipolar disorder, Major depressive disorder, RNA sequencing, Metabolomics, EGR1, Medicine, Genetics, QH426-470
Abstract

Abstract Background Psychiatric disorders are multigenic diseases with complex etiology that contribute significantly to human morbidity and mortality. Although clinically distinct, several disorders share many symptoms, suggesting common underlying molecular changes exist that may implicate important regulators of pathogenesis and provide new therapeutic targets. Methods We performed RNA sequencing on tissue from the anterior cingulate cortex, dorsolateral prefrontal cortex, and nucleus accumbens from three groups of 24 patients each diagnosed with schizophrenia, bipolar disorder, or major depressive disorder, and from 24 control subjects. We identified differentially expressed genes and validated the results in an independent cohort. Anterior cingulate cortex samples were also subjected to metabolomic analysis. ChIP-seq data were used to characterize binding of the transcription factor EGR1. Results We compared molecular signatures across the three brain regions and disorders in the transcriptomes of post-mortem human brain samples. The most significant disease-related differences were in the anterior cingulate cortex of schizophrenia samples compared to controls. Transcriptional changes were assessed in an independent cohort, revealing the transcription factor EGR1 as significantly down-regulated in both cohorts and as a potential regulator of broader transcription changes observed in schizophrenia patients. Additionally, broad down-regulation of genes specific to neurons and concordant up-regulation of genes specific to astrocytes was observed in schizophrenia and bipolar disorder patients relative to controls. Metabolomic profiling identified disruption of GABA levels in schizophrenia patients. Conclusions We provide a comprehensive post-mortem transcriptome profile of three psychiatric disorders across three brain regions. We highlight a high-confidence set of independently validated genes differentially expressed between schizophrenia and control patients in the anterior cingulate cortex and integrate transcriptional changes with untargeted metabolite profiling.

Published
2017
Full Text
View/download PDF

50. Growth hormone deficiency with advanced bone age: phenotypic interaction between GHRH receptor and CYP21A2 mutations diagnosed by sanger and whole exome sequencing

Author

Fernanda A. Correa, Marcela M. França, Qing Fang, Qianyi Ma, Tania A. Bachega, Andresa Rodrigues, Bilge A. Ozel, Jun Z. Li, Berenice B. Mendonca, Alexander A. L. Jorge, Luciani R. Carvalho, Sally A. Camper, and Ivo J. P Arnhold

Subjects
Medicine, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract

SUMMARY Isolated growth hormone deficiency (IGHD) is the most common pituitary hormone deficiency and, clinically, patients have delayed bone age. High sequence similarity between CYP21A2 gene and CYP21A1P pseudogene poses difficulties for exome sequencing interpretation. A 7.5 year-old boy born to second-degree cousins presented with severe short stature (height SDS −3.7) and bone age of 6 years. Clonidine and combined pituitary stimulation tests revealed GH deficiency. Pituitary MRI was normal. The patient was successfully treated with rGH. Surprisingly, at 10.8 years, his bone age had advanced to 13 years, but physical exam, LH and testosterone levels remained prepubertal. An ACTH stimulation test disclosed a non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency explaining the bone age advancement and, therefore, treatment with cortisone acetate was added. The genetic diagnosis of a homozygous mutation in GHRHR (p.Leu144His), a homozygous CYP21A2 mutation (p.Val282Leu) and CYP21A1P pseudogene duplication was established by Sanger sequencing, MLPA and whole-exome sequencing. We report the unusual clinical presentation of a patient born to consanguineous parents with two recessive endocrine diseases: non-classic congenital adrenal hyperplasia modifying the classical GH deficiency phenotype. We used a method of paired read mapping aided by neighbouring mis-matches to overcome the challenges of exome-sequencing in the presence of a pseudogene.

Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results