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1. Genome-Wide Meta-Analysis of Late-Onset Alzheimer’s Disease Using Rare Variant Imputation in 65,602 Subjects Identifies Novel Rare Variant Locus NCK2: The International Genomics of Alzheimer’s Project (IGAP)

Author

Yuk Yee Leung, Lindsay A. Farrer, Yi Zhao, Amanda B. Kuzma, Jean-Charles Lambert, Alessandra Chesi, Xia R, Haines Jl, Haut J, Anita L. DeStefano, Chouraki, Julie Williams, William S. Bush, Leonenko G, Achilleas N. Pitsillides, John J. Farrell, Richard Mayeux, Fulton-Howard B, Xueqiu Jian, van Duijn C, Edward B. Lee, Sudha Seshadri, Sandra Barral, Li M, Jennifer E. Below, Rebecca Sims, Kara L. Hamilton-Nelson, J. C. Bis, Céline Bellenguez, Struan F.A. Grant, Otto Valladares, B. Grenier-Boley, Schellenberg Gd, Peter Holmans, Margaret A. Pericak-Vance, Comic H, Maria Carolina Dalmasso, Badri N. Vardarajan, Penelope Benchek, Phillips-Cremins Je, Philippe Amouyel, Brian W. Kunkle, Adam C. Naj, Zhang Y, Alfredo Ramirez, Pavel P. Kuksa, Chen H, Jin Sha, Li-San Wang, Lee C, van der Lee Sj, and Josée Dupuis

Subjects
Genetics, 0303 health sciences, TREM2, Haplotype, Genome-wide association study, Locus (genetics), Biology, Minor allele frequency, 03 medical and health sciences, 0302 clinical medicine, Genotype, 030217 neurology & neurosurgery, Imputation (genetics), 030304 developmental biology, Genetic association
Abstract

Risk for late-onset Alzheimer’s disease (LOAD) is driven by multiple loci primarily identified by genome-wide association studies, many of which are common variants with minor allele frequencies (MAF)> 0.01. To identify additional common and rare LOAD risk variants, we performed a GWAS on 25,170 LOAD subjects and 41,052 cognitively normal controls in 44 datasets from the International Genomics of Alzheimer’s Project (IGAP). Existing genotype data was imputed using the dense, high-resolution Haplotype Reference Consortium (HRC) r1.1 reference panel. Stage 1 associations of P−5 were meta-analyzed with the European Alzheimer’s Disease Biobank (EADB) (n=20,301 cases; 21,839 controls) (stage 2 combined IGAP and EADB). An expanded meta-analysis was performed using a GWAS of parental AD/dementia history in the UK Biobank (UKBB) (n=35,214 cases; 180,791 controls) (stage 3 combined IGAP, EADB, and UKBB). Common variant (MAF≥0.01) associations were identified for 29 loci in stage 2, including novel genome-wide significant associations at TSPAN14 (P=2.33×10−12), SHARPIN (P=1.56×10−9), and ATF5/SIGLEC11 (P=1.03×10−8), and newly significant associations without using AD proxy cases in MTSS1L/IL34 (P=1.80×10−8), APH1B (P=2.10×10−13), and CLNK (P=2.24×10−10). Rare variant (MAFAPOE and TREM2, and a novel association of a rare variant (rs143080277; MAF=0.0054; P=2.69×10−9) in NCK2, further strengthened with the inclusion of UKBB data in stage 3 (P=7.17×10−13). Single-nucleus sequence data shows that NCK2 is highly expressed in amyloid-responsive microglial cells, suggesting a role in LOAD pathology.

Published
2021
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2. Genome‐wide meta‐analysis of late‐onset Alzheimer’s disease using rare variant imputation in 65,602 subjects identifies risk loci with roles in memory, neurodevelopment, and cardiometabolic traits: The international genomics of Alzheimer’s project (IGAP)

Author

Brian W. Kunkle, Amanda B. Kuzma, Adam C. Naj, Brian Fulton-Howard, Philippe Amouyel, Julie Williams, Ganna Leonenko, Peter Holmans, Jin Sha, Jonathan L. Haines, Li-San Wang, Benjamin Grenier-Boley, Alfredo Ramirez, Xueqiu Jian, J. C. Bis, Vincent Chouraki, Rebecca Sims, Josée Dupuis, Yi Zhao, Cornelia M. van Duijn, Gerard D. Schellenberg, Achilleas N. Pitsillides, Anita L. DeStefano, Sudha Seshadri, Hata Karamujić-Čomić, Jean-Charles Lambert, Maria Carolina Dalmasso, Lindsay A. Farrer, Margaret A. Pericak-Vance, Sven J. van der Lee, and Rui Xia

Subjects
Genetics, Epidemiology, Health Policy, Genomics, Late onset, Disease, Biology, Omics, Genome, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Meta-analysis, Neurology (clinical), Geriatrics and Gerontology, Imputation (genetics)
Published
2020
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3. Analysis of individual families implicates noncoding DNA variation and multiple biological pathways in Alzheimer’s disease risk

Author

Richard Mayeux, Alzheimer’s Disease Sequencing, Margaret A. Pericak-Vance, Rafael A. Nafikov, Ellen M. Wijsman, Cornelia M. van Duijn, Patrick A. Navas, J. C. Bis, Mohamad Saad, Andrea R. V. R. Horimoto, Badri N. Vardarajan, Debby W. Tsuang, Harkirat Sohi, Tyler R. Day, Gary W. Beecham, Sandra Barral, Elizabeth E. Blue, Eden R. Martin, Timothy A. Thornton, and Alejandro Q. Nato

Subjects
Genetics, Epidemiology, Health Policy, Disease, Biology, Noncoding DNA, Biological pathway, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Variation (linguistics), Developmental Neuroscience, Disease risk, Neurology (clinical), Geriatrics and Gerontology
Published
2020
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4. Genetic variants for head size share genes and pathways with cancer

Author

Shihua Li, Melissa J. Green, Nagata M, Miyamoto S, Le Grand Q, Pourcain Bs, Grabe Hj, Catherine Helmer, William R. Reay, Nele Friedrich, Mazoyer B, Seshadri S, Per Hoffmann, Simon Haworth, Veronica Witte A, Yang Q, Max Lam, Teunissen Mw, Fang-Chi Hsu, Debette S, Murray J. Cairns, Amod Ar, Setoh K, Windham Bg, Shareefa Dalvie, Georg Homuth, Charlie S. DeCarli, Gennady V. Roshchupkin, Céline S. Reinbold, Mühleisen Tw, Nakahara S, Van der Auwera S, Xueqiu Jian, Cecil Ca, Jean-François Dartigues, Alexa S. Beiser, Stein Jl, Houlden H, Christiane Jockwitz, Moebus S, Claudia L. Satizabal, Tavia E. Evans, Matsuda F, Cora E. Lewis, Wittfeld K, Calhoun Vd, van der Lugt A, Teumer A, Pausova Z, W. T. Longstreth, Aniket Mishra, Tomáš Paus, Vernooij Mw, Medland Se, Palmer Nd, Ahmad R. Hariri, Adrian Preda, Clifford R. Jack, van Erp Tg, Amaia Carrion-Castillo, Werring Dj, Gwénaëlle Catheline, Asta Håberg, Robin Bülow, Sven Cichon, Yann Quidé, Muetzel R, Tabara Y, Sidney S, Cheung C, Brunner Hg, Annchen R. Knodt, Mosley Th, van Dam-Nolen Dh, Hostettler Ic, Jean Shin, Shapland Cy, Reut Avinun, Crivello F, Mäkitie O, Fornage M, Yoshida K, Villringer A, Lim K, Schreiner Pj, Bowden Dw, Thompson Pm, Daniel Bos, Uhlmann A, Enlund-Cerullo M, Schmidt R, Hieab H.H. Adams, Neda Jahanshad, Frauke Beyer, Gloria H.Y. Li, Fabio Macciardi, Lamballais S, Kämpe A, Judith M. Ford, Poot Ra, J. C. Bis, Yoichiro Kamatani, Ami Tsuchida, Markus Scholz, Ikram Ma, Andersson S, Lenore J. Launer, Stein Dj, Koudstaal Pj, Barry I. Freedman, Barbara Franke, Ikram Mk, Sim K, Marie-Gabrielle Duperron, Bryan Rn, Svenja Caspers, Pawlak Ma, Tonya White, Maria J. Knol, Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium, and Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Consortium

Subjects
Genetics, 0303 health sciences, education.field_of_study, biology, Population, Wnt signaling pathway, Macrocephaly, Cancer, medicine.disease, Biological pathway, 03 medical and health sciences, 0302 clinical medicine, medicine, biology.protein, PTEN, Human height, medicine.symptom, education, Gene, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract

The size of the human head is determined by growth in the first years of life, while the rest of the body typically grows until early adulthood1. Such complex developmental processes are regulated by various genes and growth pathways2. Rare genetic syndromes have revealed genes that affect head size3, but the genetic drivers of variation in head size within the general population remain largely unknown. To elucidate biological pathways underlying the growth of the human head, we performed the largest genome-wide association study on human head size to date (N = 79,107). We identified 67 genetic loci, 50 of which are novel, and found that these loci are preferentially associated with head size and mostly independent from height. In subsequent neuroimaging analyses, the majority of genetic variants demonstrated widespread effects on the brain, whereas the effects of 17 variants could be localized to one or two specific brain regions. Through hypothesis-free approaches, we find a strong overlap of head size variants with both cancer pathways and cancer genes. Gene set analyses showed enrichment for different types of cancer and the p53, Wnt and ErbB signalling pathway. Genes overlapping or close to lead variants – such as TP53, PTEN and APC – were enriched for genes involved in macrocephaly syndromes (up to 37-fold) and high-fidelity cancer genes (up to 9-fold), whereas this enrichment was not seen for human height variants. This indicates that genes regulating early brain and cranial growth are associated with a propensity to neoplasia later in life, irrespective of height. Our results warrant further investigations of the link between head size and cancer, as well as its clinical implications in the general population.

Published
2020
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5. Population Stratification at the Phenotypic Variance level and Implication for the Analysis of Whole Genome Sequencing Data from Multiple Studies

Author

Ethan M. Lange, Matthew P. Conomos, Tamar Sofer, Xiuwen Zheng, Kenneth Rice, O’Connell, J. C. Bis, Stephanie M. Gogarten, Cecilia A. Laurie, Jennifer A. Brody, Bruce M. Psaty, Adam A. Szpiro, Yan Gao, Timothy A. Thornton, and L. A. Cupples

Subjects
Whole genome sequencing, 0303 health sciences, 030305 genetics & heredity, Variance (accounting), Biology, Population stratification, Statistical power, 3. Good health, Term (time), 03 medical and health sciences, Sample size determination, Statistics, False positive paradox, Allele frequency, 030304 developmental biology
Abstract

SummaryIn modern Whole Genome Sequencing (WGS) epidemiological studies, participant-level data from multiple studies are often pooled and results are obtained from a single analysis. We consider the impact of differential phenotype variances by study, which we term ‘variance stratification’. Unaccounted for, variance stratification can lead to both decreased statistical power, and increased false positives rates, depending on how allele frequencies, sample sizes, and phenotypic variances vary across the studies that are pooled. We describe a WGS-appropriate analysis approach, implemented in freely-available software, which allows study-specific variances and thereby improves performance in practice. We also illustrate the variance stratification problem, its solutions, and a corresponding diagnostic procedure in data from the Trans-Omics for Precision Medicine Whole Genome Sequencing Program (TOPMed), used in association tests for hemoglobin concentrations and BMI.

Published
2020
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6. Genome-wide meta-analysis of variant-by-diuretic interactions as modulators of lipid traits in persons of European and African ancestry

Author

Xiaohui Li, James D. Stewart, Rikje Ruiter, Yongmei Liu, Joop Jukema, Donna K. Arnett, Leslie A. Lange, Daniel S. Evans, Jerome I. Rotter, Solomon K. Musani, Susan R. Heckbert, Christy L. Avery, L. de las Fuentes, D. C. Rao, C E de Keyser, Steve Cummings, L. A. Cupples, Kerri L. Wiggins, Y-Di Chen, David J. Stott, Vilmundur Gudnason, Ulrich Broeckel, Yun J. Sung, T.B. Harris, B. H. Stricker, J. C. Bis, M. A. Ikram, Kent D. Taylor, Traci M. Bartz, Fangui Sun, Nona Sotoodehnia, Nicholas L. Smith, Colleen M. Sitlani, L. J. Launer, Eric A. Whitsel, Alexander P. Reiner, A.G. Uitterlinden, Karen Schwander, Xuejiang Guo, Adolfo Correa, Hanfei Xu, Albert V. Smith, Til Stürmer, James S. Floyd, James G. Wilson, Ramachandran S. Vasan, Evan L. Busch, Bruce M. Psaty, Stella Trompet, Ian Ford, and Epidemiology

Subjects
0301 basic medicine, medicine.medical_specialty, medicine.medical_treatment, European Continental Ancestry Group, Blood lipids, Locus (genetics), Disease, Cardiovascular, 030226 pharmacology & pharmacy, White People, Article, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Internal medicine, Genetics, medicine, 2.1 Biological and endogenous factors, Humans, Pharmacology & Pharmacy, Aetiology, Diuretics, BAALC, African Americans, Pharmacology, business.industry, Cholesterol, Human Genome, Genetic Variation, Pharmacology and Pharmaceutical Sciences, medicine.disease, R1, Lipids, Black or African American, Heart Disease, Good Health and Well Being, 030104 developmental biology, Endocrinology, chemistry, Heart failure, Meta-analysis, Hypertension, Molecular Medicine, Diuretic, business, Genome-Wide Association Study
Abstract

Hypertension (HTN) is a significant risk factor for cardiovascular morbidity and mortality. Metabolic abnormalities, including adverse cholesterol and triglycerides (TG) profiles, are frequent comorbid findings with HTN and contribute to cardiovascular disease. Diuretics, which are used to treat HTN and heart failure, have been associated with worsening of fasting lipid concentrations. Genome-wide meta-analyses with 39,710 European-ancestry (EA) individuals and 9925 African-ancestry (AA) individuals were performed to identify genetic variants that modify the effect of loop or thiazide diuretic use on blood lipid concentrations. Both longitudinal and cross sectional data were used to compute cohort-specific interaction results, which were then combined through meta-analysis in each ancestry. These ancestry-specific results were further combined through trans-ancestry meta-analysis. Analysis of EA data identified two genome-wide significant (p

Published
2020

7. Pharmacogenomics study of thiazide diuretics and QT interval in multi-ethnic populations: the cohorts for heart and aging research in genomic epidemiology

Author

C M van Duijn, James S. Floyd, Maarit A. Laaksonen, André G. Uitterlinden, Colleen M. Sitlani, Y-Di Chen, H J Lin, Christopher Newton-Cheh, Kent D. Taylor, Albert V. Smith, Til Stürmer, Kari E. North, Peter W. Macfarlane, Dennis O. Mook-Kanamori, Raymond Noordam, Yun Li, Jun Li, Tamar Sofer, Raul Mendez-Giraldez, Adrienne M. Stilp, Cathy C. Laurie, Ian Ford, Christy L. Avery, Stella Trompet, Nona Sotoodehnia, Jeffrey Roach, T.B. Harris, Jennifer A. Brody, Susan R. Heckbert, L. A. Cupples, J. C. Bis, Ruifang Li-Gao, Christopher J. O'Donnell, Vilmundur Gudnason, Robert C. Kaplan, Brendan M. Buckley, R. de Mutsert, Jan A. Kors, Steve Cummings, Elsayed Z. Soliman, Xiaohui Li, Kati Kristiansson, Linda Broer, Alexander P. Reiner, Joop Jukema, Aaron Isaacs, Evan L. Busch, Craig R. Lee, Amanda A. Seyerle, Heather M. Highland, Kathleen F. Kerr, Bruce M. Psaty, Leslie A. Lange, Qing Duan, Veikko Salomaa, Kenneth Rice, James D. Stewart, Stephanie M. Gogarten, E. A. Whitsel, Kirk C. Wilhelmsen, Daniel S. Evans, Yongmei Liu, Bruno H. Stricker, Fangui Sun, Kimmo Porthan, A. Hofman, Gina M. Peloso, L. J. Launer, Kerri L. Wiggins, Melanie D. Napier, Jerome I. Rotter, Frits R. Rosendaal, James G. Wilson, Ramachandran S. Vasan, Kardiologian yksikkö, Department of Medicine, Clinicum, Genetica & Celbiologie, Biochemie, RS: CARIM - R1.01 - Blood proteins & engineering, RS: CARIM - R1.06 - Genetic Epidemiology and Genomics of cardiovascular diseases, RS: FHML MaCSBio, Epidemiology, Internal Medicine, Medical Informatics, and Erasmus MC other

Subjects
Male, 0301 basic medicine, Influencing antihypertensive response, Aging, Sodium Chloride Symporter Inhibitors, Blood-pressure response, Gene-environment interactions, Ethnic populations, VARIANTS, Cardiovascular, Bioinformatics, Cohort Studies, Electrocardiography, Cardiovascular drugs, Heart Rate, Polymorphism (computer science), HYPERTENSIVE PATIENTS, Epidemiology, 80 and over, Ethnicity, WIDE ASSOCIATION, Pharmacology & Pharmacy, Longitudinal Studies, Aged, 80 and over, Wide association, Genomewide association, Variants, Single Nucleotide, Pharmacology and Pharmaceutical Sciences, Genomics, Middle Aged, CARDIOVASCULAR DRUGS, 3. Good health, 317 Pharmacy, Molecular Medicine, Female, Cohort study, medicine.drug, Adult, medicine.medical_specialty, INFLUENCING ANTIHYPERTENSIVE RESPONSE, MEDLINE, UNITED-STATES, Polymorphism, Single Nucleotide, QT interval, Article, 03 medical and health sciences, BLOOD-PRESSURE RESPONSE, Genetics, medicine, Humans, Polymorphism, Thiazide, Hypertensive patients, Aged, Pharmacology, Selection bias, SELECTION BIAS, business.industry, Human Genome, R1, GENE-ENVIRONMENT INTERACTIONS, United States, 030104 developmental biology, Pharmacogenetics, Pharmacogenomics, GENOMEWIDE ASSOCIATION, business
Abstract

Thiazide diuretics, commonly used antihypertensives, may cause QT interval (QT) prolongation, a risk factor for highly fatal and difficult to predict ventricular arrhythmias. We examined whether common single-nucleotide polymorphisms (SNPs) modified the association between thiazide use and QT or its component parts (QRS interval, JT interval) by performing ancestry-specific, transethnic and cross-phenotype genome-wide analyses of European (66%), African American (15%) and Hispanic (19%) populations (N = 78 199), leveraging longitudinal data, incorporating corrected standard errors to account for underestimation of interaction estimate variances and evaluating evidence for pathway enrichment. Although no loci achieved genome-wide significance (P

Published
2018

8. GWAS for executive function and processing speed suggests involvement of the CADM2 gene

Author

Igor Rudan, Daniel I. Chasman, Helena Schmidt, Stefan Herms, Sharon L.R. Kardia, Oliver Stegle, Alison Pattie, Jenna Price, Gerardo Heiss, Karen A. Mather, L. J. Launer, Johan G. Eriksson, Christopher Oldmeadow, Ian Ford, Saira Saeed Mirza, Alan F. Wright, Ozren Polasek, Joshua M. Shulman, Maria K. Jonsdottir, André G. Uitterlinden, Rodney J. Scott, Kurt Lohman, Anita L. DeStefano, Peter W. Schofield, Perminder S. Sachdev, Stefania Bandinelli, Johan Wouter Jukema, John M. Starr, Rudolf S N Fehrmann, Y. C. Hsieh, William M. Meeks, Paul M. Ridker, R.G.J. Westendorp, Le Yu, J. C. van Swieten, Vilmundur Gudnason, Myriam Fornage, Melissa Garcia, Carla A. Ibrahim-Verbaas, James F. Wilson, Jean-Charles Lambert, Qiong Yang, Laura H. Coker, Stella Trompet, Lina Zgaga, Jennifer A. Smith, David J. Llewellyn, Nicole A. Kochan, Ben A. Oostra, Katja Petrovic, Peter Hoffmann, Qi Sun, James T. Becker, Najaf Amin, Vincent Chouraki, Brendan M. Buckley, D C Liewald, Jun Ding, Christiane Wolf, P. L. DeJager, Reinhold Schmidt, Chloe Fawns-Ritchie, Stéphanie Debette, Jing Wang, J. C. Bis, Nicola J. Armstrong, David J. Stott, Albert Hofman, Nazanin Karbalai, G. Eiriksdottir, Luke C. Pilling, D. S. Knopman, Maaike Schuur, Alexa S. Beiser, Annette L. Fitzpatrick, David A. Bennett, Aarno Palotie, Lude Franke, Sven Cichon, Mirna Kirin, Markus M. Nöthen, Thomas H. Mosley, Lynda M. Rose, Alan J. Gow, Caroline Hayward, Lori B. Chibnik, Ian J. Deary, Albert V. Smith, Jan Bressler, T.B. Harris, Stephen T. Turner, David J. Porteous, C M van Duijn, M. A. Ikram, Elizabeth G. Holliday, Mike A. Nalls, Luigi Ferrucci, Sudha Seshadri, Francine Grodstein, Marlene C. W. Stewart, Philip A. Wolf, Alexander Teumer, P.E. Slagboom, Jerome I. Rotter, Blair H. Smith, Juha Karjalainen, Susan M. Resnick, A.J.M. de Craen, Toshiko Tanaka, Alan D. Penman, Hans-Jörgen Grabe, Gary Davies, Oscar L. Lopez, Yongmei Liu, Kristine Yaffe, Veronique Vitart, Stela McLachlan, Katri Räikkönen, Rebecca F. Gottesman, Rhoda Au, Lynne J. Hocking, Carsten Oliver Schmidt, John Attia, Bruce M. Psaty, Wei Zhao, Jari Lahti, Epidemiology, Neurology, Clinical Genetics, Internal Medicine, [ 1 ] Erasmus Univ, Med Ctr, Dept Epidemiol, Genet Epidemiol Unit, Rotterdam, Netherlands [ 2 ] Erasmus Univ, Med Ctr, Dept Neurol, Rotterdam, Netherlands [ 3 ] Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Human Genet Ctr, Houston, TX 77030 USA [ 4 ] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA [ 5 ] Univ Bordeaux, Epidemiol & Biostat, U897, INSERM, Bordeaux, France [ 6 ] Bordeaux Univ Hosp, Dept Neurol, Bordeaux, France [ 7 ] Iceland Heart Assoc, Kopavogur, Iceland [ 8 ] Univ Iceland, Fac Med, Reykjavik, Iceland [ 9 ] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA [ 10 ] Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh, Midlothian, Scotland [ 11 ] Leiden Univ, Med Ctr, Dept Cardiol, Leiden, Netherlands [ 12 ] Leiden Univ, Med Ctr, Dept Gerontol & Geriatr, Leiden, Netherlands [ 13 ] Univ Michigan, Dept Epidemiol, Ann Arbor, MI 48109 USA [ 14 ] Max Planck Inst Psychiat, RG Stat Genet, Munich, Germany [ 15 ] Brigham & Womens Hosp, Div Neurol, Program Translat Neuropsychiat Gen, Boston, MA 02115 USA [ 16 ] Wake Forest Sch Med, Dept Epidemiol, Winston Salem, NC USA [ 17 ] Univ Edinburgh, Inst Genet & Mol Med, MRC Human Genet Unit, Edinburgh, Midlothian, Scotland [ 18 ] Univ Edinburgh, Ctr Populat Hlth Sci, Edinburgh, Midlothian, Scotland [ 19 ] Med Univ & Gen Hosp Graz, Dept Neurol, Graz, Austria [ 20 ] Univ Split, Dept Publ Hlth, Split, Croatia [ 21 ] Trintiy Coll Dublin, Dept Publ Hlth & Primary Care, Dublin, Ireland [ 22 ] Res Ctr Juelich, Inst Neurosci & Med INM1, Julich, Germany [ 23 ] Univ Basel, Dept Biomed, Div Med Genet, Basel, Switzerland [ 24 ] Univ Bonn, Inst Human Genet, Life & Brain Res Ctr, Dept Genom, Bonn, Germany [ 25 ] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands [ 26 ] Univ Helsinki, Inst Behav Sci, Helsinki, Finland [ 27 ] Folkhalsan Res Ctr, Helsinki, Finland [ 28 ] Univ Exeter, Sch Med, Inst Biomed & Clin Sci, Exeter, Devon, England [ 29 ] Univ Med Greifswald, Inst Community Med, Greifswald, Germany [ 30 ] Univ New S Wales, UNSW Med, Sch Psychiat, Ctr Hlth Brain Ageing, Sydney, NSW, Australia [ 31 ] Univ Lille Nord France, Inst Pasteur Lille, U1167, INSERM, Lille, France [ 32 ] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA [ 33 ] Harvard Univ, Sch Med, Boston, MA USA [ 34 ] NIA, Lab Behav Neurosci, NIH, Baltimore, MD 21224 USA [ 35 ] Brigham & Womens Hosp, Div Prevent Med, 75 Francis St, Boston, MA 02115 USA [ 36 ] Univ Newcastle, Hunter Med Res Inst, Newcastle, NSW 2300, Australia [ 37 ] Univ Newcastle, Fac Hlth, Newcastle, NSW 2300, Australia [ 38 ] Univ Dundee, Med Res Inst, Dundee, Scotland [ 39 ] NHLBI, Framingham Heart Study, Framingham, MA USA [ 40 ] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA [ 41 ] Erasmus Univ, Med Ctr, Dept Epidemiol, Rotterdam, Netherlands [ 42 ] Netherlands Consortium Hlth Ageing, Leiden, Netherlands [ 43 ] NIA, Lab Epidemiol & Populat Sci, Bethesda, MD 20892 USA [ 44 ] Univ Edinburgh, Dept Psychol, Edinburgh, Midlothian, Scotland [ 45 ] Wake Forest Sch Med, Div Publ Hlth Sci & Neurol, Winston Salem, NC USA [ 46 ] Max Planck Inst Intelligent Syst, Max Planck Inst Dev Biol, Tubingen, Germany [ 47 ] Univ Pittsburgh, Dept Neurol, Pittsburgh, PA 15260 USA [ 48 ] Univ Med Greifswald, Interfaculty Inst Genet & Funct Genom, Greifswald, Germany [ 49 ] Univ Glasgow, Robertson Ctr Biostat, Glasgow, Lanark, Scotland [ 50 ] Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA USA [ 51 ] Univ Pittsburgh, Dept Psychol, Pittsburgh, PA 15260 USA [ 52 ] Landspitali Hosp, Reykjavik, Iceland Organization-Enhanced Name(s) Landspitali National University Hospital [ 53 ] NIA, Lab Neurogenet, Bethesda, MD 20892 USA [ 54 ] Mayo Clin, Dept Internal Med, Div Nephrol & Hypertens, Rochester, MN USA [ 55 ] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA [ 56 ] Univ Calif San Francisco, Dept Neurol, San Francisco, CA USA [ 57 ] Univ Calif San Francisco, Dept Epidemiol, San Francisco, CA USA [ 58 ] San Francisco VA Med Ctr, San Francisco, CA USA [ 59 ] Mayo Clin, Dept Neurol, Rochester, MN USA [ 60 ] Univ Mississippi, Med Ctr, Dept Med, Div Geriatr, Jackson, MS 39216 USA [ 61 ] Univ N Carolina, Dept Epidemiol, Gillings Sch Global Publ Hlth, Chapel Hill, NC USA [ 62 ] Univ Newcastle, Fac Hlth, Sch Med & Publ Hlth, Newcastle, NSW 2300, Australia [ 63 ] NIA, Translat Gerontol Branch, Baltimore, MD 21224 USA [ 64 ] Univ Glasgow, Dept Cardiovasc & Med Sci, Glasgow, Lanark, Scotland [ 65 ] Alzheimer Scotland Res Ctr, Edinburgh, Midlothian, Scotland [ 66 ] Univ Aberdeen, Div Appl Med, Aberdeen, Scotland [ 67 ] Garvan Inst Med Res, Canc Res Program, Sydney, NSW, Australia [ 68 ] Univ New S Wales, Sch Math & Stat, Sydney, NSW, Australia [ 69 ] Univ New S Wales, Prince Wales Clin Sch, Sydney, NSW, Australia [ 70 ] Baylor Coll Med, Dept Neurol, Houston, TX 77030 USA [ 71 ] Texas Childrens Hosp, Jan & Dan Duncan Neurol Res Inst, Dept Mol & Human Genet, Houston, TX 77030 USA [ 72 ] Univ Exeter, Sch Med, Epidemiol & Publ Hlth Grp, Exeter, Devon, England [ 73 ] Prince Wales Hosp, Neuropsychiat Inst, Sydney, NSW, Australia [ 74 ] Wellcome Trust Sanger Inst, Wellcome Trust Genome Campus, Cambridge, England [ 75 ] Univ Helsinki, Inst Mol Med Finland FIMM, Helsinki, Finland [ 76 ] Univ Helsinki, Dept Med Genet, Helsinki, Finland [ 77 ] Univ Cent Hosp, Helsinki, Finland [ 78 ] Taipei Med Univ, Sch Publ Hlth, Taipei, Taiwan [ 79 ] Univ Helsinki, Dept Gen Practice & Primary Hlth Care, Helsinki, Finland [ 80 ] Natl Inst Hlth & Welf, Helsinki, Finland [ 81 ] Univ Helsinki, Cent Hosp, Unit Gen Practice, Helsinki, Finland [ 82 ] Vasa Cent Hosp, Vaasa, Finland [ 83 ] Univ Mississippi, Med Ctr, Ctr Biostat & Bioinformat, Jackson, MS 39216 USA [ 84 ] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA [ 85 ] Rush Univ, Med Ctr, Rush Alzheimers Dis Ctr, Chicago, IL 60612 USA [ 86 ] Cedars Sinai Med Ctr, Med Genet Inst, Los Angeles, CA 90048 USA [ 87 ] Harbor UCLA Med Ctr, Angeles BioMed Res Inst, Inst Translat Genom & Populat Sci, Torrance, CA 90509 USA [ 88 ] Harbor UCLA Med Ctr, Dept Pediat, Div Genet Outcomes, Torrance, CA 90509 USA [ 89 ] German Ctr Neurodegenerat Dis DZNE, Bonn, Germany [ 90 ] Leiden Univ, Med Ctr, Dept Mol Epidemiol, Leiden, Netherlands [ 91 ] Leiden Acad Vital & Ageing, Leiden, Netherlands [ 92 ] Univ Coll Cork, Dept Pharmacol & Therapeut, Cork, Ireland [ 93 ] Erasmus Univ, Med Ctr, Dept Internal Med, Rotterdam, Netherlands [ 94 ] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA [ 95 ] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA [ 96 ] Grp Hlth, Grp Hlth Res Inst, Seattle, WA USA [ 97 ] HELIOS Hosp Stralsund, Univ Med Greifswald, Dept Psychiat & Psychotherapy, Stralsund, Germany [ 98 ] Azienda Sanitaria Firenze, Geriatr Unit, Florence, Italy [ 99 ] Univ Edinburgh, Inst Genet & Mol Med, Ctr Genom & Expt Med, Edinburgh, Midlothian, Scotland [ 100 ] Wake Forest Univ, Bowman Gray Sch Med, Dept Internal Med, Winston Salem, NC 27103 USA [ 101 ] Univ Texas Hlth Sci Ctr Houston, Inst Mol Med, Houston, TX 77030 USA [ 102 ] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX 77030 USA [ 103 ] Erasmus Univ, Med Ctr, Dept Radiol, Rotterdam, Netherlands [ 104 ] Univ Mississippi, Med Ctr, Dept Med & Neurol, Jackson, MS 39216 USA, Human genetics, Amsterdam Neuroscience - Neurodegeneration, Damage and Repair in Cancer Development and Cancer Treatment (DARE), Guided Treatment in Optimal Selected Cancer Patients (GUTS), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), and Stem Cell Aging Leukemia and Lymphoma (SALL)

Subjects
0301 basic medicine, Male, DISORDER, Trail Making Test, LOCI, Genome-wide association study, INTELLIGENCE, Neuropsychological Tests, Cohort Studies, Exon, Executive Function, 0302 clinical medicine, Cognition, SCHIZOPHRENIA, ONSET ALZHEIMERS-DISEASE, CADM2 protein, human, genetics [Cell Adhesion Molecules], gamma-Aminobutyric Acid, Genetics, Aged, 80 and over, PSC12, physiology [Cognition], COMMON VARIANTS, Genomics, Middle Aged, genetics [Genetic Variation], 3. Good health, physiology [Executive Function], Psychiatry and Mental health, genetics [European Continental Ancestry Group], Schizophrenia, Female, Psychology, EXPRESSION, genetics [White People], physiology [Cell Adhesion Molecules], Polymorphism, Single Nucleotide, White People, Article, 03 medical and health sciences, Cellular and Molecular Neuroscience, Genetic variation, medicine, SNP, Humans, ddc:610, GENOME-WIDE ASSOCIATION, Molecular Biology, Gene, Genetic Association Studies, Aged, LINKAGE ANALYSIS, 9. Industry and infrastructure, Genetic Variation, medicine.disease, COGNITIVE FUNCTION, Introns, 030104 developmental biology, Cell Adhesion Molecules, 030217 neurology & neurosurgery, Stroop effect, Genome-Wide Association Study
Abstract

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files. This article is open access. To identify common variants contributing to normal variation in two specific domains of cognitive functioning, we conducted a genome-wide association study (GWAS) of executive functioning and information processing speed in non-demented older adults from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) consortium. Neuropsychological testing was available for 5429-32 070 subjects of European ancestry aged 45 years or older, free of dementia and clinical stroke at the time of cognitive testing from 20 cohorts in the discovery phase. We analyzed performance on the Trail Making Test parts A and B, the Letter Digit Substitution Test (LDST), the Digit Symbol Substitution Task (DSST), semantic and phonemic fluency tests, and the Stroop Color and Word Test. Replication was sought in 1311-21860 subjects from 20 independent cohorts. A significant association was observed in the discovery cohorts for the single-nucleotide polymorphism (SNP) rs17518584 (discovery P-value=3.12 × 10(-8)) and in the joint discovery and replication meta-analysis (P-value=3.28 × 10(-9) after adjustment for age, gender and education) in an intron of the gene cell adhesion molecule 2 (CADM2) for performance on the LDST/DSST. Rs17518584 is located about 170 kb upstream of the transcription start site of the major transcript for the CADM2 gene, but is within an intron of a variant transcript that includes an alternative first exon. The variant is associated with expression of CADM2 in the cingulate cortex (P-value=4 × 10(-4)). The protein encoded by CADM2 is involved in glutamate signaling (P-value=7.22 × 10(-15)), gamma-aminobutyric acid (GABA) transport (P-value=1.36 × 10(-11)) and neuron cell-cell adhesion (P-value=1.48 × 10(-13)). Our findings suggest that genetic variation in the CADM2 gene is associated with individual differences in information processing speed. National Foundation for Alzheimer's disease and related disorders Institut Pasteur de Lille Centre National de Genotypage Inserm FRC (fondation pour la recherche sur le cerveau) Rotary LABEX (laboratory of excellence program investment for the future) DISTALZ grant (Development of Innovative Strategies for a Transdisciplinary approach to ALZheimer's disease) MEDIALZ Project - ERDF (European Regional Development Fund) 11001003 Conseil Regional Nord Pas de Calais Fondation pour la Recherche Medicale Caisse Nationale Maladie des Travailleurs Salaries Direction Generale de la Sante MGEN Institut de la Longevite Agence Francaise de Securite Sanitaire des Produits de Sante Aquitaine and Bourgogne Regional Councils Fondation de France joint French Ministry of Research/INSERM 'Cohortes et collections de donnees biologiques' program Eisai Wellcome Trust British Heart Foundation Chief Scientist Office of the Scottish Executive NIA N01-AG-12100 National Heart, Lung and Blood Institute Contracts HHSN268201100005C HHSN268201100006C HHSN268201100007C HHSN268201100008C HHSN268201100009C HHSN268201100010C HHSN268201100011C HHSN268201100012C R01HL70825 R01HL087641 R01HL59367 R01HL086694 National Human Genome Research Institute U01HG004402 NIH Roadmap for Medical Research Austrian Science Fond (FWF) P20545-P05 P13180 Intramural Research Program of the NIH, National Institute on Aging NHLBI HHSN268201200036C HHSN268200800007C N01HC55222 N01HC85079 N01HC85080 N01HC85081 N01HC85082 N01HC85083 N01HC850863 U01HL080295 R01HL087652 R01HL105756 R01HL103612 R01HL120393 National Institute of Neurological Disorders and Stroke (NINDS) National Institute on Aging (NIA) R01AG023629 R01AG15928 R01AG20098 R01AG027058 National Center for Advancing Translational Sciences CTSI UL1TR000124 National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) DK063491 Medical Research Council (UK) European Commission Framework 6 project EUROSPAN LSHG-CT-2006-018947 Republic of Croatia Ministry of Science, Education and Sports 108-1080315-0302 Netherlands Organization for Scientific Research (NWO) Internationale Stichting Alzheimer Onderzoek (ISAO) Hersenstichting Nederland (HSN) Centre for Medical Systems Biology (CMSB) in the framework of the Netherlands Genomics Initiative (NGI) Russian Foundation for Basic Research (RFBR) National Heart, Lung and Blood Institute's Framingham Heart Study N01-HC-25195 Affymetrix, Inc N02-HL-6-4278 U01 HL096917 R01 HL093029 Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine Boston Medical Center National Institute of Neurological Disorders and Stroke NS17950 National Institute of Aging U01 AG049505 AG033193 AG008122 AG16495 Agence National de la Recherche Leducq Foundation National Heart, Lung and Blood Institute HL054464 HL054457 HL054481 HL071917 HL87660 HL043851 HL080467 National Institute of Neurological Disorders and Stroke of the National Institutes of Health NS041558 Chief Scientist Office of the Scottish Government Health Directorates CZD/16/6 Scottish Funding Council HR03006 Academy of Finland Finnish Diabetes Research Society Folkhalsan Research Foundation Novo Nordisk Foundation Finska Lakaresallskapet Signe and Ane Gyllenberg Foundation University of Helsinki Ministry of Education Ahokas Foundation Emil Aaltonen Foundation Juho Vainio Foundation Wellcome Trust WT089062 University of Newcastle's Strategic Initiative Fund Vincent Fairfax Family Foundation Hunter Medical Research Institute Italian Ministry of Health ICS 110.1RS97.71 US National Institute on Aging N01[AG]916413 N01[AG]821336 263 MD 9164 13 263 MD 821336 Intramural Research Program, National Institute on Aging, National Institutes of Health BBSRC Royal Society Chief Scientist Office of the Scottish Government Research Into Ageing UK Biotechnology and Biological Sciences Research Council (BBSRC) Engineering and Physical Sciences Research Council (EPSRC) Economic and Social Research Council (ESRC) MRC NHMRC 401184 Australian National Health & Medical Research Council 350833 568969 Capacity Building Grant 568940 NHMRC Project 525453 National Institutes of Health CA87969 CA49449 HL34594 U01HG004399 DK058845 CA65725 CA67262 CA50385 5UO1CA098233 EY09611 EY015473 HG004728 HL35464 CA55075 CA134958 DK070756 MRC Human Genetics Unit Arthritis Research UK European Union LSHG-CT-2006-018947 Bristol-Myers Squibb Netherlands Heart Foundation 2001 D 032 European commission 223004 Netherlands Genomics Initiative (Netherlands Consortium for Healthy Aging) 050-060-810 Netherlands Organisation of Scientific Research NWO Investments 175.010.2005.011 911-03-012 Research Institute for Diseases in the Elderly 014-93-015 Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) project 050-060-810 Erasmus Medical Center Erasmus University, Rotterdam Netherlands Organization for the Health Research and Development (ZonMw) Research Institute for Diseases in the Elderly (RIDE) Ministry of Education, Culture and Science Ministry for Health, Welfare and Sports European Commission 49 (DG XII) Municipality of Rotterdam ZonMW Veni Grant 916.13.054 NIA Grants P30AG10161 R01AG15819 R01AG17917 R01AG30146 K08AG34290 K25AG41906 Federal Ministry of Education and Research 01ZZ9603 01ZZ0103 01ZZ0403 Ministry of Cultural Affairs Social Ministry of the Federal State of Mecklenburg-West Pomerania National Cancer Institute CA047988 Donald W Reynolds Foundation Fondation Leducq Amgen info:eu-repo/grantAgreement/EC/FP7/223004

Published
2016
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9. GWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes

Author

Tina Shah, E. C. M. van Leeuwen, Jingjing Liang, Susan M. Ring, Alexander Teumer, P Anugu, Salman M. Tajuddin, Aaron Isaacs, Jorgen Engmann, Marcus Dörr, Kenneth Rice, Anne B. Newman, Sonia Shah, Lenore J. Launer, Diana Kuh, Panos Roussos, P. De Vries, Bo Hedblad, Xiaofeng Zhu, Walter Palmas, John E. Deanfield, Debbie A Lawlor, Ganesh Chauhan, Dennis O. Mook-Kanamori, André G. Uitterlinden, Sudha Seshadri, Ilja M. Nolte, Elmo Mannarino, Daniel H. O'Leary, Susan R. Heckbert, Bogdan Pasaniuc, Solomon K. Musani, Rebecca Hardy, Rainer Malik, Lesca M. Holdt, Lars Lind, Reinhold Schmidt, R. de Mutsert, Aroon D. Hingorani, Riccardo E. Marioni, P. Amouyel, Albert V. Smith, Janne Pott, Eric E. Schadt, Lyytikäinen L-P., Raymond Noordam, Stéphanie Debette, Oscar H. Franco, Vincent Plagnol, Gerardo Heiss, Brenda W.J.H. Penninx, SG Wannamethee, Carl D. Langefeld, Stella Trompet, C.M. van Duijn, Tessel E. Galesloot, Peter K. Joshi, Maryam Kavousi, Juan P. Casas, Joanna M. Wardlaw, P. Giral, Julian Halcox, Björkegren Jlm., U de Faire, Andries J. Smit, Christina L. Wassel, Christopher J. O'Donnell, Matthew Traylor, Uwe Völker, Mika Kivimäki, Jenna Price, Quenna Wong, Chris Finan, Wayne D. Rosamond, Markus Loeffler, Harry Campbell, L Lu, Jerome I. Rotter, Joop Jukema, Karl Gertow, Edith Hofer, Hugh S. Markus, Albert Hofman, Peter H. Whincup, James G. Wilson, Michelle K. Evans, Enzo Grossi, Matthias Sitzer, Martin Dichgans, Oscar L. Rueda-Ochoa, J. C. Bis, Klodian Dhana, Ralph Burkhardt, Harold Snieder, Kiemeney Lalm., Daniel Teupser, A C Morrison, Markus Scholz, Ulf Schminke, Richard W Morris, Meena Kumari, Caroline Dale, Helena Schmidt, Sara Hägg, Niina Pitkänen, Fabrizio Veglia, Donald W. Bowden, Olli T. Raitakari, Joachim Thiery, Anders Hamsten, Muralidharan Sargurupremraj, Hwang S-J., Elena Tremoli, Stela McLachlan, Amanda J. Cox, Kent D. Taylor, Frank Beutner, Henry Völzke, Terho Lehtimäki, Abbas Dehghan, Ruth C. Lovering, Rachael P. Huntley, Mike A. Nalls, Jemma C. Hopewell, Erik Ingelsson, Claudia Giambartolomei, Bruce M. Psaty, Annie Britton, A Seldenrijk, Bengt Sennblad, Olle Melander, J. de Graaf, Adolfo Correa, Fernando Rivadeneira, Oscar Franzén, Laura M. Raffield, Alan B. Zonderman, Rona J. Strawbridge, Thomas W. Winkler, Ian J. Deary, Misa Graff, Wendy S. Post, Andrew Wong, T.B. Harris, Yasaman Saba, Arno Ruusalepp, James F. Wilson, Vilmundur Gudnason, Eric Boerwinkle, Damiano Baldassarre, Cristiano Fava, S.E. Humphries, Sudhir Kurl, Rainer Rauramaa, Christophe Tzourio, Xuejiang Guo, Nora Franceschini, Xiaoling Zhang, Biochemie, RS: FHML MaCSBio, RS: CARIM - R1.06 - Genetic Epidemiology and Genomics of cardiovascular diseases, RS: CARIM - R1.01 - Blood proteins & engineering, Life Course Epidemiology (LCE), Groningen Kidney Center (GKC), Vascular Ageing Programme (VAP), Faculty of Medicine (UI), Læknadeild (HÍ), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), Háskóli Íslands, University of Iceland, Giambartolomei, Claudia [0000-0003-2786-1225], Huntley, Rachael P [0000-0001-6718-3559], Lovering, Ruth C [0000-0002-9791-0064], Tajuddin, Salman M [0000-0002-7919-8528], Winkler, Thomas W [0000-0003-0292-5421], Nolte, Ilja M [0000-0001-5047-4077], Scholz, Markus [0000-0002-4059-1779], Joshi, Peter K [0000-0002-6361-5059], Isaacs, Aaron [0000-0001-5037-4834], Correa, Adolfo [0000-0002-9501-600X], Teumer, Alexander [0000-0002-8309-094X], Wong, Andrew [0000-0003-2079-4779], Newman, Anne B [0000-0002-0106-1150], Sennblad, Bengt [0000-0002-4360-8003], Baldassarre, Damiano [0000-0002-2766-8882], Kuh, Diana [0000-0001-7386-2857], Schadt, Eric E [0000-0002-7892-8808], Rivadeneira, Fernando [0000-0001-9435-9441], Jukema, J Wouter [0000-0002-3246-8359], Rice, Kenneth [0000-0002-3071-7278], Dhana, Klodian [0000-0002-6397-7009], Dichgans, Martin [0000-0002-0654-387X], Traylor, Matthew [0000-0001-6624-8621], Kivimaki, Mika [0000-0002-4699-5627], Roussos, Panos [0000-0002-4640-6239], Amouyel, Philippe [0000-0001-9088-234X], Burkhardt, Ralph [0000-0003-1924-1202], Morris, Richard W [0000-0001-7240-4563], Hägg, Sara [0000-0002-2452-1500], Lawlor, Deborah A [0000-0002-6793-2262], Wilson, James F [0000-0001-5751-9178], Wardlaw, Joanna M [0000-0002-9812-6642], Lyytikäinen, Leo-Pekka [0000-0002-7200-5455], Gudnason, Vilmundur [0000-0001-5696-0084], Apollo - University of Cambridge Repository, Psychiatry, APH - Mental Health, APH - Digital Health, Epidemiology, Internal Medicine, and Experimental Immunology

Subjects
0301 basic medicine, Candidate gene, Vascular damage Radboud Institute for Health Sciences [Radboudumc 16], General Physics and Astronomy, Genome-wide association study, Coronary Disease, VARIANTS, Carotid Intima-Media Thickness, Coronary artery disease, Protein-Lysine 6-Oxidase, Risk Factors, Medicine, genetics, Cardiac and Cardiovascular Systems, Blóðrásarsjúkdómar, lcsh:Science, GENE-PRODUCT, cardiovascular genetics, Multidisciplinary, Kardiologi, Plaque, Atherosclerotic, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], Cardiology, cardiovascular system, Medical genetics, CORONARY-ARTERY-DISEASE, HEART, Amino Acid Oxidoreductases, Erfðarannsóknir, Medical Genetics, medicine.medical_specialty, MEGASTROKE Consortium, Science, Quantitative Trait Loci, ADAMTS9 Protein, INTEGRATIVE ANALYSIS, Locus (genetics), 610 Medicine & health, Quantitative trait locus, Polymorphism, Single Nucleotide, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, All institutes and research themes of the Radboud University Medical Center, 360 Social problems & social services, Internal medicine, MD Multidisciplinary, Humans, Erfðafræði, intima media thickness, Genetic Predisposition to Disease, cardiovascular diseases, GENOME-WIDE ASSOCIATION, METAANALYSIS, Genetic association, Medicinsk genetik, business.industry, General Chemistry, medicine.disease, 030104 developmental biology, Intima-media thickness, genome-wide association studies, quantitative trait loci, lcsh:Q, atherosclerosis, Lod Score, hjarta, business, Genome-Wide Association Study
Abstract

Publisher's version (útgefin grein), Carotid artery intima media thickness (cIMT) and carotid plaque are measures of subclinical atherosclerosis associated with ischemic stroke and coronary heart disease (CHD). Here, we undertake meta-analyses of genome-wide association studies (GWAS) in 71,128 individuals for cIMT, and 48,434 individuals for carotid plaque traits. We identify eight novel susceptibility loci for cIMT, one independent association at the previously-identified PINX1 locus, and one novel locus for carotid plaque. Colocalization analysis with nearby vascular expression quantitative loci (cis-eQTLs) derived from arterial wall and metabolic tissues obtained from patients with CHD identifies candidate genes at two potentially additional loci, ADAMTS9 and LOXL4. LD score regression reveals significant genetic correlations between cIMT and plaque traits, and both cIMT and plaque with CHD, any stroke subtype and ischemic stroke. Our study provides insights into genes and tissue-specific regulatory mechanisms linking atherosclerosis both to its functional genomic origins and its clinical consequences in humans., The work was supported by the following grants: National Institute of Health grants: R21HL123677, R21-HL140385, DK104806-01A1, R01-MD012765-01A1 (NF), National Institutes of Health awards R01HG009120, R01HG006399, U01CA194393, T32NS048004 (CG), the American Heart Association Grant #17POST33350042 (PV), the British Heart Foundation (RG/13/5/30112) and the National Institute for Health Research University College London Hospitals Biomedical Research Centre (RCL and RPH), the British Heart Foundation FS/14/55/30806 (JCH), the German Federal Ministry of Education and Research (BMBF) in the context of the e:Med program (e:AtheroSysMed), the DFG as part of the CRC 1123 (B3), and the FP7/2007-2103 European Union project CVgenes@target (grant agreement number Health-F2-2013-601456). We thank Li-Ming Gan for assistance with the STARNET study and Jon White for assistance with UCLEB analyses. Additional acknowledgements are included in Supplementary Note 2.

Published
2018
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10. PR interval genome-wide association meta-analysis identifies 50 loci associated with atrial and atrioventricular electrical activity

Author

Bruno H. Stricker, Antonietta Robino, Gandin Ilaria, Marylyn D. Ritchie, Mark Eijgelsheim, Hilma Holm, Marcus Dörr, Philipp S. Wild, Jessica van Setten, Stephan B. Felix, Maristella Steri, Jared W. Magnani, Brendan M. Buckley, Peter P. Pramstaller, Claudia T. Silva Aldana, Niek Verweij, Tim D. Spector, Ruth J. F. Loos, Dan M. Roden, Martina Müller-Nurasyid, Mina K. Chung, Sandosh Padmanabhan, Stefania Bandinelli, Harm-Jan Westra, James F. Wilson, Honghuang Lin, Braxton D. Mitchell, Patrick T. Ellinor, Patricia B. Munroe, Harold Snieder, Thomas Münzel, Sheila Ulivi, Andrew A. Hicks, Nona Sotoodehnia, Daniel S. Evans, Annamaria Iorio, Peter W. Macfarlane, Vilmundur Gudnason, Christy L. Avery, Caroline Hayward, Cornelia M. van Duijn, John Barnard, Alvaro Alonso, Dana C. Crawford, Uwe Völker, David R. Van Wagoner, Tamara B. Harris, Harry Campbell, Ozren Polasek, Daniel F. Gudbjartsson, Ilja M. Nolte, Bouwe P. Krijthe, Eric Boerwinkle, Moritz F. Sinner, Elsayed Z. Soliman, Mika Kähönen, Christian Müller, Renate B. Schnabel, Unnur Thorsteinsdottir, Leo-Pekka Lyytikäinen, George J. Papanicolaou, Ivana Kolcic, Stella Trompet, Jerome I. Rotter, Dan E. Arking, Kirill V. Tarasov, Igor Rudan, Bruce M. Psaty, Gianfranco Sinagra, Alexander Teumer, Yalda Jamshidi, David O. Arnar, Toshiko Tanaka, Melanie Waldenberger, Henry J. Lin, Luigi Ferrucci, Susan R. Heckbert, Jan A. Kors, Irene Mateo Leach, Joel S. Bader, Konstantin Strauch, Albert V. Smith, Paul I.W. de Bakker, Stefan Blankenberg, J. C. Bis, Edward G. Lakatta, Lenore J. Launer, Thomas Meitinger, Anna F. Dominiczak, Marcel den Hoed, Steven A. Lubitz, Stefan Kääb, David J. Stott, Francesco Cucca, Olli T. Raitakari, Afshin Parsa, Nilesh J. Samani, Josh C. Denny, Lude Franke, Oscar H. Franco, Yongmei Liu, Folkert W. Asselbergs, Henry Völzke, Terho Lehtimäki, Arne Pfeufer, Annette Peters, David Schlessinger, Xiaoyan Yin, Jennifer A. Brody, J. Wouter Jukema, Paolo Gasparini, Tanja Zeller, Aaron Isaacs, Anne M. Butler, Sina A. Gharib, Kathleen F. Kerr, Jonathan D. Smith, Pim van der Harst, André G. Uitterlinden, Quince Gibson, Yuki Bradford, Brenton R. Swenson, Emelia J. Benjamin, Georg Ehret, Kari Stefansson, Fabiola M. Del Greco, Biochemie, RS: CARIM - R1.01 - Blood proteins & engineering, RS: CARIM - R1.06 - Genetic Epidemiology and Genomics of cardiovascular diseases, RS: FHML MaCSBio, van Setten, Jessica, Brody, Jennifer A, Jamshidi, Yalda, Swenson, Brenton R, Butler, Anne M, Campbell, Harry, Del Greco, Fabiola M, Evans, Daniel S, Gibson, Quince, Gudbjartsson, Daniel F, Kerr, Kathleen F, Krijthe, Bouwe P, Lyytikäinen, Leo-Pekka, Müller, Christian, Müller-Nurasyid, Martina, Nolte, Ilja M, Padmanabhan, Sandosh, Ritchie, Marylyn D, Robino, Antonietta, Smith, Albert V, Steri, Maristella, Tanaka, Toshiko, Teumer, Alexander, Trompet, Stella, Ulivi, Sheila, Verweij, Niek, Yin, Xiaoyan, Arnar, David O, Asselbergs, Folkert W, Bader, Joel S, Barnard, John, Bis, Josh, Blankenberg, Stefan, Boerwinkle, Eric, Bradford, Yuki, Buckley, Brendan M, Chung, Mina K, Crawford, Dana, den Hoed, Marcel, Denny, Josh C, Dominiczak, Anna F, Ehret, Georg B, Eijgelsheim, Mark, Ellinor, Patrick T, Felix, Stephan B, Franco, Oscar H, Franke, Lude, Harris, Tamara B, Holm, Hilma, Gandin, Ilaria, Iorio, Annamaria, Kähönen, Mika, Kolcic, Ivana, Kors, Jan A, Lakatta, Edward G, Launer, Lenore J, Lin, Honghuang, Lin, Henry J, Loos, Ruth J F, Lubitz, Steven A, Macfarlane, Peter W, Magnani, Jared W, Leach, Irene Mateo, Meitinger, Thoma, Mitchell, Braxton D, Munzel, Thoma, Papanicolaou, George J, Peters, Annette, Pfeufer, Arne, Pramstaller, Peter P, Raitakari, Olli T, Rotter, Jerome I, Rudan, Igor, Samani, Nilesh J, Schlessinger, David, Silva Aldana, Claudia T, Sinner, Moritz F, Smith, Jonathan D, Snieder, Harold, Soliman, Elsayed Z, Spector, Timothy D, Stott, David J, Strauch, Konstantin, Tarasov, Kirill V, Thorsteinsdottir, Unnur, Uitterlinden, Andre G, Van Wagoner, David R, Völker, Uwe, Völzke, Henry, Waldenberger, Melanie, Jan Westra, Harm, Wild, Philipp S, Zeller, Tanja, Alonso, Alvaro, Avery, Christy L, Bandinelli, Stefania, Benjamin, Emelia J, Cucca, Francesco, Dörr, Marcu, Ferrucci, Luigi, Gasparini, Paolo, Gudnason, Vilmundur, Hayward, Caroline, Heckbert, Susan R, Hicks, Andrew A, Jukema, J Wouter, Kääb, Stefan, Lehtimäki, Terho, Liu, Yongmei, Munroe, Patricia B, Parsa, Afshin, Polasek, Ozren, Psaty, Bruce M, Roden, Dan M, Schnabel, Renate B, Sinagra, Gianfranco, Stefansson, Kari, Stricker, Bruno H, van der Harst, Pim, van Duijn, Cornelia M, Wilson, James F, Gharib, Sina A, de Bakker, Paul I W, Isaacs, Aaron, Arking, Dan E, Sotoodehnia, Nona, Faculty of Medicine (UI), Læknadeild (HÍ), School of Engineering and Natural Sciences (UI), Verkfræði- og náttúruvísindasvið (HÍ), School of Health Sciences (UI), Heilbrigðisvísindasvið (HÍ), Háskóli Íslands (HÍ), University of Iceland (UI), Epidemiology, Medical Informatics, Internal Medicine, Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Cardiovascular Centre (CVC), and Stem Cell Aging Leukemia and Lymphoma (SALL)

Subjects
Male, QRS duration, Epidemiology, Genome-wide association study, Biochemistry, Linkage Disequilibrium, Electrocardiography, 0302 clinical medicine, Atrioventricular Conduction, lcsh:Science, COMMON VARIANTS, Heart Depolarization, Canal de iones, Cardiovascular system, Gene Locus, Blood, cardiovascular system, Qrs Interval, FIBRILLATION, Enfermedades cardiovasculares, Human, Missense Mutation, Heart block, Science, HEART-RATE, Single-nucleotide polymorphism, Missense/genetics, Physics and Astronomy(all), Factor de transcripción, European, General Biochemistry, Genetics and Molecular Biology, Article, PR interval genome, atrial electrical activity, atrioventricular electrical activity, 03 medical and health sciences, CARDIAC CONDUCTION, Cardiac conduction, Humans, Sistema cardiovascular, Common variants, Sangre, Cardiovascular genetics, medicine.disease, Heart-rate, Enfermedades, Electrophysiological Phenomena, 030104 developmental biology, Heart Block, Electric Activity, Mutation, lcsh:Q, Cell Junction, Cohorts, Meta-Analysis, 0301 basic medicine, Chemistry(all), Transcription Factor, General Physics and Astronomy, 030204 cardiovascular system & hematology, Fibrilación auricular, Electrophysiological Phenomena/genetics, RARE, Ion Channel, Heart Rate, Risk Factors, Atrial Fibrillation, EPIDEMIOLOGY, Bloqueo cardíaco, SNPS, Genetics, RISK, Multidisciplinary, Genome, Atrial fibrillation, Genetic Analysis, Atrioventricular Node/physiology, Atrial Function, Phenotype, Heart Disease, Rare, Atrioventricular Node, Female, medicine.symptom, QRS DURATION, Atrial Function/physiology, Medical Genetics, SNPs, Signal Transduction, Risk, Heart Diseases, Mutation, Missense, macromolecular substances, Biology, QRS complex, medicine, Disequilibrium, Linkage Disequilibrium/genetics, cardiovascular diseases, PR interval, Medicinsk genetik, Fibrillation, Biochemistry, Genetics and Molecular Biology(all), Risk Factor, African, General Chemistry, COHORTS, Pr Interval, Gene Linkage Disequilibrium, Genetics and Molecular Biology(all), Genome-Wide Association Study
Abstract

Publisher's version (útgefin grein). Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations., Electrocardiographic PR interval measures atrio-ventricular depolarization and conduction, and abnormal PR interval is a risk factor for atrial fibrillation and heart block. Our genome-wide association study of over 92,000 European-descent individuals identifies 44 PR interval loci (34 novel). Examination of these loci reveals known and previously not-yet-reported biological processes involved in cardiac atrial electrical activity. Genes in these loci are over-represented in cardiac disease processes including heart block and atrial fibrillation. Variants in over half of the 44 loci were associated with atrial or blood transcript expression levels, or were in high linkage disequilibrium with missense variants. Six additional loci were identified either by meta-analysis of ~105,000 African and European-descent individuals and/or by pleiotropic analyses combining PR interval with heart rate, QRS interval, and atrial fibrillation. These findings implicate developmental pathways, and identify transcription factors, ion-channel genes, and cell-junction/cell-signaling proteins in atrio-ventricular conduction, identifying potential targets for drug development., Acknowledgements per cohort are listed in Supplementary Note 2. We thank the following studies for sharing their summary level results: QRS voltage (van der Harst et al., 2016)[12], heart rate (den Hoed et al., 2013)[35], RR interval (Eijgelsheim et al., 2010)[11], atrial fibrillation (Christophersen et al., 2017[15]), and CARe-COGENT AA PR Consortium (Butler et al., 2012)[33]. We acknowledge Dr. Vinicius Tragante for his help generating the author list.

Published
2018
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11. Discovering patterns of pleiotropy in genome-wide association studies

Author

Harold Snieder, Moritz F. Sinner, Daniel F. Gudbjartsson, Niek Verweij, PM Pramstaller, B. D. Mitchell, Stephan B. Felix, Elsayed Z. Soliman, R. J. F. Loos, T.B. Harris, Mika Kähönen, Philipp S. Wild, Christy L. Avery, Kirill V. Tarasov, Stefania Bandinelli, Stefan Kääb, Tim D. Spector, Patrick T. Ellinor, David J. Stott, Renate B. Schnabel, Igor Rudan, O Polasekd, Brendan M. Buckley, Thomas Meitinger, James F. Wilson, Honghuang Lin, Gandin Ilaria, CM Duijn van, James P. Brody, L. J. Launer, Xiaoyan Yin, Ritchie, CT Aldana Silva, Paolo Gasparini, Dan M. Roden, Diane M. Crawford, Eric Boerwinkle, Davíð O. Arnar, Annette Peters, Caroline Hayward, Ilja M. Nolte, Terho Lehtimäki, Joop Jukema, Pi Bakker de, Thomas Münzel, Steven R. Cummings, Henry Völzke, Peter W. Macfarlane, John Barnard, Fabiola M Del Greco, Dan E. Arking, Anna F. Dominiczak, Patricia B. Munroe, Jonathan D. Smith, Anne M. Butler, Bruno H. Stricker, Stefan Blankenberg, Pv Harst der, S. Ulivi, Jerome I. Rotter, Hilma Holm, Alvaro Alonso, Haonan Lin, Gianfranco Sinagra, Alexander Teumer, Q Gibson, Bruce M. Psaty, Uwe Völker, Olli T. Raitakari, Annamaria Iorio, Bouwe P. Krijthe, Lude Franke, Folkert W. Asselbergs, Jared W. Magnani, G. Ehret, Susan R. Heckbert, L Ferrucci, Edward G. Lakatta, N. Sotoodehnia, Harry Campbell, Toshiko Tanaka, Wagoner van, JS Baderab, Yalda Jamshidi, Daniel S. Evans, David Schlessinger, Kari Stefansson, Nilesh J. Samani, Martina Müller-Nurasyid, Mark Eijgelsheim, Vilmundar Gudnason, Brenton R. Swenson, Sina A. Gharib, Kathleen F. Kerr, Josh C. Denny, Maristella Steri, E J Benjamin, George J. Papanicolaou, Unnur Thorsteinsdottir, Ivana Kolcic, Yuki Bradford, Mina K. Chung, Yongmei Liu, M. Waldenberger, Stella Trompet, Hoed, Jv Setten, Tanja Zeller, Jan A. Kors, Francesco Cucca, Irene Mateo Leach, A.G. Uitterlinden, Albert V. Smith, Craig Muller, Andrew A. Hicks, A Isaacs, Leo-Pekka Lyytikäinen, Konstantin Strauch, Steven A. Lubitz, Antonietta Robino, J Zhana, A. Pfeufer, Sandosh Padmanabhan, Afshin Parsa, Harm-Jan Westra, Marcus Dörr, and J. C. Bis

Subjects
False discovery rate, Linkage disequilibrium, Genotype-phenotype distinction, Pleiotropy, Genotype, SNP, Genome-wide association study, Computational biology, Biology, Genetic association
Abstract

MotivationGenome-wide association studies have had great success in identifying human genetic variants associated with disease, disease risk factors, and other biomedical phenotypes. Many variants are associated with multiple traits, even after correction for trait-trait correlation. Discovering subsets of variants associated with a shared subset of phenotypes could help reveal disease mechanisms, suggest new therapeutic options, and increase the power to detect additional variants with similar pattern of associations. Here we introduce two methods based on a Bayesian framework, SNP And Pleiotropic PHenotype Organization (SAPPHO), one modeling independent phenotypes (SAPPHO-I) and the other incorporating a full phenotype covariance structure (SAPPHO-C). These two methods learn patterns of pleiotropy from genotype and phenotype data, using identified associations to discover additional associations with shared patterns.ResultsThe SAPPHO methods, along with other recent approaches for pleiotropic association tests, were assessed using data from the Atherosclerotic Risk in Communities (ARIC) study of 8,000 individuals, whose gold-standard associations were provided by meta-analysis of 40,000 to 100,000 individuals from the CHARGE consortium. Using power to detect gold-standard associations at genome-wide significance (0.05 family-wise error rate) as a metric, SAPPHO performed best. The SAPPHO methods were also uniquely able to select the most significant variants in a parsimonious model, excluding other less likely variants within a linkage disequilibrium block. For meta-analysis, the SAPPHO methods implement summary modes that use sufficient statistics rather than full phenotype and genotype data. Meta-analysis applied to CHARGE detected 16 additional associations to the gold-standard loci, as well as 124 novel loci, at 0.05 false discovery rate. Reasons for the superior performance were explored by performing simulations over a range of scenarios describing different genetic architectures. With SAPPHO we were able to learn genetic structures that were hidden using the traditional univariate tests.Availabilityhttps://bitbucket.org/baderlab/fast/wiki/Home. SAPPHO software is available under the GNU General Public License, v2.

Published
2018
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12. Large-scale pharmacogenomic study of sulfonylureas and the QT, JT and QRS intervals: CHARGE Pharmacogenomics Working Group

Author

David J. Stott, Jin Li, James G. Wilson, Nona Sotoodehnia, Y-Di Chen, Elsayed Z. Soliman, L. A. Cupples, Yongmei Liu, Henry J. Lin, Stephanie M. Gogarten, James S. Floyd, J. C. Bis, Susan R. Heckbert, Linda Broer, Dennis O. Mook-Kanamori, Jeffrey Roach, T.B. Harris, Kerri L. Wiggins, Melanie D. Napier, Joop Jukema, Vilmundur Gudnason, Robert C. Kaplan, Xiaohui Li, Cathy C. Laurie, P.E. Slagboom, Raul Mendez-Giraldez, Kenneth Rice, Kirk C. Wilhelmsen, Jennifer A. Brody, Jan A. Kors, Naveed Sattar, Evan L. Busch, Daniel S. Evans, Stella Trompet, Albert V. Smith, Amanda A. Seyerle, L. J. Launer, Til Stürmer, Raymond Noordam, Ruifang Li-Gao, Bruce M. Psaty, Yun Li, Jerome I. Rotter, Frits R. Rosendaal, Bruno H. Stricker, Kathleen F. Kerr, Kent D. Taylor, John D. Eicher, Steve Cummings, James D. Stewart, Christy L. Avery, R. de Mutsert, Colleen M. Sitlani, Andrew D. Johnson, Leslie A. Lange, Qing Duan, A.G. Uitterlinden, Eric A. Whitsel, Alexander P. Reiner, Epidemiology, Internal Medicine, and Medical Informatics

Subjects
0301 basic medicine, Male, Genome-wide association study, Type 2 diabetes, Pharmacology, Cardiovascular, Electrocardiography, Ethnicity, Medicine, Pharmacology & Pharmacy, Pharmacology and Pharmaceutical Sciences, Middle Aged, 3. Good health, Heart Disease, Cardiovascular Diseases, Cardiology, Molecular Medicine, Female, Patient Safety, Type 2, medicine.medical_specialty, Drug-Related Side Effects and Adverse Reactions, Pharmacogenomic Testing, Article, 03 medical and health sciences, QRS complex, Clinical Research, Internal medicine, Diabetes Mellitus, Genetics, Humans, Adverse effect, Aged, Cytochrome P-450 CYP2C9, business.industry, Human Genome, Repeated measures design, Genetic Variation, medicine.disease, 030104 developmental biology, Sulfonylurea Compounds, Good Health and Well Being, Diabetes Mellitus, Type 2, Pharmacogenetics, Pharmacogenomics, business, Genome-Wide Association Study
Abstract

Sulfonylureas, a commonly-used class of medication used to treat type 2 diabetes, have been associated with an increased risk of cardiovascular disease. Their effects on QT interval duration and related electrocardiographic phenotypes are potential mechanisms for this adverse effect. In eleven ethnically diverse cohorts that included 71 857 European, African American, and Hispanic/Latino ancestry individuals with repeated measures of medication use and electrocardiogram (ECG) measurements, we conducted a pharmacogenomic genome-wide association study of sulfonylurea use and three ECG phenotypes: QT, JT, and QRS intervals. In ancestry-specific meta-analyses, 8 novel pharmacogenomic loci met the threshold for genome-wide significance (P < 5 x 10−8), and a pharmacokinetic variant in CYP2C9 (rs1057910) that has been associated with sulfonylurea-related treatment effects and other adverse drug reactions in previous studies was replicated. Additional research is needed to replicate the novel findings and to understand their biological basis.

Published
2018

13. Genome-wide association meta-analysis of PR interval identifies 47 novel loci associated with atrial and atrioventricular electrical activity

Author

Aaron Isaacs, Sina A. Gharib, Kathleen F. Kerr, Lenore J. Launer, Yuki Bradford, J. Wouter Jukema, Stefan Kääb, Ruth J. F. Loos, Philipp S. Wild, Igor Rudan, Moritz F. Sinner, Annamaria Iorio, David J. Stott, Sheila Ulivi, Martina Müller-Nurasyid, Jerome I. Rotter, Andrew A. Hicks, Leo-Pekka Lyytikäinen, Vilmundur Gudnason, Dan M. Roden, Dana C. Crawford, James F. Wilson, Renate B. Schnabel, Eric Boerwinkle, Mina K. Chung, M. Fabiola Del Greco, Jan A. Kors, Honghuang Lin, Dan E. Arking, Annette Peters, Daniel S. Evans, Kari Stefansson, Francesco Cucca, Harold Snieder, Nona Sotoodehnia, Claudia T. Silva Aldana, Paul I.W. de Bakker, David Schlessinger, Pim van der Harst, Irene Mateo Leach, Kirill V. Tarasov, Marylyn D. Ritchie, Xiaoyan Yin, Marcus Dörr, Jennifer A. Brody, Patrick T. Ellinor, Olli T. Raitakari, Christy L. Avery, Peter W. Macfarlane, Paolo Gasparini, Susan R. Heckbert, John Barnard, Jessica van Setten, Anna F. Dominiczak, Henry Völzke, Edward G. Lakatta, Nilesh J. Samani, Tamara B. Harris, Brenton R. Swenson, Joel S. Bader, Thomas Münzel, Patricia B. Munroe, Hilma Holm, Stefania Bandinelli, Christian Müller, Bruno H. Stricker, Oscar H. Franco, Yongmei Liu, Ivana Kolcic, Peter P. Pramstaller, Josh C. Denny, Maristella Steri, Henry J. Lin, Luigi Ferrucci, Arne Pfeufer, Antonietta Robino, Bruce M. Psaty, Niek Verweij, Lude Franke, Mark Eijgelsheim, Afshin Parsa, Toshiko Tanaka, Folkert W. Asselbergs, Terho Lehtimäki, Stella Trompet, Alvaro Alonso, Harm-Jan Westra, David O. Arnar, Jared W. Magnani, Bouwe P. Krijthe, Cornelia M. van Duijn, Brendan M. Buckley, Jonathan D. Smith, Tim D. Spector, George J. Papanicolaou, Anne M. Butler, Emelia J. Benjamin, Tanja Zeller, Quince Gibson, David R. Van Wagoner, André G. Uitterlinden, Albert V. Smith, Stephan B. Felix, Uwe Völker, Yalda Jamshidi, Ozren Polasek, Daniel F. Gudbjartsson, Harry Campbell, Caroline Hayward, Ilja M. Nolte, Elsayed Z. Soliman, Georg Ehret, Mika Kähönen, Konstantin Strauch, Steven A. Lubitz, Melanie Waldenberger, Alexander Teumer, Sandosh Padmanabhan, Braxton D. Mitchell, Gianfranco Sinagra, Gandin Ilaria, Thomas Meitinger, Marcel den Hoed, Stefan Blankenberg, and J. C. Bis

Subjects
Genetics, QRS complex, Heart block, medicine, cardiovascular system, Missense mutation, Genome-wide association study, Atrial fibrillation, PR interval, Biology, medicine.disease, Genome, Gene
Abstract

Electrocardiographic PR interval measures atrial and atrioventricular depolarization and conduction, and abnormal PR interval is a risk factor for atrial fibrillation and heart block. We performed a genome-wide association study in over 92,000 individuals of European descent and identified 44 loci associated with PR interval (34 novel). Examination of the 44 loci revealed known and novel biological processes involved in cardiac atrial electrical activity, and genes in these loci were highly over-represented in several cardiac disease processes. Nearly half of the 61 independent index variants in the 44 loci were associated with atrial or blood transcript expression levels, or were in high linkage disequilibrium with one or more missense variants. Cardiac regulatory regions of the genome as measured by cardiac DNA hypersensitivity sites were enriched for variants associated with PR interval, compared to non-cardiac regulatory regions. Joint analyses combining PR interval with heart rate, QRS interval, and atrial fibrillation identified additional new pleiotropic loci. The majority of associations discovered in European-descent populations were also present in African-American populations. Meta-analysis examining over 105,000 individuals of African and European descent identified additional novel PR loci. These additional analyses identified another 13 novel loci. Together, these findings underscore the power of GWAS to extend knowledge of the molecular underpinnings of clinical processes.

Published
2018
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14. A genome-wide association meta-analysis of plasma Aβ peptides concentrations in the elderly

Author

Anais Mounier, James T. Becker, Vincent Chouraki, Robert S. Rogers, P. Amouyel, Florie Demiautte, R. F. A. G. de Bruijn, Richard Mayeux, Annette L. Fitzpatrick, J. C. Bis, J. F. Dartigues, Carla A. Ibrahim-Verbaas, A. Hofman, Christophe Tzourio, Benjamin Grenier-Boley, M. A. Ikram, Mark Lathrop, A.G. Uitterlinden, Oscar L. Lopez, Claudine Berr, Nicole Schupf, M.M.B. Breteler, Christiane Reitz, Annick Alpérovitch, J-C Lambert, C M van Duijn, Susanna Schraen, Luc Buée, Charlotte Delay, and Julien Chapuis

Subjects
Aging, Amyloid beta, Locus (genetics), Genome-wide association study, Biology, Polymorphism, Single Nucleotide, APP protein, human, White People, Article, Cellular and Molecular Neuroscience, Amyloid beta-Protein Precursor, SDG 3 - Good Health and Well-being, blood [Amyloid beta-Peptides], metabolism [Amyloid beta-Protein Precursor], blood [Aging], medicine, Humans, ddc:610, Senile plaques, Molecular Biology, Gene, Amyloid beta-Peptides, CTXN3 protein, human, HEK 293 cells, Membrane Proteins, amyloid beta-protein (1-40), amyloid beta-protein (1-42), medicine.disease, Peptide Fragments, genetics [European Continental Ancestry Group], genetics [Membrane Proteins], Psychiatry and Mental health, HEK293 Cells, Membrane protein, Biochemistry, genetics [Amyloid beta-Protein Precursor], blood [Peptide Fragments], genetics [Aging], biology.protein, Alzheimer's disease, metabolism [Membrane Proteins], Genome-Wide Association Study
Abstract

Amyloid beta (Aβ) peptides are the major components of senile plaques, one of the main pathological hallmarks of Alzheimer disease (AD). However, Aβ peptides' functions are not fully understood and seem to be highly pleiotropic. We hypothesized that plasma Aβ peptides concentrations could be a suitable endophenotype for a genome-wide association study (GWAS) designed to (i) identify novel genetic factors involved in amyloid precursor protein metabolism and (ii) highlight relevant Aβ-related physiological and pathophysiological processes. Hence, we performed a genome-wide association meta-analysis of four studies totaling 3 528 healthy individuals of European descent and for whom plasma Aβ 1-40 and Aβ 1 -42 peptides levels had been quantified. Although we did not observe any genome-wide significant locus, we identified 18 suggestive loci (P

Published
2014
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15. Allelic differences between Europeans and Chinese for CREB1 SNPs and their implications in gene expression regulation, hippocampal structure and function, and bipolar disorder susceptibility

Author

C. Henry, Arthur W. Toga, Margaret J. Wright, Michael Gill, Huiqing Shi, Xiong-Jian Luo, Marcella Rietschel, Jason L. Stein, Alejandro Arias Vasquez, Cathryn M. Lewis, Derek W. Morris, Sarah E. Bergen, Ming Li, Aiden Corvin, Markus M. Nöthen, Manuel Mattheisen, Stéphane Jamain, April Hargreaves, Derrek P. Hibar, Gary Donohoe, Lenore J. Launer, Andreas Meyer-Lindenberg, Lin Gan, Qiang Lin, Thomas G. Schulze, A. Heinz, Nicholas G. Martin, Darina Czamara, Stéphanie Debette, Sven Cichon, Paul M. Thompson, Bruno Etain, J. C. Bis, Mikael Landén, Christina M. Hultman, Bing Su, Sarah E. Medland, Mohammad Arfan Ikram, Lei Shi, Marion Leboyer, Myriam Fornage, Henrik Walter, Susanne Erk, P.F. Sullivan, Barbara Franke, Frank Bellivier, Bertram Müller-Myhsok, Sudha Seshadri, Radiology & Nuclear Medicine, and Epidemiology

Subjects
Male, Bipolar Disorder, CREB1 protein, human, Neuropsychological Tests, genetics [Gene Expression Regulation], Hippocampus, 0302 clinical medicine, Gene Frequency, genetics [Cyclic AMP Response Element-Binding Protein], Cyclic AMP Response Element-Binding Protein, Genetics, Aged, 80 and over, 0303 health sciences, education.field_of_study, Age Factors, Middle Aged, 3. Good health, Psychiatry and Mental health, genetics [European Continental Ancestry Group], Phenotype, genetics [Polymorphism, Single Nucleotide], Major depressive disorder, Female, ethnology [Bipolar Disorder], Adult, Population, genetics [White People], Single-nucleotide polymorphism, Neuroimaging, Biology, Polymorphism, Single Nucleotide, metabolism [RNA, Messenger], White People, Article, 03 medical and health sciences, Cellular and Molecular Neuroscience, Asian People, medicine, Humans, Genetic Predisposition to Disease, ddc:610, RNA, Messenger, Allele, education, Molecular Biology, Allele frequency, Genetic Association Studies, 030304 developmental biology, Aged, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], genetics [Asian Continental Ancestry Group], Genetic heterogeneity, genetics [Asian People], Computational Biology, medicine.disease, Genetic hitchhiking, pathology [Hippocampus], Gene Expression Regulation, Genetic marker, Case-Control Studies, genetics [Gene Frequency], 030217 neurology & neurosurgery, genetics [Bipolar Disorder]
Abstract

Item does not contain fulltext Bipolar disorder (BD) is a polygenic disorder that shares substantial genetic risk factors with major depressive disorder (MDD). Genetic analyses have reported numerous BD susceptibility genes, while some variants, such as single-nucleotide polymorphisms (SNPs) in CACNA1C have been successfully replicated, many others have not and subsequently their effects on the intermediate phenotypes cannot be verified. Here, we studied the MDD-related gene CREB1 in a set of independent BD sample groups of European ancestry (a total of 64 888 subjects) and identified multiple SNPs significantly associated with BD (the most significant being SNP rs6785[A], P=6.32 x 10(-5), odds ratio (OR)=1.090). Risk SNPs were then subjected to further analyses in healthy Europeans for intermediate phenotypes of BD, including hippocampal volume, hippocampal function and cognitive performance. Our results showed that the risk SNPs were significantly associated with hippocampal volume and hippocampal function, with the risk alleles showing a decreased hippocampal volume and diminished activation of the left hippocampus, adding further evidence for their involvement in BD susceptibility. We also found the risk SNPs were strongly associated with CREB1 expression in lymphoblastoid cells (P

Published
2014
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16. Common genetic variation near the connexin-43 gene is associated with resting heart rate in African Americans: A genome-wide association study of 13,372 participants

Author

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

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

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

Published
2013
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17. Evaluation of a Genetic Risk Score to Improve Risk Prediction for Alzheimer's Disease

Author

Annette L. Fitzpatrick, P. Amouyel, Richard Mayeux, Johanna Jakobsdottir, Hieab H.H. Adams, Anita L. DeStefano, Badri N. Vardarajan, Chouraki, de Jager Pl, David A. Bennett, Jean-François Dartigues, Shubhabrata Mukherjee, Seung Hoan Choi, M. A. Ikram, Christiane Reitz, Eric B. Larson, Oscar L. Lopez, Fleur Maury, Jean-Charles Lambert, Sudha Seshadri, Lei Yu, van der Lee Sj, Albert Hofman, van Duijn C, J. C. Bis, Gudnason, L. J. Launer, A.G. Uitterlinden, Carla A. Ibrahim-Verbaas, Paul K. Crane, Céline Bellenguez, Claudine Berr, Epidemiology, Internal Medicine, and Neurology

Subjects
0301 basic medicine, Male, medicine.medical_specialty, Apolipoprotein E4, Genome-wide association study, Neuropsychological Tests, Polymorphism, Single Nucleotide, Risk Assessment, Article, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Alzheimer Disease, Predictive Value of Tests, Risk Factors, Internal medicine, Statistics, medicine, Humans, Genetic Predisposition to Disease, Genetic Testing, Genetic testing, Aged, Proportional Hazards Models, Aged, 80 and over, Psychiatric Status Rating Scales, Framingham Risk Score, medicine.diagnostic_test, business.industry, Proportional hazards model, General Neuroscience, Hazard ratio, General Medicine, Psychiatry and Mental health, Clinical Psychology, 030104 developmental biology, Meta-analysis, Educational Status, Female, Geriatrics and Gerontology, business, Risk assessment, 030217 neurology & neurosurgery, Cohort study, Genome-Wide Association Study
Abstract

Effective prevention of Alzheimer's disease (AD) requires the development of risk prediction tools permitting preclinical intervention. We constructed a genetic risk score (GRS) comprising common genetic variants associated with AD, evaluated its association with incident AD and assessed its capacity to improve risk prediction over traditional models based on age, sex, education, and APOE epsilon 4. In eight prospective cohorts included in the International Genomics of Alzheimer's Project (IGAP), we derived weighted sum of risk alleles from the 19 top SNPs reported by the IGAPGWAS in participants aged 65 and older without prevalent dementia. Hazard ratios (HR) of incident AD were estimated in Cox models. Improvement in risk prediction was measured by the difference in C-index (Delta-C), the integrated discrimination improvement (IDI) and continuous net reclassification improvement (NRI>0). Overall, 19,687 participants at risk were included, of whom 2,782 developed AD. The GRS was associated with a 17% increase in AD risk (pooled HR=1.17; 95% CI = [1.13-1.21] per standard deviation increase in GRS; p-value = 2.86x10(-16)). This association was stronger among persons with at least one APOE epsilon 4 allele (HRGRS = 1.24; 95% CI = [1.15-1.34]) than in others (HRGRS = 1.13; 95% CI = [1.08-1.18]; p(interaction) = 3.45x10(-2)). Risk prediction after seven years of follow-up showed a small improvement when adding the GRS to age, sex, APOE epsilon 4, and education (Delta-Cindex = 0.0043 [0.0019-0.0067]). Similar patterns were observed for IDI and NRI>0. In conclusion, a risk score incorporating common genetic variation outside the APOE epsilon 4 locus improved AD risk prediction and may facilitate risk stratification for prevention trials.

Published
2016

18. Novel Loci Associated With PR Interval in a Genome-Wide Association Study of 10 African American Cohorts

Author

Gerardo Heiss, P. Miguel Quibrera, Sathanur R. Srinivasan, Wei Chen, Yongmei Liu, Alvaro Alonso, Mike A. Nalls, Christopher Newton-Cheh, Guo Li, Dan E. Arking, Elsayed Z. Soliman, Wen Chi Hsueh, Alan B. Zonderman, Sarah S. Murray, Erin N. Smith, Yan A. Meng, Marian C. Limacher, Xiaoyan Yin, Brendan J. Keating, Cameron D. Palmer, J. Gustav Smith, Kari E. North, Nona Sotoodehnia, Anne M. Butler, Steven A. Lubitz, Renate B. Schnabel, Sarah G. Buxbaum, J. C. Bis, Michele K. Evans, Emelia J. Benjamin, Kathleen F. Kerr, Gerald S. Berenson, Susan R. Heckbert, Kristin D. Marciante, Eric A. Whitsel, Andrew B. Singleton, Patrick T. Ellinor, Jared W. Magnani, Reena Mehra, Alexander P. Reiner, Rajat Deo, Anne B. Newman, Jerome I. Rotter, Susan Redline, Toshiko Tanaka, Luigi Ferrucci, Bruce M. Psaty, Daniel S. Evans, Nicholas J. Schork, Yun Li, Christy L. Avery, and Zhu Ming Zhang

Subjects
Genetics, medicine.medical_specialty, Locus (genetics), Genome-wide association study, Biology, Epidemiology, medicine, International HapMap Project, PR interval, Cardiology and Cardiovascular Medicine, Genetics (clinical), Imputation (genetics), Cohort study, Genetic association
Abstract

Background— The PR interval, as measured by the resting, standard 12-lead ECG, reflects the duration of atrial/atrioventricular nodal depolarization. Substantial evidence exists for a genetic contribution to PR, including genome-wide association studies that have identified common genetic variants at 9 loci influencing PR in populations of European and Asian descent. However, few studies have examined loci associated with PR in African Americans. Methods and Results— We present results from the largest genome-wide association study to date of PR in 13 415 adults of African descent from 10 cohorts. We tested for association between PR (ms) and ≈2.8 million genotyped and imputed single-nucleotide polymorphisms. Imputation was performed using HapMap 2 YRI and CEU panels. Study-specific results, adjusted for global ancestry and clinical correlates of PR, were meta-analyzed using the inverse variance method. Variation in genome-wide test statistic distributions was noted within studies (λ range: 0.9–1.1), although not after genomic control correction was applied to the overall meta-analysis (λ: 1.008). In addition to generalizing previously reported associations with MEIS1, SCN5A, ARHGAP24, CAV1 , and TBX5 to African American populations at the genome-wide significance level ( P −8 ), we also identified a novel locus: ITGA9 , located in a region previously implicated in SCN5A expression. The 3p21 region harboring SCN5A also contained 2 additional independent secondary signals influencing PR ( P −8 ). Conclusions— This study demonstrates the ability to map novel loci in African Americans as well as the generalizability of loci associated with PR across populations of African, European, and Asian descent.

Published
2012
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19. Genetic variability within the cholesterol lowering pathway and the effectiveness of statins in reducing the risk of MI

Author

Bruce M. Psaty, J. C. Bis, Olaf H. Klungel, Anke-Hilse Maitland-van der Zee, Nicole L. Glazer, Bas J M Peters, Helmi Pett, Bruno H. Stricker, Anthonius de Boer, Kerri L. Wiggins, Epidemiology, and Cardiology

Subjects
Male, Myocardial Infarction, Pharmacology, Risk Factors, Odds Ratio, Registries, ATP Binding Cassette Transporter, Subfamily G, Member 5, Netherlands, education.field_of_study, Serine Endopeptidases, Middle Aged, Scavenger Receptors, Class B, Cholesterol, Phenotype, Treatment Outcome, Population study, Female, Proprotein Convertases, Proprotein Convertase 9, Cardiology and Cardiovascular Medicine, Low Density Lipoprotein Receptor-Related Protein-1, medicine.medical_specialty, Statin, Genotype, medicine.drug_class, Lipoproteins, Hypercholesterolemia, Population, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, Risk Assessment, Article, Internal medicine, medicine, Humans, education, Aged, Chi-Square Distribution, PCSK9, Case-control study, Lipase, Odds ratio, PPAR gamma, Logistic Models, Pharmacogenetics, Case-Control Studies, ATP-Binding Cassette Transporters, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Sterol O-Acyltransferase
Abstract

Genetic variability has been shown to affect statin responsiveness. Participants from the Utrecht Cardiovascular Pharmacogenetics (UCP) studies were enrolled from a population-based registry of pharmacy records linked to hospital discharge records (PHARMO) to investigate tagging SNPs within candidate genes involved in the cholesterol lowering pathway for modification of the effectiveness of statins in reducing the risk of myocardial infarction (MI). Patients who received a prescription for an antihypertensive drug and/or had hypercholesterolemia were selected from the PHARMO database. We designed a nested case-control study in which cases were hospitalized for MI and controls were not. Patients were contacted through their community pharmacies. For this study, only hypercholesterolemic participants were selected. Logistic regression analysis was used to investigate pharmacogenetic interactions. The Heart and Vascular Health Study (HVH) was used to replicate findings from UCP. The study population included 668 cases and 1217 controls. We selected 231 SNPs of which 209 SNPs in 27 genes passed quality control. Ten SNPs in eight genes were found to influence the effectiveness of statins in UCP, of which the most significant interaction was found with SCARB1 rs4765615. Other genes that reached statistical significance (p < 0.05) included two SNPs in PCSK9 (rs10888896 and rs505151 (E670G)), two SNPs in ABCG5 (rs4245786 and rs1864815), LIPC rs16940379, ABCA1 rs4149264, PPARG rs2972164, LRP1 rs715948, and SOAT1 rs2493121. None of the total of 5 SNPs that were available for replication in HVH reached statistical significance. In conclusion, ten SNPs were found to modify the effectiveness of statins in reducing the risk of MI in the UCP study. Five were also tested in the HVH study, but no interactions reached statistical significance. (C) 2011 Elsevier Ireland Ltd. All rights reserved.

Published
2011

20. Publisher Correction: Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits

Author

Aravinda Chakravarti, Jennifer E. Huffman, Meixia Ren, Veikko Salomaa, Christopher Newton-Cheh, Johan Sundström, Alan L. James, Joris Deelen, Raha Pazoki, Michela Traglia, Tõnu Esko, Seppo Koskinen, Christopher J. O'Donnell, Csaba P. Kovesdy, Daniel I. Chasman, Paul F. O'Reilly, Roby Joehanes, Paul M. Ridker, G. Abecasis, Lars Lind, Dragana Vuckovic, Yingchang Lu, Antonietta Robino, Anders Hamsten, Muralidharan Sargurupremraj, Caterina Barbieri, Anne U. Jackson, Anna Morgan, Claudia Langenberg, Peter S. Braund, Rainer Rettig, Murielle Bochud, Vilmundur Gudnason, Eleftheria Zeggini, David J. Stott, Joop Jukema, Nick Shrine, Jun Ding, Olle Melander, Massimo Mangino, Borbala Mifsud, Frank H. Collins, Liewald Dcm., Tineka Blake, Peter K. Joshi, Yan V. Sun, Aarno Palotie, Maciej Tomaszewski, Jarvelin M-R., Kati Kristiansson, L. J. Launer, Sara M. Willems, Ian J. Deary, Christophe Tzourio, Alan J. Gow, Caroline Hayward, Guillaume Paré, Christopher Oldmeadow, John M. Starr, Paul Elliott, Morris A. Swertz, C M van Duijn, Sekar Kathiresan, Lorna M. Lopez, Neil R Poulter, Mike A. Nalls, Erik Ingelsson, Eric Boerwinkle, Catharina A. Hartman, Giorgia Girotto, Ben A. Oostra, Markus Perola, Paul Knekt, Lyytikäinen L-P., T.B. Harris, J. C. Bis, Harriëtte Riese, J. Marrugat, Samuli Ripatti, Howson Jmm., Archie Campbell, C M Lindgren, Adam S. Butterworth, Xiuqing Guo, Lin W-Y., Priyanka Nandakumar, David Mosen-Ansorena, Alison Pattie, Marco Brumat, Annette Peters, Georgios Ntritsos, Ivana Kolcic, Alexander Teumer, Ulf Gyllensten, Joanne Knight, Stella Trompet, K. Witkowska, Hottenga J-J., Tim D. Spector, Maris Laan, Vilmantas Giedraitis, Bram P. Prins, Loos Rjf., M. H. de Borst, Antti Jula, Lynda M. Rose, Massimiliano Cocca, Daniela Toniolo, Igor Rudan, P. J. van der Most, Fu Liang Ng, Heather J. Cordell, Walter Palmas, John Danesh, John Attia, Dan E. Arking, Ganesh Chauhan, C Gieger, P. van der Harst, Penninx Bwjh., Kristin L. Ayers, Germaine C. Verwoert, Bruce M. Psaty, Jaspal S. Kooner, Ruifang Li-Gao, Benjamin Lehne, Khaw K-T., Sandosh Padmanabhan, Franco Giulianini, Erwin P. Bottinger, Roberto Elosua, Christopher P. Nelson, Ozren Polasek, D.R. Velez Edwards, Martin Farrall, Ioanna Tzoulaki, Peter Vollenweider, Uwe Völker, Albertine J. Oldehinkel, Åsa Johansson, Helen R. Warren, Evan Tzanis, Albert V. Smith, Hwang S-J., Teresa Ferreira, E.J.C. de Geus, Evangelos Evangelou, Niek Verweij, R. J. Scott, Pekka Jousilahti, Elin Org, Stefan Enroth, Dorret I. Boomsma, Harry Campbell, Andrew D. Johnson, David Conen, James F. Wilson, Edward G. Lakatta, Anuj Goel, Raymond Noordam, Najaf Amin, David P. Strachan, Martin D. Tobin, Francesco Cucca, Doney Asf., Todd L. Edwards, Jerome I. Rotter, Mika Kähönen, Hugh Watkins, Rossella Sorice, John M. C. Connell, David S. Siscovick, Sébastien Thériault, Jian'an Luan, Marty Larson, Philippe Amouyel, A C Morrison, Louise V. Wain, Reedik Mägi, Jonathan Marten, Thibaud Boutin, Nabi Shah, Weihua Zhang, Palmer Cna., Daniela Ruggiero, Zhao J-H., Olli T. Raitakari, Bernard Keavney, Peter S. Sever, Philip S. Tsao, Jie Yao, André G. Uitterlinden, Marina Evangelou, Zoltán Kutalik, Robert A. Scott, Helena Schmidt, J. Tuomilehto, Nilesh J. Samani, Quang Tri Nguyen, John Michael Gaziano, Georg Ehret, Praveen Surendran, Terho Lehtimäki, Mark J. Caulfield, Denis C. Shields, Rick Jansen, Sarin A-P., Alice Stanton, Mattias Frånberg, Cumhur Y Demirkale, Stéphanie Debette, Paolo Gasparini, Ilaria Gandin, Simon Thom, Kent D. Taylor, Andrew D. Morris, Claudia P. Cabrera, Teemu J. Niiranen, Nicholas J. Wareham, Andrew P. Morris, Yasaman Saba, Daniel Levy, Aki S. Havulinna, Kelly Cho, Sarah E. Harris, Li Lin, Janina S. Ried, Michael R. Barnes, Sarah H. Wild, Patricia B. Munroe, Vergnaud A-C., Lorenz Risch, Rona J. Strawbridge, Y. Milaneschi, John C. Chambers, Yong Qian, Cristina Menni, Anubha Mahajan, Peter Almgren, Gary Davies, Jacklyn N. Hellwege, Elizabeth G. Holliday, A. Metspalu, Ilja M. Nolte, Peter J. Munson, He Gao, Marcus Dörr, Cinzia Sala, Peter P. Pramstaller, Teresa Nutile, Wilson Pwf., Gonneke Willemsen, Markku Laakso, Chiara Batini, Harold Snieder, Ibrahim Karaman, Adriana M. Hung, Reinhold Schmidt, R. de Mutsert, Michael Boehnke, Lili Milani, Alan F. Wright, Edith Hofer, Siim Sõber, Ahmad Vaez, Albert Hofman, Oscar H. Franco, Yongmei Liu, Tatijana Zemunik, Kenneth Rice, Veronique Vitart, Marina Ciullo, Niki Dimou, Morris J. Brown, Crysovalanto Mamasoula, A.M. Erzurumluoglu, Andrew A. Hicks, Ayush Giri, Dennis O. Mook-Kanamori, Home Office, UNIVERSITY OF OULU, Commission of the European Communities, Medical Research Council (MRC), Action on Hearing Loss, British Heart Foundation, National Institute for Health Research, Imperial College Healthcare NHS Trust- BRC Funding, and UK DRI Ltd

Subjects
Genetics & Heredity, 0301 basic medicine, Netherlands Twin Register (NTR), Science & Technology, computer.internet_protocol, Million Veteran Program, Genome-wide association study, Computational biology, 06 Biological Sciences, Biology, Genetic analysis, 03 medical and health sciences, 030104 developmental biology, Genetics, Genome informatics, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, Life Sciences & Biomedicine, computer, 11 Medical and Health Sciences, XML, Developmental Biology
Abstract

In the version of this article originally published, the name of author Martin H. de Borst was coded incorrectly in the XML. The error has now been corrected in the HTML version of the paper.

Published
2018
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21. Telomere-associated polymorphisms correlate with cardiovascular disease mortality in Caucasian women: the Cardiovascular Health Study

Author

Nancy S. Jenny, Richard A. Kronmal, Masayuki Kimura, Bruce M. Psaty, Andrea N. Burnett-Hartman, Annette L. Fitzpatrick, Abraham Aviv, J. C. Bis, and Russell P. Tracy

Subjects
Oncology, Male, Risk, Aging, medicine.medical_specialty, Linkage disequilibrium, Single-nucleotide polymorphism, Disease, Biology, Bioinformatics, Polymorphism, Single Nucleotide, White People, Article, Cohort Studies, Sex Factors, Internal medicine, medicine, Leukocytes, Humans, Telomerase, Genetic association, Aged, Aged, 80 and over, Polymorphism, Genetic, Proportional hazards model, Hazard ratio, Telomere, Minor allele frequency, Cardiovascular Diseases, RNA, Female, Developmental Biology, Cohort study
Abstract

Leukocyte telomere length (LTL) is linked to cardiovascular disease (CVD); however, it is unclear if LTL has an etiologic role in CVD. To gain insight into the LTL and CVD relationship, a cohort study of CVD mortality and single nucleotide polymorphisms (SNPs) in OBFC1 and TERC, genes related to LTL, was conducted among 3271 Caucasian participants ages ≥65 years enrolled 1989–1990 in the Cardiovascular Health Study. Leukocyte DNA was genotyped for SNPs in OBFC1 (rs4387287 and rs9419958) and TERC (rs3772190) that were previously associated with LTL through genome-wide association studies. Cox regression was used to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs). The OBFC1 SNPs were in linkage disequilibrium (r2=0.99), and both SNPs were similarly associated with CVD mortality in women. For women, there was a decreased risk of CVD death associated with the minor allele (rs4387287), HR=0.7; 95% CI: 0.5–0.9 (CC vs. AC) and HR=0.5; 95% CI: 0.20–1.4 (CC vs. AA) (p-trend

Published
2011

22. P1‐237: Genome‐Wide Association Study of Executive Function

Author

Stéphanie Debette, Cornelia M. van Duijn, Ian J. Deary, Gail Davies, Sudha Seshadri, J. C. Bis, Reinhold Schmidt, Albert V. Smith, Qiong Yang, Lina Zgaga, Jan Bressler, Mohammad Arfan Ikram, Monique M.B. Breteler, Caroline Hayward, Thomas H. Mosley, Carla A. Ibrahim-Verbaas, Lenore J. Launer, Helena Schmidt, Katja Petrovic, Maaike Schuur, Mirna Kirin, Annette L. Fitzpatrick, and James Wilson

Subjects
Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Epidemiology, Health Policy, Genome-wide association study, Neurology (clinical), Computational biology, Geriatrics and Gerontology, Biology, Function (biology)
Published
2011
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23. O1‐01‐02: Genome‐wide association study of memory performance

Author

Gail Davies, Reinhold Schmidt, A. E. Smith, David A. Bennett, Katja Petrovic, Maaike Schuur, Monique M.B. Breteler, Carla A. Ibrahim-Verbaas, Stéphanie Debette, Sudha Seshadri, Mohammad Arfan Ikram, Cornelia M. van Duijn, Jim Stankovich, Helena Schmidt, Velandai Srikanth, Qiong Yang, Lina Zgaga, Harry Campbell, Caroline Hayward, Annette L. Fitzpatrick, Lei Yu, J. C. Bis, Thomas H. Mosley, Lenore J. Launer, Jan Bressler, Mirna Kirin, James Wilson, and Ian J. Deary

Subjects
Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Epidemiology, Health Policy, Genome-wide association study, Neurology (clinical), Computational biology, Geriatrics and Gerontology, Biology, Memory performance
Published
2011
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24. Erratum: Ischemic stroke is associated with the ABO locus: The EuroCLOT study

Author

Matthew Traylor, T H Mosely, Gudmar Thorleifsson, Elizabeth G. Holliday, Catherine Sudlow, N Soranzo, O Saarela, Gabriela L. Surdulescu, Peter J. Grant, Andreas Gschwendtner, Rothwell Pmw., Pirro G. Hysi, Karen L. Furie, Angela M. Carter, J. C. Bis, James F. Meschia, Dominique Arveiler, Braxton D. Mitchell, Eugenio Parati, Jean Ferrières, M Nalls, Myriam Fornage, Unnur Thorsteinsdottir, Martin Dichgans, Christopher R Levi, Mari A. Kaunisto, Hugh S. Markus, Veikko Salomaa, Robert Clarke, Aarno Palotie, Tim D. Spector, Jarmo Virtamo, Solveig Gretarsdottir, Pankaj Sharma, Marco M Ferrario, W. T. Longstreth, Williams Fmk., Rodney J. Scott, Peter Wagner, Martin Farrall, Anna Helgadottir, Kaisa Silander, Yu-Ching Cheng, Steve Bevan, Mohammad Arfan Ikram, Sudha Seshadri, Kari Stefansson, Giorgio B. Boncoraglio, Alun Evans, Albert Hofman, Dylan Hodgkiss, P. Amouyel, Jonathan Rosand, Kari Kuulasmaa, John Attia, Bruce M. Psaty, Per-Gunner Wiklund, and Anita L. DeStefano

Subjects
medicine.medical_specialty, Annals, Neurology, business.industry, ABO blood group system, Internal medicine, Ischemic stroke, medicine, Locus (genetics), Neurology (clinical), business, Neuroscience
Published
2014
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25. Variation in 24 hemostatic genes and associations with non-fatal myocardial infarction and ischemic stroke

Author

Charles Kooperberg, Nicholas L. Smith, Susan R. Heckbert, Bruce M. Psaty, S. Biagiotti, J. C. Bis, Kenneth Rice, Thomas Lumley, and Kerri L. Wiggins

Subjects
medicine.medical_specialty, Myocardial Infarction, Single-nucleotide polymorphism, Polymorphism, Single Nucleotide, Fibrin, Internal medicine, Genetic variation, medicine, Humans, Myocardial infarction, Aged, Hemostasis, Factor VIII, biology, business.industry, Haplotype, Case-control study, Genetic Variation, Plasminogen, Hematology, Middle Aged, medicine.disease, Thrombosis, Surgery, Postmenopause, Stroke, Haplotypes, Case-Control Studies, Hypertension, biology.protein, Cardiology, business, Factor XIIIa
Abstract

Arterial thrombosis involves platelet aggregation and clot formation, yet little is known about the contribution of genetic variation in fibrin-based hemostatic factors to arterial clotting risk. We hypothesized that common variation in 24 coagulation-fibrinolysis genes would contribute to risk of incident myocardial infarction (MI) or ischemic stroke (IS).We conducted a population-based, case-control study. Subjects were hypertensive adults and postmenopausal women 30-79 years of age, who sustained a first MI (n = 856) or IS (n = 368) between 1995 and 2002, and controls matched on age, hypertension status, and calendar year (n = 2,689). We investigated the risk of MI and IS associated with (i) global variation within each gene as measured by common haplotypes and (ii) individual haplotypes and single nucleotide polymorphisms (SNPs). Significance was assessed using a 0.2 threshold of the false discovery rate q-value, which accounts for multiple testing.After accounting for multiple testing, global genetic variation in factor (F) VIII was associated with IS risk. Two haplotypes in FVIII and one in FXIIIa1 were significantly associated with increased IS risk (all q-values0.2). A plasminogen gene SNP was associated with MI risk. All are new discoveries not previously reported. Another 24 tests had P-values0.05 and q-values0.2 in MI and IS analyses, 23 of which are new and hypothesis generating.Apart from the association of FVIII variation with IS, we found little evidence that common variation in the 24 candidate fibrin-based hemostasis genes strongly influences arterial thrombotic risk, but our results cannot rule out small effects.

Published
2007

26. Carbon sequestration in paddy soil as influenced by organic and inorganic amendments

Author

Md Mozammel Haque, J. C. Biswas, M. Maniruzaman, S. Akhter, and M. S. Kabir

Subjects
cowdung, poultry manure, vermicompost, greenhouse gas emission, net primary production, Environmental sciences, GE1-350
Abstract

Rice plants mediate carbon (C) emission from paddy soils but also absorb it as carbon dioxide (CO2) during photosynthesis. This means that net C emission could vary depending on rice cultivation techniques, which is not well documented in Asian regions. In the present investigation, the effect of different C sources on major greenhouse gas (GHG) fluxes and their relationships between C inputs and outputs were established by using closed static chamber technique. Total methane (CH4), nitrous oxide (N2O) and CO2 emissions were significantly higher with integrated plant nutrient system (IPNS) based fertilization with cowdung (CD), poultry manure (PM) and vermicompost (VC) than chemical fertilizer alone. Net ecosystem C budget (NECB) was positive with CD-IPNS (52–54 kg C ha−1), PM-IPNS (62–64 kg C ha−1) and VC-IPNS (53–56 kg C ha−1) but negative with chemical fertilization (−7 to −8 kg C ha−1). In control and chemical fertilizer treatments, net CO2 sequestration was negative (−602 and −87 kg CO2 ha−1), but organic amendments showed positive CO2 sequestration that varied from 68 to 94 kg CO2 ha−1 during the study periods. Organic amendment significantly improved CO2 capturing capacity by about 17–22 gm kg−1 grain yield compared to chemical fertilization (−24 to −25 gm kg−1). Rice yield also enhanced by about 14–23% with organic amendments compared to chemical fertilizer treatment. In conclusion, use of organic C sources would be very valuable practice to increase net CO2 sequestration and wet season rice yield under tropical climatic conditions.

Published
2020
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27. Novel Loci for Adiponectin Levels and Their Influence on Type 2 Diabetes and Metabolic Traits: A Multi-Ethnic Meta-Analysis of 45,891 Individuals

Author

Seppo Koskinen, Christian Herder, Daniel I. Chasman, Andrew R. Wood, Jonna L. Grimsby, J.F. Wilson, Day Inm., Massimo Mangino, Gonneke Willemsen, Robert W. Mahley, Cristian Pattaro, Nicole L. Glazer, T.B. Harris, Irene Pichler, M S Sandhu, D. van Heemst, Christine Proença, Martha Ganser, Robert A. Hegele, Richa Saxena, Eleftheria Zeggini, Markku Laakso, Peter Kraft, Judith B. Borja, Karen L. Mohlke, J B Richards, de Geus Ejc., Robert Sladek, Cristen J. Willer, Samy Hadjadj, S.M. Boekholdt, Gina M. Peloso, Kijoung Song, Sutapa Mukherjee, Gudmar Thorleifsson, Winston Hide, Mark I. McCarthy, Ruth E. Pakyz, Marian Beekman, Ayellet V. Segrè, Inga Prokopenko, Ping An, George Dedoussis, Danielle Posthuma, Jeanette Erdmann, Simon J. Griffin, Nilesh J. Samani, Inke R. König, Frank B. Hu, Lokki M-L., David M. Evans, Xiaohui Li, Valgerdur Steinthorsdottir, Aimo Ruokonen, A Pouta, Kerrin S. Small, Cecilia M. Lindgren, O Le Bacquer, Xijing Han, Florian Kronenberg, E Katsareli, Christian Dina, S. Gabriel, Jochen Spranger, James S. Pankow, M. Kloppenburg, Penninx Bwjh., Torben Hansen, Josh Smith, Jennie Hui, Gordon H. Williams, Mark Seielstad, Ingrid B. Borecki, Weihua Zhang, Peter P. Pramstaller, Stephen J. Sharp, Neil R. Robertson, Zee Ryl., Mike Sampson, Angela Silveira, C.M. van Duijn, Anders Hamsten, Peter Shrader, Denis Rybin, Chen Y-Di., Gunnar Sigurdsson, Michael Stumvoll, Russel Tracy, Mark O. Goodarzi, Göran Hallmans, Michael R. Erdos, Valeriya Lyssenko, Juha Saharinen, Sven Bergmann, Jeffrey R. O'Connell, Debbie A Lawlor, Thomas Meitinger, Yvonne Böttcher, Jérôme Delplanque, Sarah G. Buxbaum, Silvia Naitza, Shah Ebrahim, Graham A. Hitman, Angelo Scuteri, Aroon D. Hingorani, Heribert Schunkert, François Pattou, Claudia Lamina, A L Elliott, Sekar Kathiresan, Dawn M. Waterworth, Jennifer A. Brody, Thomas Quertermous, Leena Peltonen, Josephine M. Egan, Daniel J. Rader, J F Peden, Yarnell Jwg., Daniel S. Pearson, Pfeiffer Afh., P S Chines, N Vogelzangs, Susan Redline, Alka M. Kanaya, T B Harris, J. V. van Vliet-Ostaptchouk, Ghislain Rocheleau, Rune R. Frants, Olga D. Carlson, James G. Wilson, Melissa Garcia, Ong Rt-H., Mark J. Caulfield, Tanya M. Teslovich, Loo B-M., Beatrice Knight, Andreas Ziegler, Claudia Langenberg, Yoon Shin Cho, Paul M. Ridker, Mark J. Rieder, Praveen Sethupathy, Bert Bravenboer, J. Viikari, Matt Neville, Ioannis M. Stylianou, Andrew Walley, Jarvelin M-R., Jarred B. McAteer, Ronald M. Krauss, Augustine Kong, Oluf Pedersen, Mark J. Daly, Andrew P. Morris, Anna F. Dominiczak, Stéphane Cauchi, Michael Boehnke, Christopher J. O'Donnell, Barbara Thorand, Peter M. Nilsson, Aaron Isaacs, Deborah A. Nickerson, Roza Blagieva, Mary F. Feitosa, Nicholas J. Wareham, Robert Roberts, J S Kooner, K W van Dijk, Tiinamaija Tuomi, Paul Scheet, Lynda M. Rose, Albert V. Smith, Rafn Benediktsson, Chiara Sabatti, Candace Guiducci, Lee M. Kaplan, Aki S. Havulinna, Toby Johnson, Samuli Ripatti, Erik Ingelsson, Mario A. Morken, Carl G. P. Platou, Anke Tönjes, Qi Sun, Narisu Narisu, S J Bumpstead, Jose M. Ordovas, Alan B. Feranil, L Groop, P Chines, Sara M. Willems, Perry Jrb., Matthew A. Allison, Jan Scott, Cécile Lecoeur, Kastelein Jjp., Herman A. Taylor, Anyuan Cao, Christopher J. Groves, Lincoln D. Stein, Laura J. Scott, John Beilby, Kristin G. Ardlie, Christopher S. Franklin, Yoav Ben-Shlomo, B M Shields, N J Timpson, Marco Orrù, Amélie Bonnefond, Kiran Musunuru, Murielle Bochud, Udo Seedorf, Yongmei Liu, Guillaume Lettre, Lee J-Y., Alan R. Shuldiner, Ryan P. Welch, David J. Hunter, John Whitfield, Klaus Strassburger, Khaw K-T., Hartikainen A-L., Gunnar Sigurðsson, Lu Qi, Richard N. Bergman, G M Lathrop, Sigrid W. Fouchier, T van Herpt, David S. Siscovick, Igor Rudan, Richard M. Watanabe, Themistocles L. Assimes, Nicholas G. Martin, Ozren Polasek, Dhiraj Varma, K Kim, Oliver Hofmann, Nicholas D. Hastie, S Bumpstead, Jose C. Florez, Fernando Rivadeneira, Katharine R. Owen, Braxton D. Mitchell, Alisa K. Manning, Abbas Dehghan, Bruce Bartholow Duncan, Cisca Wijmenga, Timo T. Valle, Jaakko Kaprio, Mika Kivimäki, B Shields, Laila Simpson, Tim D. Spector, Paul W. Franks, Guangju Zhai, María Teresa Martínez-Larrad, Janssens Acjw., Kim L. Ward, Inês Barroso, Xiuqing Guo, Rosa Maria Roccasecca, Zari Dastani, Reijo Laaksonen, Wilmar Igl, Vincent Mooser, Niels Grarup, Cornelia Huth, Christian Gieger, Fabio Marroni, Jaakko Tuomilehto, Doney Asf., Andrew C. Edmondson, Christian Fuchsberger, Meena Kumari, David M. Nathan, Reedik Mägi, Solomon K. Musani, U de Faire, Knut Borch-Johnsen, Masahiro Koseki, Giuseppe Paolisso, Norman Klopp, Caroline S. Fox, Nelson B. Freimer, Mika Kähönen, Peter Henneman, Diana Zelenika, K Willems-Vandijk, Steven A. McCarroll, Paul Elliott, Wichmann H-E., J. C. Bis, Nita G. Forouhi, Antti Jula, Witteman Jcm., Fredrik Karpe, Joseph Hung, Antje Fischer-Rosinsky, Eric J. Brunner, Elena Gonzalez, Soumya Raychaudhuri, Jian'an Luan, Josée Dupuis, Joshua C. Randall, Taesung Park, Francis S. Collins, Lori L. Bonnycastle, Andrew A. Hicks, Peter Kovacs, Thomas Illig, Maja Barbalić, David Couper, Jaspal S. Kooner, Damien C. Croteau-Chonka, Gavin Lucas, P J Wagner, Young-Jin Kim, Yurii S. Aulchenko, Aurelian Bidulescu, Ingrid Meulenbelt, Pilar Galan, Iris M. Heid, Michael N. Weedon, Serena Sanna, Sarah H. Wild, Hivert M-F., Patricia B. Munroe, Johan G. Eriksson, Teresa Ferreira, Robert A. Scott, A. Sandbaek, Kenneth Rice, Veronique Vitart, Xin Yuan, Leslie A. Lange, Hilma Holm, Jorge R. Kizer, Timothy M. Frayling, Marika Kaakinen, Liu C-T., Petersen A-K., Peter Schwarz, G B Walters, Palmer Cna., Jean Tichet, Bernhard Paulweber, Ying Wu, Alyson Hall, Christopher T. Johansen, David Masson, Martin Ladouceur, Christie M. Ballantyne, Tai E-S., Robert Luben, Guillaume Charpentier, Angela Döring, Philip J. Barter, Ruth McPherson, Benjamin F. Voight, Wolfgang Rathmann, Mark Walker, Markus Perola, M. A. Province, Veikko Salomaa, James B. Meigs, George Davey Smith, Robert Clarke, Gerard Waeber, Stefania Bandinelli, Sally L. Ricketts, Kaisa Silander, Loos Rjf., Amanda J. Bennett, John C. Chambers, Marilyn C. Cornelis, L A Cupples, Andrew T. Hattersley, M Sandhu, Marju Orho-Melander, C M van Duijn, Olli T. Raitakari, David Meyre, Ida Surakka, Jouke-Jan Hottenga, Uh H-W., Kari Stefansson, David Melzer, P E Slagboom, Kristian Midthjell, Robert K. Semple, James P. Pirruccello, Aloysius G Lieverse, Åsa Johansson, Michael Roden, Felicity Payne, Eric J.G. Sijbrands, N P Burtt, David R. Hillman, Michael Marmot, Todd Green, Eric E. Schadt, Sijbrands Ejg., Tien Yin Wong, Coin Ljm., K B Boström, Olov Rolandsson, A D Morris, David Altshuler, Harald Grallert, L C Groop, Alan F. Wright, Karen Kapur, Xueling Sim, Philippe Froguel, K O Kyvik, T. Lauritzen, Linda S. Adair, Yavuz Ariyurek, Talin Haritunians, Toshiko Tanaka, Albert Hofman, MariaGrazia Franzosi, Nicholas L. Smith, Laura Crisponi, Andrew B. Singleton, A Uitterlinden, Bo Isomaa, Y A Kesaniemi, Anne U. Jackson, Christa Meisinger, Holly E. Syddall, Dorret I. Boomsma, Harry Campbell, Gonçalo R. Abecasis, Lyudmyla Kedenko, Christine Cavalcanti-Proença, G Crawford, Scott M. Grundy, Johnson Prv., Nuotio M-L., I Chen, J.H. Smit, Anuj Goel, M Li, David P. Strachan, Kenechi Ejebe, Beverley Balkau, Neelam Hassanali, Kristian Hveem, Pierre Meneton, R. Gwilliam, A J Swift, Caroline Hayward, J. Graessler, Carina Zabena, B. St Pourcain, Michel Marre, Margot Haun, Lyytikäinen L-P., Ben A. Oostra, Stefan Coassin, M. van Hoek, Nigel W. Rayner, John R. Thompson, Kurt Lohman, Ulla Sovio, Unnur Thorsteinsdottir, Naveed Sattar, Lyle J. Palmer, Ulf Gyllensten, A Elliott, Muredach P. Reilly, A Swift, Luigi Ferrucci, Syvänen A-C., Simon C. Potter, T.W. van Haeften, G Wu, Stefan Böhringer, Grant W. 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Amsterdam Cardiovascular Sciences, Vascular Medicine, Cardiology, Human genetics, Psychiatry, NCA - Attention & Cognition, EMGO - Lifestyle, overweight and diabetes, Lääketieteen yksikkö - School of Medicine, University of Tampere, Institute for Molecular Medicine Finland, Hjelt Institute (-2014), Clinicum, Department of General Practice and Primary Health Care, Department of Public Health, Haartman Institute (-2014), Transplantation Laboratory, Biostatistics Helsinki, Quantitative Genetics, Complex Disease Genetics, Genetic Epidemiology, DIAGRAM+ Consortium, MAGIC Consortium, GLGC Investigators, MuTHER Consortium, DIAGRAM Consortium, GIANT Consortium, Global B Pgen Consortium, Procardis Consortium, MAGIC investigators, GLGC Consortium, Olson, J., Kronmal, R., Robbins, J., Chaves, PH., Burke, G., Kuller, LH., Tracy, R., Gottdiener, J., Prineas, R., Becker, JT., Enright, P., Klein, R., and O'Leary, DH.

Subjects
Netherlands Twin Register (NTR), Male, Insulin Resistance/genetics, VARIANTS, 0302 clinical medicine, POPULATION, African Americans, blood/genetics, 0303 health sciences, education.field_of_study, Adiponectin/blood, Adiponectin/genetics, Asian Continental Ancestry Group, Cholesterol, HDL/genetics, Diabetes Mellitus, Type 2/genetics, European Continental Ancestry Group, Female, Gene Expression, Genetic Predisposition to Disease, Genome-Wide Association Study, Glucose Tolerance Test, Humans, Metabolic Networks and Pathways, Polymorphism, Single Nucleotide, Waist-Hip Ratio, Global B Pgen Consortium, MAGIC investigators, 3. Good health, Cholesterol, Medicine, Adiponectin, Type 2, medicine.medical_specialty, HDL, Biolääketieteet - Biomedicine, Single-nucleotide polymorphism, DIAGRAM Consortium, White People, Molecular Genetics, GLGC Consortium, 03 medical and health sciences, Asian People, SDG 3 - Good Health and Well-being, GIANT Consortium, Diabetes Mellitus, Genetics, DIAGRAM+ Consortium, GENOME-WIDE ASSOCIATION, Polymorphism, education, Biology, Molecular Biology, Ecology, Evolution, Behavior and Systematics, 0604 Genetics, Science & Technology, GLGC Investigators, nutritional and metabolic diseases, ta3121, medicine.disease, Obesity, Black or African American, blood/genetics, African Americans, Asian Continental Ancestry Group, Cholesterol, genetics, Diabetes Mellitus, genetics, European Continental Ancestry Group, Female, Gene Expression, Genetic Predisposition to Disease, Genome-Wide Association Study, Glucose Tolerance Test, Humans, Insulin Resistance, genetics, Male, Metabolic Networks and Pathways, Polymorphism, Single Nucleotide, Waist-Hip Ratio, Endocrinology, Diabetes Mellitus, Type 2, Developmental Biology, Type 2/genetics, Cancer Research, Type 2 diabetes, QH426-470, 030204 cardiovascular system & hematology, LIPID CONCENTRATIONS, GENETICS & HEREDITY, Genetics (clinical), RISK, 2. Zero hunger, INSULIN-RESISTANCE, Glucose tolerance test, medicine.diagnostic_test, MAGIC Consortium, Single Nucleotide, ADIPOSE-TISSUE, CORONARY-ARTERY-DISEASE, Life Sciences & Biomedicine, Research Article, Clinical Research Design, GENETIC-BASIS, Population, Insulin resistance, Internal medicine, Diabetes mellitus, medicine, ddc:610, 030304 developmental biology, RECEPTOR, Cholesterol, HDL, Human Genetics, HDL/genetics, 3121 General medicine, internal medicine and other clinical medicine, MuTHER Consortium, 3111 Biomedicine, Procardis Consortium, Insulin Resistance
Abstract

Circulating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (P = 4.5×10−8–1.2×10−43). Using a novel method to combine data across ethnicities (N = 4,232 African Americans, N = 1,776 Asians, and N = 29,347 Europeans), we identified two additional novel loci. Expression analyses of 436 human adipocyte samples revealed that mRNA levels of 18 genes at candidate regions were associated with adiponectin concentrations after accounting for multiple testing (p, Author Summary Serum adiponectin levels are highly heritable and are inversely correlated with the risk of type 2 diabetes (T2D), coronary artery disease, stroke, and several metabolic traits. To identify common genetic variants associated with adiponectin levels and risk of T2D and metabolic traits, we conducted a meta-analysis of genome-wide association studies of 45,891 multi-ethnic individuals. In addition to confirming that variants at the ADIPOQ and CDH13 loci influence adiponectin levels, our analyses revealed that 10 new loci also affecting circulating adiponectin levels. We demonstrated that expression levels of several genes in these candidate regions are associated with serum adiponectin levels. Using a powerful novel method to assess the contribution of the identified variants with other traits using summary-level results from large-scale GWAS consortia, we provide evidence that the risk alleles for adiponectin are associated with deleterious changes in T2D risk and metabolic syndrome traits (triglycerides, HDL, post-prandial glucose, insulin, and waist-to-hip ratio), demonstrating that the identified loci, taken together, impact upon metabolic disease.

Published
2012
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28. Four Novel Loci (19q13, 6q24, 12q24, and 5q14) Influence the Microcirculation In Vivo

Author

Barbara E.K. Klein, Paul Mitchell, Elizabeth G. Holliday, Gerald Liew, F.M. Amirul Islam, Samantha J. Fahy, Terri L. Young, David S. Siscovick, Susan R. Heckbert, Barbara McKnight, Nicholas G. Martin, John Attia, Bruce M. Psaty, Rodney J. Scott, Vilmundur Gudnason, Tamara B. Harris, Fernando Rivadeneira, Albert Hofman, Tien Yin Wong, Nicole L. Glazer, Annie K McAuley, Mary Frances Cotch, Gudny Eiriksdottir, M. Arfan Ikram, Xueling Sim, André G. Uitterlinden, Eric Boerwinkle, J. C. Bis, Theru A. Sivakumaran, Albert V. Smith, Kerri L. Wiggins, Sudha K. Iyengar, Thomas Lumley, Ching-Yu Cheng, Ning Cheung, Ronald Klein, Kent D. Taylor, Johannes R. Vingerling, Thor Aspelund, Jie Jin Wang, David A. Mackey, Christopher J Hammond, Fridbert Jonasson, E. Shyong Tai, Quansheng Xi, Linda Kao, M. Kamran Ikram, Stuart MacGregor, Cornelia M. van Duijn, Toby Andrew, Monique M.B. Breteler, Alex W. Hewitt, Paulus T. V. M. de Jong, Xiaohui Li, Jerome I. Rotter, Lenore J. Launer, and Richard A. Jensen

Subjects
Cancer Research, lcsh:Genetics, lcsh:QH426-470, In vivo, Genetics, Correction, Computational biology, Biology, Molecular Biology, Genetics (clinical), Ecology, Evolution, Behavior and Systematics, Microcirculation
Abstract

The second author's name contained an error. Sim Xueling should be Xueling Sim. The correct citation is: Ikram MK, Sim X, Jensen RA, Cotch MF, Hewitt AW, et al. (2010) Four Novel Loci (19q13, 6q24, 12q24, and 5q14) Influence the Microcirculation In Vivo. PLoS Genet 6(10): e1001184. doi:10.1371/journal.pgen.1001184.

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