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34 results on '"Pulit, S.L."'

1. Identification of an Amino Acid Motif in HLA–DRβ1 That Distinguishes Uveitis in Patients With Juvenile Idiopathic Arthritis

Author

Haasnoot, A.M.J.W., Schilham, M.W., Kamphuis, S., Muller, P.C.E.H., Heiligenhaus, A., Foell, D., Minden, K., Ophoff, R.A., Radstake, T.R.D.J., Hollander, A.I. den, Reinards, T.H.C.M., Hiddingh, S., Schalij-Delfos, N.E., Hoppenreijs, E.P.A.H., Rossum, M.A.J. van, Wouters, C., Saurenmann, R.K., Berg, J.M. van den, Wulffraat, N.M., Cate, R. ten, Boer, J.H. de, Pulit, S.L., Kuiper, J.J.W., ICON-JIA Study Grp, Pediatrics, General Paediatrics, AII - Amsterdam institute for Infection and Immunity, AII - Inflammatory diseases, Paediatric Infectious Diseases / Rheumatology / Immunology, and University of Zurich

Subjects
0301 basic medicine, Male, Linkage disequilibrium, genetic structures, 2745 Rheumatology, Amino Acid Motifs, Medizin, Arthritis, Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12], Cohort Studies, Genotype, Odds Ratio, Immunology and Allergy, Child, biology, Child, Preschool, 2723 Immunology and Allergy, Female, Uveitis, Inflammatory diseases Radboud Institute for Molecular Life Sciences [Radboudumc 5], musculoskeletal diseases, Adolescent, Immunology, 610 Medicine & health, Human leukocyte antigen, Major histocompatibility complex, 03 medical and health sciences, All institutes and research themes of the Radboud University Medical Center, Rheumatology, medicine, Genetic predisposition, Humans, Genetic Predisposition to Disease, Alleles, Genetic Association Studies, 2403 Immunology, business.industry, Odds ratio, medicine.disease, Arthritis, Juvenile, eye diseases, 030104 developmental biology, 10036 Medical Clinic, Genetic Loci, biology.protein, business, HLA-DRB1 Chains
Abstract

Objective: Uveitis is a visually debilitating disorder that affects up to 30% of children with the most common forms of juvenile idiopathic arthritis (JIA). The disease mechanisms predisposing only a subgroup of children to uveitis are unknown. This study was undertaken to identify genetic susceptibility loci for uveitis in JIA, using a genome-wide association study in 522 children with JIA. Methods: Two cohorts of JIA patients with ophthalmologic follow-up data were genotyped. Data were then imputed using a genome-wide imputation reference panel, and an HLA-specific reference panel was used for imputing amino acids and HLA types in the major histocompatibility complex (MHC). After imputation, genome-wide and MHC-specific analyses were performed, and a reverse immunology approach was utilized to model antigen presentation at 13 common HLA–DRβ1 alleles. Results: Presence of the amino acid serine at position 11 (serine 11) in HLA–DRβ1 was associated with an increased risk of uveitis in JIA patients (odds ratio [OR] 2.60, P = 5.43 × 10−10) and was specific to girls (Pfemales = 7.61 × 10−10 versus Pmales = 0.18). Serine 11 resides in the YST motif in the peptide-binding groove of HLA–DRβ1; all 3 amino acids in this motif are in perfect linkage disequilibrium and show identical association with disease. Quantitative prediction of binding affinity revealed that HLA–DRβ1 alleles with the YST motif could be distinguished on the basis of discernable peptide-binding preferences. Conclusion: These findings highlight a genetically distinct, sexually dimorphic feature of JIA with uveitis as compared to JIA without uveitis. The association could be indicative of the potential involvement of antigen presentation by HLA–DRβ1 in the development of uveitis in JIA. The results of this study may advance our progress toward improved treatments for, and possible prevention of, the sight-threatening complications of uveitis in children with JIA.

Published
2018
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2. Genetic and lifestyle risk factors for MRI-defined brain infarcts in a population-based setting

Author

Chauhan, G., Adams, H.H.H., Satizabal, C.L., Bis, J.C., Teumer, A., Sargurupremraj, M., Hofer, E., Trompet, S., Hilal, S., Smith, A.V., Jian, X.Q., Malik, R., Traylor, M., Pulit, S.L., Amouyel, P., Mazoyer, B., Zhu, Y.C., Kaffashian, S., Schilling, S., Beecham, G.W., Montine, T.J., Schellenberg, G.D., Kjartansson, O., Gudnason, V., Knopman, D.S., Griswold, M.E., Windham, B.G., Gottesman, R.F., Mosley, T.H., Schmidt, R., Saba, Y., Schmidt, H., Takeuchi, F., Yamaguchi, S., Nabika, T., Kato, N., Rajan, K.B., Aggarwal, N.T., Jager, P.L. de, Evans, D.A., Psaty, B.M., Rotter, J.I., Rice, K., Lopez, O.L., Liao, J.M., Chen, C., Cheng, C.Y., Wong, T.Y., Ikram, M.K., Lee, S.J. van der, Amin, N., Chouraki, V., DeStefano, A.L., Aparicio, H.J., Romero, J.R., Maillard, P., DeCarli, C., Wardlaw, J.M., Hernandez, M.D.V., Luciano, M., Liewald, D., Deary, I.J., Starr, J.M., Bastin, M.E., Maniega, S.M., Slagboom, P.E., Beekman, M., Deelen, J., Uh, H.W., Lemmens, R., Brodaty, H., Wright, M.J., Ames, D., Boncoraglio, G.B., Hopewell, J.C., Beecham, A.H., Blanton, S.H., Wright, C.B., Sacco, R.L., Wen, W., Thalamuthu, A., Armstrong, N.J., Chong, E., Schofield, P.R., Kwok, J.B., Grond, J. van der, Stott, D.J., Ford, I., Jukema, J.W., Vernooij, M.W., Hofman, A., Uitterlinden, A.G., Lugt, A. van der, Wittfeld, K., Grabe, H.J., Hosten, N., Sarnowski, B. von, Volker, U., Levi, C., Jimenez-Conde, J., Sharma, P., Sudlow, C.L.M., Rosand, J., Woo, D., Cole, J.W., Meschia, J.F., Slowik, A., Thijs, V., Lindgren, A., Melander, O., Grewal, R.P., Rundek, T., Rexrode, K., Rothwell, P.M., Arnett, D.K., Jern, C., Johnson, J.A., Benavente, O.R., Wasssertheil-Smoller, S., Lee, J.M., Wong, Q., Mitchell, B.D., Rich, S.S., McArdle, P.F., Geerlings, M.I., Graaf, Y. van der, Bakker, P.I.W. de, Asselbergs, F.W., Srikanth, V., Thomson, R., McWhirter, R., Moran, C., Callisaya, M., Phan, T., Rutten-Jacobs, L.C.A., Bevan, S., Tzourio, C., Mather, K.A., Sachdev, P.S., Duijn, C.M. van, Worrall, B.B., Dichgans, M., Kittner, S.J., Markus, H.S., Ikram, M.A., Fornage, M., Launer, L.J., Seshadri, S., Longstreth, W.T., Debette, S., Stroke Genetics Network SiGN, ISGC, METASTROKE, ADGC, and CHARGE Consortium

Subjects
Meta-analysis, Mendelian Randomization, Blood Pressure, Polymorphisms, Genome-wide Association, Silent, Insights, Small Vessel Disease, Matter Hyperintensity Volume, Ischemic Stroke, Doenças Cardio e Cérebro-vasculares
Abstract

Collaborators (845): Astrid M. Vicente Free PMC article:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6369905/ Objective: To explore genetic and lifestyle risk factors of MRI-defined brain infarcts (BI) in large population-based cohorts. Methods: We performed meta-analyses of genome-wide association studies (GWAS) and examined associations of vascular risk factors and their genetic risk scores (GRS) with MRI-defined BI and a subset of BI, namely, small subcortical BI (SSBI), in 18 population-based cohorts (n = 20,949) from 5 ethnicities (3,726 with BI, 2,021 with SSBI). Top loci were followed up in 7 population-based cohorts (n = 6,862; 1,483 with BI, 630 with SBBI), and we tested associations with related phenotypes including ischemic stroke and pathologically defined BI. Results: The mean prevalence was 17.7% for BI and 10.5% for SSBI, steeply rising after age 65. Two loci showed genome-wide significant association with BI: FBN2, p = 1.77 × 10-8; and LINC00539/ZDHHC20, p = 5.82 × 10-9. Both have been associated with blood pressure (BP)-related phenotypes, but did not replicate in the smaller follow-up sample or show associations with related phenotypes. Age- and sex-adjusted associations with BI and SSBI were observed for BP traits (p value for BI, p [BI] = 9.38 × 10-25; p [SSBI] = 5.23 × 10-14 for hypertension), smoking (p [BI] = 4.4 × 10-10; p [SSBI] = 1.2 × 10-4), diabetes (p [BI] = 1.7 × 10-8; p [SSBI] = 2.8 × 10-3), previous cardiovascular disease (p [BI] = 1.0 × 10-18; p [SSBI] = 2.3 × 10-7), stroke (p [BI] = 3.9 × 10-69; p [SSBI] = 3.2 × 10-24), and MRI-defined white matter hyperintensity burden (p [BI] = 1.43 × 10-157; p [SSBI] = 3.16 × 10-106), but not with body mass index or cholesterol. GRS of BP traits were associated with BI and SSBI (p ≤ 0.0022), without indication of directional pleiotropy. Conclusion: In this multiethnic GWAS meta-analysis, including over 20,000 population-based participants, we identified genetic risk loci for BI requiring validation once additional large datasets become available. High BP, including genetically determined, was the most significant modifiable, causal risk factor for BI. info:eu-repo/semantics/publishedVersion

Published
2019

3. WGS-based telomere length analysis in Dutch family trios implicates stronger maternal inheritance and a role for RRM1 gene

Author

Nersisyan, Lilit, Nikoghosyan, Maria, Arakelyan, Arsen, Francioli, Laurent, Menelaou, A. (Androniki), Pulit, S.L. (Sara L.), Elbers, C.C. (Clara C.), Kloosterman, Wigard, van Setten, J. (Jessica), Nijman, Isaac, Renkens, Ivo, de Bakker, P.I.W. (Paul I. W.), Dijk, Freerk, Neerincx, Pieter, Deelen, Patrick, Kanterakis, Alexandros, Dijkstra, Martijn, Byelas, H. (Heorhiy), van der Velde, K.J. (K. Joeri), Platteel, Mathieu, Swertz, M.A. (Morris A.), Wijmenga, Cisca, Palamara, P.F. (Pier Francesco), Pe’er, I. (Itsik), Ye, K. (Kai), Lameijer, Eric-Wubbo, Moed, M.H. (Matthijs H.), Beekman, M. (Marian), Craen, Anton, Suchiman, H.E.D. (H. Eka D.), Slagboom, Eline, Guryev, Victor, Abdellaoui, Abdel, Jan Hottenga, J. (Jouke), Kattenberg, M. (Mathijs), Willemsen, Gonneke, Boomsma, Dorret, van Leeuwen, E.M. (Elisabeth M.), Karssen, Lennart, Amin, N. (Najaf), Rivadeneira, F. (Fernando), Isaacs, A. (Aaron), Hofman, A. (Albert), Uitterlinden, André, Duijn, Cornelia, van Oven, M. (Mannis), Kayser, M. (Manfred), Vermaat, Martijn, Laros, Jeroen, Dunnen, Johan, Enckevort, David, Mei, Hailiang, Li, M. (Mingkun), Stoneking, M. (Mark), Schaik, Barbera, Bot, Jan, Marschall, Tobias, Schönhuth, Alexander, Hehir-Kwa, Jayne, Handsaker, Robert, Polak, P. (Paz), Sohail, M. (Mashaal), Vuzman, D. (Dana), Estrada, Karol, McCarroll, S.A. (Steven A.), Sunyaev, S.R. (Shamil R.), Hormozdiari, Fereydoun, Koval, Vyacheslav, Medina-Gomez, C. (Carolina), Oostra, B. (Ben), Veldink, Jan, van den Berg, L.H. (Leonard H.), Pitts, S.J. (Steven J.), Potluri, S. (Shobha), Sundar, P. (Purnima), Cox, D.R. (David R.), Knijff, Peter, Li, Q. (Qibin), Li, Y. (Yingrui), Du, Yuanping, Chen, Ruoyan, Cao, H. (Hongzhi), Wang, J. (Jun), Li, N. (Ning), Cao, S. (Sujie), Bovenberg, Jasper, Ommen, Gert-Jan, The Genome of the Netherlands Consortium, Biological Psychology, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Mental Health, APH - Methodology, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Department of Health and Life Sciences, Groningen Research Institute for Asthma and COPD (GRIAC), Stem Cell Aging Leukemia and Lymphoma (SALL), Experimental Immunology, CCA - Cancer biology and immunology, Epidemiology and Data Science, Amsterdam Gastroenterology Endocrinology Metabolism, Epidemiology, Internal Medicine, Genetic Identification, Clinical Genetics, and Genome of the Netherlands Consortium

Subjects
Male, Telomere Homeostasis/genetics, Netherlands Twin Register (NTR), Non-Mendelian inheritance, lcsh:Medicine, Datasets as Topic, Ribonucleoside Diphosphate Reductase/genetics, Genome of the Netherlands consortium, Genome informatics, Genome, 0302 clinical medicine, Models, 80 and over, Inheritance Patterns, lcsh:Science, Child, Netherlands, Genetics, Aged, 80 and over, 0303 health sciences, Multidisciplinary, Age Factors, Functional genomics, Single Nucleotide, ASSOCIATION, Telomere, Middle Aged, 030220 oncology & carcinogenesis, Trait, Female, Maternal Inheritance, Biotechnology, Maternal Age, Adult, Ribonucleoside Diphosphate Reductase, Adolescent, Offspring, PROTEINS, Quantitative trait locus, Biology, Polymorphism, Single Nucleotide, Article, Paternal Age, 03 medical and health sciences, Young Adult, Sex Factors, LUNG-CANCER, Genetic, Humans, Polymorphism, Telomere/metabolism, General, Gene, METAANALYSIS, 030304 developmental biology, Aged, Whole genome sequencing, Models, Genetic, Whole Genome Sequencing, Human Genome, lcsh:R, Telomere Homeostasis, SIZE, SUBUNIT, CELLS, Linear Models, lcsh:Q, Genome-Wide Association Study
Abstract

Telomere length (TL) regulation is an important factor in ageing, reproduction and cancer development. Genetic, hereditary and environmental factors regulating TL are currently widely investigated, however, their relative contribution to TL variability is still understudied. We have used whole genome sequencing data of 250 family trios from the Genome of the Netherlands project to perform computational measurement of TL and a series of regression and genome-wide association analyses to reveal TL inheritance patterns and associated genetic factors. Our results confirm that TL is a largely heritable trait, primarily with mother’s, and, to a lesser extent, with father’s TL having the strongest influence on the offspring. In this cohort, mother’s, but not father’s age at conception was positively linked to offspring TL. Age-related TL attrition of 40 bp/year had relatively small influence on TL variability. Finally, we have identified TL-associated variations in ribonuclease reductase catalytic subunit M1 (RRM1 gene), which is known to regulate telomere maintenance in yeast. We also highlight the importance of multivariate approach and the limitations of existing tools for the analysis of TL as a polygenic heritable quantitative trait.

Published
2019
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4. Reconsidering the causality of TIA1 mutations in ALS

Author

Van Der Spek, R.A., Van Rheenen, W., Pulit, S.L., Kenna, K.P., Ticozzi, N., Kooyman, M., Mclaughlin, R.L., Moisse, M., Van Eijk, K.R., Van Vugt, J.J.F.A., Lacoangeli, A., Andersen, P., Basak, A.N., Blair, I., De Carvalho, M., Chio, A., Corcia, P., Couratier, P., Drory, V.E., Glass, J.D., Hardiman, O., Mora, J.S., Morrison, K.E., Mitne-Neto, M., Robberecht, W., Shaw, P.J., Panades, M.P., Van Damme, P., Silani, V., Gotkine, M., Weber, M., Van Es, M.A., Landers, J.E., Al-Chalabi, A., Van Den Berg, L.H., Veldink, J.H., and CONSOR, PMALSS

Published
2018

5. Project MinE: study design and pilot analyses of a large-scale whole-genome sequencing study in amyotrophic lateral sclerosis

Author

Project, M.A.S.C., van Rheenen, W., Pulit, S.L., Dekker, A.M., Al Khleifat, A., Brands, W.J., Iacoangeli, A., Kenna, K.P., Kavak, E., Kooyman, M., McLaughlin, R.L., Middelkoop, B., Moisse, M., Schellevis, R.D., Shatunov, A., Sproviero, W., Tazelaar, G.H.P., van der Spek, R.A.A., van Doormaal, P.T.C., van Eijk, K.R., van Vugt, J., Basak, A.N., Blair, I.P., Glass, J.D., Hardiman, O., Hide, W., Landers, J.E., Mora, J.S., Morrison, K.E., Newhouse, S., Robberecht, W., Shaw, C.E., Shaw, P.J., van Damme, P., van Es, M.A., Wray, N.R., Al-Chalabi, A., van Den Berg, L.H., and Veldink, J.H.

Abstract

The most recent genome-wide association study in amyotrophic lateral sclerosis (ALS) demonstrates a disproportionate contribution from low-frequency variants to genetic susceptibility to disease. We have therefore begun Project MinE, an international collaboration that seeks to analyze whole-genome sequence data of at least 15 000 ALS patients and 7500 controls. Here, we report on the design of Project MinE and pilot analyses of successfully sequenced 1169 ALS patients and 608 controls drawn from the Netherlands. As has become characteristic of sequencing studies, we find an abundance of rare genetic variation (minor allele frequency < 0.1%), the vast majority of which is absent in public datasets. Principal component analysis reveals local geographical clustering of these variants within The Netherlands. We use the whole-genome sequence data to explore the implications of poor geographical matching of cases and controls in a sequence-based disease study and to investigate how ancestry-matched, externally sequenced controls can induce false positive associations. Also, we have publicly released genome-wide minor allele counts in cases and controls, as well as results from genic burden tests.

Published
2018

6. Association of NIPA1 repeat expansions with amyotrophic lateral sclerosis in a large international cohort

Author

Tazelaar, G.H.P., Dekker, A.M., van Vugt, J.J.F.A., van der Spek, R.A., Westeneng, H.-J., Kool, L.J.B.G., Kenna, K.P., van Rheenen, W., Pulit, S.L., McLaughlin, R.L., Sproviero, W., Iacoangeli, A., Hübers, A., Brenner, D., Morrison, K.E., Shaw, P.J., Shaw, C.E., Panadés, M.P., Mora Pardina, J.S., Glass, J.D., Hardiman, O., Al-Chalabi, A., van Damme, P., Robberecht, W., Landers, J.E., Ludolph, A.C., Weishaupt, J.H., van den Berg, L.H., Veldink, J.H., van Es, M.A., and Project MinE ALS Sequencing Consortium, .

Subjects
Male, Internationality, Neuroscience(all), Research Support, Non-U.S. Gov't, NIPA1, Clinical Neurology, Amyotrophic Lateral Sclerosis/genetics, Repeat expansion, Amyotrophic lateral sclerosis, Cohort Studies, DNA Repeat Expansion/genetics, Ageing, Logistic Models, Meta-Analysis as Topic, Journal Article, Humans, Female, Membrane Proteins/genetics, Geriatrics and Gerontology, Peptides/genetics, Genetic Association Studies, Developmental Biology
Abstract

NIPA1 (nonimprinted in Prader-Willi/Angelman syndrome 1) mutations are known to cause hereditary spastic paraplegia type 6, a neurodegenerative disease that phenotypically overlaps to some extent with amyotrophic lateral sclerosis (ALS). Previously, a genomewide screen for copy number variants found an association with rare deletions in NIPA1 and ALS, and subsequent genetic analyses revealed that long (or expanded) polyalanine repeats in NIPA1 convey increased ALS susceptibility. We set out to perform a large-scale replication study to further investigate the role of NIPA1 polyalanine expansions with ALS, in which we characterized NIPA1 repeat size in an independent international cohort of 3955 patients with ALS and 2276 unaffected controls and combined our results with previous reports. Meta-analysis on a total of 6245 patients with ALS and 5051 controls showed an overall increased risk of ALS in those with expanded (>8) GCG repeat length (odds ratio = 1.50, p = 3.8×10-5). Together with previous reports, these findings provide evidence for an association of an expanded polyalanine repeat in NIPA1 and ALS.

Published
2018

7. CHCHD10 variants in amyotrophic lateral sclerosis: where Is the evidence?

Author

Consortium, P.M.A.L.S.S., Veldink, J.H., Shaw, P.J., Tazelaar, G.H.P., van Rheenen, W., Pulit, S.L., van der Spek, R., Dekker, A.M., Moisse, M., McLaughlin, R.L., Sproviero, W., Kenna, K.P., Kooyman, M., van Doormaal, P.T.C., van Eijk, K.E., Middelkoop, B.M., Schellevis , R.D., Brands, W.J., Al-Chalabi , A., Morrison, K.E., Newhouse, S.E., Shaw, C.E., van Es, M.A., Nazli Basak, A., Akçimen, F., Kocoglu, C., Tunca, C., Povedano, M., Mora, J.S., Glass , J.D., van Damme, P., Robberecht , W., Hardiman, O., Landers, J.E., and van den Berg, L.H.

Abstract

Objective: After the initial report of a CHCHD10 mutation in mitochondrial disease with features resembling amyotrophic lateral sclerosis (ALS), CHCHD10 mutations have been considered to be a frequent cause for ALS. However, the exact pathogenicity and clinical significance of these mutations remain unclear. Here, we aimed to determine the role of CHCHD10 mutations in ALS.\ud Methods: We analyzed 4,365 whole genome sequenced ALS patients and 1,832 controls from 7 different countries and examined all nonsynonymous single nucleotide variants in CHCHD10. These were tested for association with ALS, independently and in aggregate using several genetic burden tests (including sequence kernel association test [SKAT], optimal unified test \ud [SKAT-O], and Firth logistic regression).\ud Results: We identified 3 new variants in cases, but only 1 was ALS-specific. lso, 1 control-specific mutation was identified. There was no increased burden of rare coding mutations among ALS patients compared to controls \ud (p=0.86, p=0.86, and p=0.88 for SKAT, SKAT-O, and Firth, respectively). The few carriers with potential pathogenic CHCHD10 mutations exhibited a slowly progressive ALS-like phenotype with atypical features such as myopathy and\ud deafness. \ud Interpretation: CHCHD10 mutations seem to be a far less prevalent cause of pure ALS than previously suggested, and instead appear related to more complex phenotypes. There appears to be insufficient evidence for the pathogenicity of most previously reported variants in pure ALS. This study shows that routine testing for CHCHD10 mutations in pure ALS is not recommended and illustrates the importance of sufficient genetic and functional evidence in establishing pathogenicity of genetic variants.

Published
2018

8. Genetic and lifestyle risk factors for MRI-defined brain infarcts in a population-based setting.

Author

Aparicio H.J., Del C. Valdes Hernandez M., Luciano M., Liewald D., Deary I.J., Starr J.M., Bastin M.E., Maniega S.M., Slagboom P.E., Beekman M., Deelen J., Uh H.-W., Lemmens R., Brodaty H., Wright M.J., Ames D., Boncoraglio G.B., Hopewell J.C., Beecham A.H., Blanton S.H., Wright C.B., Sacco R.L., Wen W., Thalamuthu A., Armstrong N.J., Chong E., Schofield P.R., Kwok J.B., van der Grond J., Stott D.J., Ford I., Jukema J.W., Vernooij M.W., Hofman A., Uitterlinden A.G., van der Lugt A., Wittfeld K., Grabe H.J., Hosten N., von Sarnowski B., Volker U., Levi C., Jimenez-Conde J., Sharma P., Sudlow C.L.M., Rosand J., Woo D., Cole J.W., Meschia J.F., Slowik A., Thijs V., Lindgren A., Melander O., Grewal R.P., Rundek T., Rexrode K., Rothwell P.M., Arnett D.K., Jern C., Johnson J.A., Benavente O.R., Wasssertheil-Smoller S., Lee J.-M., Wong Q., Mitchell B.D., Rich S.S., McArdle P.F., Geerlings M.I., van der Graaf Y., de Bakker P.I.W., Asselbergs F.W., Srikanth V., Thomson R., McWhirter R., Moran C., Callisaya M., Phan T., Rutten-Jacobs L.C.A., Bevan S., Tzourio C., Mather K.A., Sachdev P.S., van Duijn C.M., Worrall B.B., Dichgans M., Kittner S.J., Markus H.S., Ikram M.A., Fornage M., Launer L.J., Seshadri S., Longstreth W.T., Debette S., Chauhan G., Adams H.H.H., Satizabal C.L., Bis J.C., Teumer A., Sargurupremraj M., Hofer E., Trompet S., Hilal S., Smith A.V., Jian X., Malik R., Traylor M., Pulit S.L., Amouyel P., Mazoyer B., Zhu Y.-C., Kaffashian S., Schilling S., Beecham G.W., Montine T.J., Schellenberg G.D., Kjartansson O., Gudnason V., Knopman D.S., Griswold M.E., Windham B.G., Gottesman R.F., Mosley T.H., Schmidt R., Saba Y., Schmidt H., Takeuchi F., Yamaguchi S., Nabika T., Kato N., Rajan K.B., Aggarwal N.T., De Jager P.L., Evans D.A., Psaty B.M., Rotter J.I., Rice K., Lopez O.L., Liao J., Chen C., Cheng C.-Y., Wong T.Y., Ikram M.K., van der Lee S.J., Amin N., Chouraki V., Destefano A.L., Romero J.R., Maillard P., Decarli C., Wardlaw J.M., Aparicio H.J., Del C. Valdes Hernandez M., Luciano M., Liewald D., Deary I.J., Starr J.M., Bastin M.E., Maniega S.M., Slagboom P.E., Beekman M., Deelen J., Uh H.-W., Lemmens R., Brodaty H., Wright M.J., Ames D., Boncoraglio G.B., Hopewell J.C., Beecham A.H., Blanton S.H., Wright C.B., Sacco R.L., Wen W., Thalamuthu A., Armstrong N.J., Chong E., Schofield P.R., Kwok J.B., van der Grond J., Stott D.J., Ford I., Jukema J.W., Vernooij M.W., Hofman A., Uitterlinden A.G., van der Lugt A., Wittfeld K., Grabe H.J., Hosten N., von Sarnowski B., Volker U., Levi C., Jimenez-Conde J., Sharma P., Sudlow C.L.M., Rosand J., Woo D., Cole J.W., Meschia J.F., Slowik A., Thijs V., Lindgren A., Melander O., Grewal R.P., Rundek T., Rexrode K., Rothwell P.M., Arnett D.K., Jern C., Johnson J.A., Benavente O.R., Wasssertheil-Smoller S., Lee J.-M., Wong Q., Mitchell B.D., Rich S.S., McArdle P.F., Geerlings M.I., van der Graaf Y., de Bakker P.I.W., Asselbergs F.W., Srikanth V., Thomson R., McWhirter R., Moran C., Callisaya M., Phan T., Rutten-Jacobs L.C.A., Bevan S., Tzourio C., Mather K.A., Sachdev P.S., van Duijn C.M., Worrall B.B., Dichgans M., Kittner S.J., Markus H.S., Ikram M.A., Fornage M., Launer L.J., Seshadri S., Longstreth W.T., Debette S., Chauhan G., Adams H.H.H., Satizabal C.L., Bis J.C., Teumer A., Sargurupremraj M., Hofer E., Trompet S., Hilal S., Smith A.V., Jian X., Malik R., Traylor M., Pulit S.L., Amouyel P., Mazoyer B., Zhu Y.-C., Kaffashian S., Schilling S., Beecham G.W., Montine T.J., Schellenberg G.D., Kjartansson O., Gudnason V., Knopman D.S., Griswold M.E., Windham B.G., Gottesman R.F., Mosley T.H., Schmidt R., Saba Y., Schmidt H., Takeuchi F., Yamaguchi S., Nabika T., Kato N., Rajan K.B., Aggarwal N.T., De Jager P.L., Evans D.A., Psaty B.M., Rotter J.I., Rice K., Lopez O.L., Liao J., Chen C., Cheng C.-Y., Wong T.Y., Ikram M.K., van der Lee S.J., Amin N., Chouraki V., Destefano A.L., Romero J.R., Maillard P., Decarli C., and Wardlaw J.M.

Abstract

Objective To explore genetic and lifestyle risk factors of MRI-defined brain infarcts (BI) in large population-based cohorts. Methods We performed meta-analyses of genome-wide association studies (GWAS) and examined associations of vascular risk factors and their genetic risk scores (GRS) with MRI-defined BI and a subset of BI, namely, small subcortical BI (SSBI), in 18 population-based cohorts (n=20,949) from 5 ethnicities (3,726 with BI, 2,021 with SSBI). Top loci were followed up in 7 population-based cohorts (n = 6,862; 1,483 with BI, 630 with SBBI), and we tested associations with related phenotypes including ischemic stroke and pathologically defined BI. Results The mean prevalence was 17.7% for BI and 10.5% for SSBI, steeply rising after age 65. Two loci showed genome-wide significant association with BI: FBN2, p = 1.77 x 10-8; and LINC00539/ZDHHC20, p = 5.82 x 10-9. Both have been associated with blood pressure (BP)-related phenotypes, but did not replicate in the smaller follow-up sample or show associations with related phenotypes. Age- and sex-adjusted associations with BI and SSBI were observed for BP traits (p value for BI, p[BI] = 9.38 x 10-25; p [SSBI] = 5.23 x 10-14 for hypertension), smoking (p[BI]= 4.4 x 10-10; p [SSBI] = 1.2 x 10 -4), diabetes (p[BI] = 1.7 x 10 -8; p [SSBI] = 2.8 x 10 -3), previous cardiovascular disease (p [BI] = 1.0 x 10-18; p [SSBI] = 2.3 x 10-7), stroke (p [BI] = 3.9 x 10-69; p [SSBI] = 3.2 x 10 -24), and MRI-defined white matter hyperintensity burden (p [BI]=1.43 x 10-157; p [SSBI] = 3.16 x 10-106), but not with body mass index or cholesterol. GRS of BP traits were associated with BI and SSBI (p <= 0.0022), without indication of directional pleiotropy. Conclusion In this multiethnic GWAS meta-analysis, including over 20,000 population-based participants, we identified genetic risk loci for BI requiring validation once additional large datasets become available. High BP, including genetically determined, was the most significa

Published
2019

9. WGS-based telomere length analysis in Dutch family trios implicates stronger maternal inheritance and a role for RRM1 gene

Author

Nersisyan, L. (Lilit), Nikoghosyan, M. (Maria), Arakelyan, A. (Arsen), Francioli, L.C. (Laurent), Menelaou, A. (Androniki), Pulit, S.L. (Sara), Elbers, C.C. (Clara), Kloosterman, W.P. (Wigard), Setten, J. (Jessica) van, Nijman, I.J. (Isaac ), Renkens, I. (Ivo), de Bakker, P.I.W. (Paul I. W.), Dijk, F. (Freerk) van, Neerincx, P.B.T. (Pieter B T), Deelen, P. (Patrick), Kanterakis, A. (Alexandros), Dijkstra, M. (Martijn), Byelas, H. (Heorhiy), van der Velde, K.J. (K. Joeri), Platteel, I. (Inge), Swertz, M.A. (Morris A.), Wijmenga, C. (Cisca), Palamara, P.F. (Pier Francesco), Peer, I. (Itsik), Ye, K. (Kai), Lameijer, E.-W. (Eric-Wubbo), Moed, H. (Heleen), Beekman, M. (Marian), Craen, A.J. (Anton) de, Suchiman, H.E.D. (H. Eka D.), Slagboom, P.E. (Eline), Guryev, V. (Victor), Abdellaoui, A. (Abdel), Hottenga, J.J. (Jouke Jan), Kattenberg, V.M. (Mathijs), Willemsen, G.A.H.M. (Gonneke), Boomsma, D.I. (Dorret), van Leeuwen, E.M. (Elisabeth M.), Karssen, L.C. (Lennart), Amin, N. (Najaf), Rivadeneira, F. (Fernando), Isaacs, A.J. (Aaron), Hofman, A. (Albert), Uitterlinden, A.G. (André), Duijn, C.M. (Cornelia) van, Oven, M. (Mannis) van, Kayser, M.H. (Manfred), Vermaat, M. (Martijn), Laros, J.F.J. (Jeroen F.), Dunnen, J.T. (Johan) den, Enckevort, D. (David) van, Mei, S. (Shan), Li, M. (Mingkun), Stoneking, M. (Mark), Schaik, B.D.C. (Barbera) van, Bot, J.J. (Jan), Marschall, T. (Tanja), Schönhuth, A. (Alexander), Hehir-Kwa, J. (Jayne), Handsaker, R.E. (Robert), Polak, P., Sohail, M. (Mashaal), Vuzman, D. (Dana), Estrada Gil, K. (Karol), McCarroll, S.A. (Steve), Sunyaev, S.R. (Shamil), Hormozdiari, F. (Fereydoun), Koval, V. (Vyacheslav), Medina-Gomez, M.C. (Carolina), Oostra, B.A. (Ben), Veldink, J.H. (Jan), Berg, L.H. (Leonard) van den, Pitts, S.J. (Steven J.), Potluri, S. (Shobha), Sundar, P. (Purnima), Cox, D.R. (David), Knijff, P. (Peter) de, Li, Q. (Qibin), Li, Y. (Yingrui), Du, Y. (Yuanping), Chen, R. (Ruoyan), Cao, H. (Hongzhi), Wang, J. (Jun), Li, N. (Ning), Cao, S. (Sujie), Bovenberg, J.A. (Jasper), Ommen, G.J. (Gert) van, Nersisyan, L. (Lilit), Nikoghosyan, M. (Maria), Arakelyan, A. (Arsen), Francioli, L.C. (Laurent), Menelaou, A. (Androniki), Pulit, S.L. (Sara), Elbers, C.C. (Clara), Kloosterman, W.P. (Wigard), Setten, J. (Jessica) van, Nijman, I.J. (Isaac ), Renkens, I. (Ivo), de Bakker, P.I.W. (Paul I. W.), Dijk, F. (Freerk) van, Neerincx, P.B.T. (Pieter B T), Deelen, P. (Patrick), Kanterakis, A. (Alexandros), Dijkstra, M. (Martijn), Byelas, H. (Heorhiy), van der Velde, K.J. (K. Joeri), Platteel, I. (Inge), Swertz, M.A. (Morris A.), Wijmenga, C. (Cisca), Palamara, P.F. (Pier Francesco), Peer, I. (Itsik), Ye, K. (Kai), Lameijer, E.-W. (Eric-Wubbo), Moed, H. (Heleen), Beekman, M. (Marian), Craen, A.J. (Anton) de, Suchiman, H.E.D. (H. Eka D.), Slagboom, P.E. (Eline), Guryev, V. (Victor), Abdellaoui, A. (Abdel), Hottenga, J.J. (Jouke Jan), Kattenberg, V.M. (Mathijs), Willemsen, G.A.H.M. (Gonneke), Boomsma, D.I. (Dorret), van Leeuwen, E.M. (Elisabeth M.), Karssen, L.C. (Lennart), Amin, N. (Najaf), Rivadeneira, F. (Fernando), Isaacs, A.J. (Aaron), Hofman, A. (Albert), Uitterlinden, A.G. (André), Duijn, C.M. (Cornelia) van, Oven, M. (Mannis) van, Kayser, M.H. (Manfred), Vermaat, M. (Martijn), Laros, J.F.J. (Jeroen F.), Dunnen, J.T. (Johan) den, Enckevort, D. (David) van, Mei, S. (Shan), Li, M. (Mingkun), Stoneking, M. (Mark), Schaik, B.D.C. (Barbera) van, Bot, J.J. (Jan), Marschall, T. (Tanja), Schönhuth, A. (Alexander), Hehir-Kwa, J. (Jayne), Handsaker, R.E. (Robert), Polak, P., Sohail, M. (Mashaal), Vuzman, D. (Dana), Estrada Gil, K. (Karol), McCarroll, S.A. (Steve), Sunyaev, S.R. (Shamil), Hormozdiari, F. (Fereydoun), Koval, V. (Vyacheslav), Medina-Gomez, M.C. (Carolina), Oostra, B.A. (Ben), Veldink, J.H. (Jan), Berg, L.H. (Leonard) van den, Pitts, S.J. (Steven J.), Potluri, S. (Shobha), Sundar, P. (Purnima), Cox, D.R. (David), Knijff, P. (Peter) de, Li, Q. (Qibin), Li, Y. (Yingrui), Du, Y. (Yuanping), Chen, R. (Ruoyan), Cao, H. (Hongzhi), Wang, J. (Jun), Li, N. (Ning), Cao, S. (Sujie), Bovenberg, J.A. (Jasper), and Ommen, G.J. (Gert) van

Abstract

Telomere length (TL) regulation is an important factor in ageing, reproduction and cancer development. Genetic, hereditary and environmental factors regulating TL are currently widely investigated, however, their relative contribution to TL variability is still understudied. We have used whole genome sequencing data of 250 family trios from the Genome of the Netherlands project to perform computational measurement of TL and a series of regression and genome-wide association analyses to reveal TL inheritance patterns and associated genetic factors. Our results confirm that TL is a largely heritable trait, primarily with mother’s, and, to a lesser extent, with father’s TL having the strongest influence on the offspring. In this cohort, mother’s, but not father’s age at conception was positively linked to offspring TL. Age-related TL attrition of 40 bp/year had relatively small influence on TL variability. Finally, we have identified TL-associated variations in ribonuclease reductase catalytic subunit M1 (RRM1 gene), which is known to regulate telomere maintenance in yeast. We also highlight the importance of multivariate approach and the limitations of existing tools for the analysis of TL as a polygenic heritable quantitative trait.

Published
2019
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10. Skewed X-inactivation is common in the general female population

Author

Shvetsova, E. (Ekaterina), Sofronova, A. (Alina), Monajemi, R. (Ramin), Gagalova, K. (Kristina), Draisma, G. (Gerrit), White, S.J. (Stefan), Santen, G.W.E. (Gijs), Chuva De Sousa Lopes, S.M. (Susana M.), Heijmans, B.T. (Bastiaan T.), van Meurs, J. (Joyce), Jansen, R. (Rick), Franke, L. (Lude), Kielbasa, S.M. (Szymon M.), Dunnen, J.T. (Johan) den, ‘t Hoen, P.A.C. (Peter A. C.), Heijmans, B.T. (Bastiaan T), Meurs, J.B.J. (Joyce) van, Boomsma, D.I. (Dorret), Pool, R. (Reńe), Dongen, J. (Jenny) van, Hottenga, J.J. (Jouke Jan), Greevenbroek, M.M. van, Stehouwer, C.D. (Coen Da), Kallen, C.J. van der, Schalkwijk, C.G. (Casper), Wijmenga, C. (Cisca), Zhernakova, S. (Sasha), Tigchelaar, E.F. (Ettje F.), Slagboom, P.E. (Eline), Beekman, M. (Marian), Deelen, J. (Joris), Heemst, D. (Diana) van, Veldink, J.H. (Jan), Berg, L.H. (Leonard) van den, Duijn, C.M. (Cornelia) van, Hofman, B.A. (Bert A), Uitterlinden, A.G. (André), Jhamai, P.M. (Mila), Verbiest, M.M.P.J. (Michael), Suchiman, H.E.D. (H Eka D), Verkerk, M. (Marijn), Breggen, R. (Ruud) van der, van Rooij, J. (Jeroen), Lakenberg, N. (Nico), Mei, S. (Shan), Bot, J. (Jan), Zhernakova, D.V. (Dasha V), van ’t Hof, P. (Peter), Deelen, P. (Patrick), Nooren, I. (Irene), Moed, H. (Heleen), Vermaat, M. (Martijn), Luijk, R. (René), Jan Bonder, M. (Marc), Iterson, M. (Maarten) van, van Dijk, F. (Freerk), Van Galen, M. (Michiel), Arindrarto, W. (Wibowo), Swertz, M.A. (Morris A), Zwet, E.W. (Erik) van, Isaacs, A.J. (Aaron), Francioli, L.C. (Laurent), Menelaou, A. (Androniki), Pulit, S.L. (Sara), Dijk, F. (Freerk) van, Palamara, P.F. (Pier Francesco), Elbers, C.C. (Clara), Neerincx, P.B.T. (Pieter B T), Ye, K. (K.), Guryev, V. (Victor), Kloosterman, W. (Wp), Abdellaoui, A. (Abdel), van Leeuwen, E. (Em), Oven, M. (Mannis) van, Li, M. (M.), Laros, J. (Jf), Karssen, L.C. (Lennart), Kanterakis, A. (Alexandros), Amin, N. (Najaf), Hottenga, J. (Jj), Lameijer, E. (Ew), Kattenberg, V.M. (Mathijs), Dijkstra, M. (Martijn), Byelas, H. (Heorhiy), Setten, J. (Jessica) van, van Schaik, B. (Bd), Bot, J.J. (Jan), Nijman, I. (Ij), Renkens, I. (Ivo), Marschall, T. (Tanja), Schönhuth, A. (A.), Hehir-Kwa, J. (Jayne), Handsaker, R.E. (Robert), Polak, P., Sohail, M. (Mashaal), Vuzman, D. (Dana), Hormozdiari, F. (Fereydoun), Enckevort, D. (David) van, Mei, H. (H.), Koval, V. (Vyacheslav), Moed, M. (Mh), van der Velde, K. (Kj), Rivadeneira Ramirez, F. (Fernando), Estrada Gil, K. (Karol), Medina-Gomez, M.C. (Carolina), McCarroll, S. (Sa), de Craen, A. (Aj), Suchiman, H. (He), Hofman, B. (Ba), Oostra, B.A. (Ben), Uitterlinden, A. (Ag), Willemsen, G.A.H.M. (Gonneke), Platteel, I. (Inge), Veldink, J. (Jh), van den Berg, L. (Lh), Pitts, S. (Sj), Potluri, S. (Shobha), Sundar, P. (Purnima), Cox, D. (Dr), Sunyaev, S. (Sr), den Dunnen, J. (Jt), Stoneking, M. (Mark), Knijff, P. (Peter) de, Kayser, M.H. (Manfred), Li, Q. (Q.), Li, Y. (Y.), Du, Y. (Y.), Chen, R. (R.), Cao, H. (H.), Li, N. (N.), Cao, S. (Sherry), Wang, J. (J.), Bovenberg, J.A. (Jasper), Peer, I. (Itsik), Slagboom, P. (Pe), van Duijn, C. (Cm), Boomsma, D. (Di), van Ommen, G. (Gj), de Bakker, P. (Pi), Swertz, M. (Ma), Wijmenga, C. (C.), Shvetsova, E. (Ekaterina), Sofronova, A. (Alina), Monajemi, R. (Ramin), Gagalova, K. (Kristina), Draisma, G. (Gerrit), White, S.J. (Stefan), Santen, G.W.E. (Gijs), Chuva De Sousa Lopes, S.M. (Susana M.), Heijmans, B.T. (Bastiaan T.), van Meurs, J. (Joyce), Jansen, R. (Rick), Franke, L. (Lude), Kielbasa, S.M. (Szymon M.), Dunnen, J.T. (Johan) den, ‘t Hoen, P.A.C. (Peter A. C.), Heijmans, B.T. (Bastiaan T), Meurs, J.B.J. (Joyce) van, Boomsma, D.I. (Dorret), Pool, R. (Reńe), Dongen, J. (Jenny) van, Hottenga, J.J. (Jouke Jan), Greevenbroek, M.M. van, Stehouwer, C.D. (Coen Da), Kallen, C.J. van der, Schalkwijk, C.G. (Casper), Wijmenga, C. (Cisca), Zhernakova, S. (Sasha), Tigchelaar, E.F. (Ettje F.), Slagboom, P.E. (Eline), Beekman, M. (Marian), Deelen, J. (Joris), Heemst, D. (Diana) van, Veldink, J.H. (Jan), Berg, L.H. (Leonard) van den, Duijn, C.M. (Cornelia) van, Hofman, B.A. (Bert A), Uitterlinden, A.G. (André), Jhamai, P.M. (Mila), Verbiest, M.M.P.J. (Michael), Suchiman, H.E.D. (H Eka D), Verkerk, M. (Marijn), Breggen, R. (Ruud) van der, van Rooij, J. (Jeroen), Lakenberg, N. (Nico), Mei, S. (Shan), Bot, J. (Jan), Zhernakova, D.V. (Dasha V), van ’t Hof, P. (Peter), Deelen, P. (Patrick), Nooren, I. (Irene), Moed, H. (Heleen), Vermaat, M. (Martijn), Luijk, R. (René), Jan Bonder, M. (Marc), Iterson, M. (Maarten) van, van Dijk, F. (Freerk), Van Galen, M. (Michiel), Arindrarto, W. (Wibowo), Swertz, M.A. (Morris A), Zwet, E.W. (Erik) van, Isaacs, A.J. (Aaron), Francioli, L.C. (Laurent), Menelaou, A. (Androniki), Pulit, S.L. (Sara), Dijk, F. (Freerk) van, Palamara, P.F. (Pier Francesco), Elbers, C.C. (Clara), Neerincx, P.B.T. (Pieter B T), Ye, K. (K.), Guryev, V. (Victor), Kloosterman, W. (Wp), Abdellaoui, A. (Abdel), van Leeuwen, E. (Em), Oven, M. (Mannis) van, Li, M. (M.), Laros, J. (Jf), Karssen, L.C. (Lennart), Kanterakis, A. (Alexandros), Amin, N. (Najaf), Hottenga, J. (Jj), Lameijer, E. (Ew), Kattenberg, V.M. (Mathijs), Dijkstra, M. (Martijn), Byelas, H. (Heorhiy), Setten, J. (Jessica) van, van Schaik, B. (Bd), Bot, J.J. (Jan), Nijman, I. (Ij), Renkens, I. (Ivo), Marschall, T. (Tanja), Schönhuth, A. (A.), Hehir-Kwa, J. (Jayne), Handsaker, R.E. (Robert), Polak, P., Sohail, M. (Mashaal), Vuzman, D. (Dana), Hormozdiari, F. (Fereydoun), Enckevort, D. (David) van, Mei, H. (H.), Koval, V. (Vyacheslav), Moed, M. (Mh), van der Velde, K. (Kj), Rivadeneira Ramirez, F. (Fernando), Estrada Gil, K. (Karol), Medina-Gomez, M.C. (Carolina), McCarroll, S. (Sa), de Craen, A. (Aj), Suchiman, H. (He), Hofman, B. (Ba), Oostra, B.A. (Ben), Uitterlinden, A. (Ag), Willemsen, G.A.H.M. (Gonneke), Platteel, I. (Inge), Veldink, J. (Jh), van den Berg, L. (Lh), Pitts, S. (Sj), Potluri, S. (Shobha), Sundar, P. (Purnima), Cox, D. (Dr), Sunyaev, S. (Sr), den Dunnen, J. (Jt), Stoneking, M. (Mark), Knijff, P. (Peter) de, Kayser, M.H. (Manfred), Li, Q. (Q.), Li, Y. (Y.), Du, Y. (Y.), Chen, R. (R.), Cao, H. (H.), Li, N. (N.), Cao, S. (Sherry), Wang, J. (J.), Bovenberg, J.A. (Jasper), Peer, I. (Itsik), Slagboom, P. (Pe), van Duijn, C. (Cm), Boomsma, D. (Di), van Ommen, G. (Gj), de Bakker, P. (Pi), Swertz, M. (Ma), and Wijmenga, C. (C.)

Abstract

X-inactivation is a well-established dosage compensation mechanism ensuring that X-chromosomal genes are expressed at comparable levels in males and females. Skewed X-inactivation is often explained by negative selection of one of the alleles. We demonstrate that imbalanced expression of the paternal and maternal X-chromosomes is common in the general population and that the random nature of the X-inactivation mechanism can be sufficient to explain the imbalance. To this end, we analyzed blood-derived RNA and whole-genome sequencing data from 79 female children and their parents from the Genome of the Netherlands project. We calculated the median ratio of the paternal over total counts at all X-chromosomal heterozygous single-nucleotide variants with coverage ≥10. We identified two individuals where the same X-chromosome was inactivated in all cells. Imbalanced expression of the two X-chromosomes (ratios ≤0.35 or ≥0.65) was observed in nearly 50% of the population. The empirically observed skewing is explained by a theoretical model where X-inactivation takes place in an embryonic stage in which eight cells give rise to the hematopoietic compartment. Genes escaping X-inactivation are expressed from both alleles and therefore demonstrate less skewing than inactivated genes. Using this characteristic, we identified three novel escapee genes (SSR4, REPS2, and SEPT6), but did not find support for many previously reported escapee genes in blood. Our collective data suggest that skewed X-inactivation is common in the general population. This may contribute to manifestation of symptoms in carriers of recessive X-linked disorders. We recommend that X-inactivation results should not be used lightly in the interpretation of X-linked variants.

Published
2018
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11. GWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes

Author

Franceschini, N. (Nora), Giambartolomei, C. (Claudia), Vries, P.S. (Paul) de, Finan, C. (Chris), Bis, J.C. (Joshua), Huntley, R.P. (Rachael P.), Lovering, R.C. (Ruth C.), Tajuddin, S.M. (Salman M.), Winkler, T.W. (Thomas W.), Graff, M. (Misa), Kavousi, M. (Maryam), Dale, C. (Caroline), Smith, A.V. (Albert), Hofer, E. (Edith), Leeuwen, E.M. (Elisa) van, Nolte, I.M. (Ilja), Lu, L. (Lingyi), Scholz, M. (Markus), Sargurupremraj, M. (Muralidharan), Pitkanen, N. (Niina), Franzén, O. (Oscar), Joshi, P.K. (Peter), Noordam, R. (Raymond), Marioni, R.E. (Riccardo), Hwang, S.-J. (Shih-Jen), Musani, S.K. (Solomon K.), Schminke, U. (Ulf), Palmas, W. (Walter), Isaacs, A.J. (Aaron), Correa, D.D., Zonderman, A.B., Hofman, A. (Albert), Teumer, A. (Alexander), Cox, A.J. (Amanda J.), Uitterlinden, A.G. (André), Wong, A. (Andrew), Smit, A.J. (Andries), Newman, A.B. (Anne B.), Britton, A.R., Ruusalepp, A. (Arno), Sennblad, B. (Bengt), Hedblad, B. (Bo), Pasaniuc, B. (Bogdan), Penninx, B.W.J.H. (Brenda), Langefeld, C.D. (Carl D.), Wassel, C.L. (Christina), Tzourio, C. (Christophe), Fava, C. (Cristiano), Baldassarre, D. (Damiano), O’Leary, D.H. (Daniel H.), Teupser, D. (Daniel), Kuh, D. (Diana), Tremoli, E. (Elena), Mannarino, E. (Elmo), Grossi, E. (Enzo), Boerwinkle, E.A. (Eric), Schadt, E.E. (Eric E.), Ingelsson, E. (Erik), Veglia, F. (Fabrizio), Rivadeneira Ramirez, F. (Fernando), Beutner, F. (Frank), Chauhan, G. (Ganesh), Heiss, G. (Gerardo), Snieder, H. (Harold), Campbell, H. (Harry), Völzke, H. (Henry), Markus, H.S. (Hugh), Deary, I.J. (Ian), Jukema, J.W. (Jan Wouter), Graaf, J. (Jacqueline) de, Price, J. (Jacqueline), Pott, J. (Janne), Hopewell, J., Liang, J. (Jingjing), Thiery, J.P. (Joachim), Engmann, J. (Jorgen), Gertow, K. (Karl), Rice, K.M. (Kenneth), Taylor, K.D. (Kent), Dhana, K. (Klodian), Kiemeney, L.A.L.M. (Lambertus A. L. M.), Kao, W.H.L. (Wen), Raffield, L.M. (Laura M.), Launer, L.J. (Lenore), Holdt, L.M. (Lesca), Dörr, M. (Marcus), Kubisch, C. (Christian), Traylor, M. (Matthew), Sitzer, M. (Matthias), Kumari, M. (Meena), Kivimaki, M. (Mika), Nalls, M.A. (Michael), Melander, O. (Olle), Raitakari, O. (Olli), Franco, O.H. (Oscar), Rueda-Ochoa, O.L. (Oscar), Roussos, A. (Alexandra), Whincup, P.H. (Peter), Amouyel, P. (Philippe), Giral, P. (Philippe), Anugu, P. (Pramod), Wong, Q. (Quenna), Malik, R. (Rainer), Rauramaa, R. (Rainer), Burkhardt, R. (Ralph), Hardy, R. (Rebecca), Schmidt, R. (Reinhold), Mutsert, R. (Reneé) de, Strawbridge, R.J. (Rona), Wannamethee, S.G. (Goya), Hägg, S. (Sara), Shah, S. (Sonia), McLachlan, S. (Stela), Trompet, S. (Stella), Seshadri, S. (Sudha), Kurl, S. (Sudhir), Heckbert, S.R. (Susan), Ring, S.M. (Susan), Harris, T.B. (Tamara B.), Lehtimäki, T. (Terho), Galesloot, T.E. (Tessel), Shah, T. (Tina), Faire, U. (Ulf) de, Plagnol, V. (Vincent), Rosamond, W.D. (Wayne), Post, W.S. (Wendy S.), Zhu, X. (Xiaofeng), Zhang, X. (Xiaoling), Guo, X. (Xiuqing), Saba, Y. (Yasaman), Okada, Y. (Yukinori), Mishra, A. (Aniket), Rutten-Jacobs, L. (Loes), Giese, A.-K. (Anne-Katrin), van der Laan, S.W. (Sander W.), Gretarsdottir, S. (Solveig), Anderson, C.D. (Christopher D.), Chong, M. (Michael), Adams, H.H.H. (Hieab), Ago, T. (Tetsuro), Almgren, P. (Peter), Ay, H. (Hakan), Bartz, T.M. (Traci M.), Benavente, O.R. (Oscar R.), Bevan, S. (Steve), Boncoraglio, G. (Giorgio Battista), Brown, R.D. (Robert D.), Butterworth, A.S. (Adam S.), Carrera, C. (Caty), Carty, C.L. (Cara L.), Chasman, D.I. (Daniel), Chen, W-M., Cole, J.W. (John W.), Cotlarciuc, I. (Ioana), Cruchaga, C. (Carlos), Danesh, J. (John), Bakker, P.I.W. (Paul) de, DeStefano, A.L. (Anita), Hoed, M. (Marcel) den, Duan, Q. (Qing), Engelter, S.T. (Stefan), Falcone, G.J. (Guido J.), Gottesman, R.F. (Rebecca), Grewal, R.P. (Raji P.), Gustafsson, S. (Stefan), Haessler, J. (Jeff), Harris, T.B. (Tamara), Hassan, A. (Ahamad), Havulinna, A.S. (Aki), Holliday, E.G. (Elizabeth), Howard, G. (George), Hsu, F.-C. (Fang-Chi), Hyacinth, H.I. (Hyacinth I.), Ikram, M.A. (Arfan), Irvin, M.R. (Marguerite R.), Jian, X. (Xueqiu), Jimenez-Conde, J. (Jordi), Johnson, J.A. (Julie A.), Jukema, J.W. (J. Wouter), Kanai, M. (Masahiro), Keene, K.L. (Keith), Kissela, B.M. (Brett M.), Kleindorfer, D.O. (Dawn O.), Kooperberg, C. (Charles), Kubo, M. (Michiaki), Lange, L.A. (Leslie), Langefeld, C.D. (Carl), Langenberg, C. (Claudia), Lee, J.-M. (Jin-Moo), Lemmens, R. (Robin), Leys, D. (Didier), Lewis, C.M. (Cathryn), Lin, W.-Y. (Wei-Yu), Lindgren, A.G. (Arne G.), Lorentzen, E. (Erik), Magnusson, P.K. (Patrik), Maguire, J.M. (Jane), Manichaikul, A. (Ani), McArdle, P.F. (Patrick), Meschia, J.F. (James F.), Mosley, T.H. (Thomas H.), Ninomiya, T. (Toshiharu), O’Donnell, M.J. (Martin J.), Pulit, S.L. (Sara), Rannikmäe, K. (Kristiina), Reiner, A.P. (Alexander P.), Rexrode, K. (Kathryn), Rich, S.S. (Stephen), Ridker, P.M. (Paul), Rost, N.S. (Natalia), Rothwell, P.M. (Peter), Rundek, T. (Tatjana), Muir, K.W. (Keith), Sakaue, S. (Saori), Sale, M.M. (Michele M.), Salomaa, V. (Veikko), Sapkota, B.R. (Bishwa R.), Schmidt, C.O. (Carsten O.), Sharma, P. (Pankaj), Slowik, A. (Agnieszka), Sudlow, C. (Cathie), Tanislav, C. (Christian), Tatlisumak, T. (Turgut), Thijs, V. (Vincent), Thorleifsson, G. (Gudmar), Thorsteinsdottir, U. (Unnur), Tiedt, S. (Steffen), Walters, M. (Matthew), Wareham, N.J. (Nick), Wassertheil-Smoller, S. (Sylvia), Wiggins, K.L. (Kerri), Yang, Q. (Qiong Fang), Yusuf, S. (Salim), Pastinen, T. (Tomi), Schadt, E.E. (Eric), Koplev, S. (Simon), Codoni, V. (Veronica), Civelek, M. (Mete), Smith, N.L. (Nicholas), Tregouet, D.-A. (David-Alexandre), Christophersen, I.E. (Ingrid E.), Roselli, C. (Carolina), Lubitz, S.A. (Steven A.), Ellinor, P.T. (Patrick), Tai, E.S. (E. Shyong), Kooner, J.S. (Jaspal S.), Kato, N. (Norihiro), He, J. (Jiang), Harst, P. (Pim) van der, Elliott, P. (Paul), Chambers, J.C. (John C.), Takeuchi, F. (Fumihiko), Johnson, A.D. (Andrew), Sanghera, D.K. (Dharambir K.), Jern, C. (Christina), Strbian, D. (Daniel), Fernandez-Cadenas, I. (Israel), Longstreth Jr, W.T., Rolfs, A. (Arndt), Hata, J. (Jun), Woo, D. (Daniel), Rosand, J. (Jonathan), Pare, G. (Guillame), Saleheen, D. (Danish), Zwart, J-A. (John-Anker), Worrall, B.B. (Bradford B.), Kittner, T. (Thomas), Howson, J.M.M. (Joanna M. M.), Kamatani, Y. (Yoichiro), Dehghan, A. (Abbas), Seldenrijk, K.A. (Kees), Morrison, A.C. (Alanna), Hamsten, A. (Anders), Psaty, B.M. (Bruce), Duijn, C.M. (Cornelia) van, Lawlor, D.A. (Debbie), Mook-Kanamori, D.O. (Dennis O.), Bowden, D.W. (Donald), Schmidt, H. (Helena), Wilson, J.F. (James F.), Wilson, J.F. (James), Rotter, J.I. (Jerome I.), Wardlaw, J.M. (J.), Deanfield, J. (John), Halcox, J. (Julian), Lyytikäinen, L.-P. (Leo-Pekka), Loeffler, M. (Markus), Evans, M.K. (Michele), Debette, S. (Stéphanie), Humphries, S.E. (Steve), Völker, U. (Uwe), Gudnason, V. (Vilmundur), Hingorani, A. (Aroon), Björkegren, J.L.M. (Johan L.M.), Casas, J.P. (Juan), Ódonnell, C.J. (Christopher), Morris, R.W. (Richard), Franceschini, N. (Nora), Giambartolomei, C. (Claudia), Vries, P.S. (Paul) de, Finan, C. (Chris), Bis, J.C. (Joshua), Huntley, R.P. (Rachael P.), Lovering, R.C. (Ruth C.), Tajuddin, S.M. (Salman M.), Winkler, T.W. (Thomas W.), Graff, M. (Misa), Kavousi, M. (Maryam), Dale, C. (Caroline), Smith, A.V. (Albert), Hofer, E. (Edith), Leeuwen, E.M. (Elisa) van, Nolte, I.M. (Ilja), Lu, L. (Lingyi), Scholz, M. (Markus), Sargurupremraj, M. (Muralidharan), Pitkanen, N. (Niina), Franzén, O. (Oscar), Joshi, P.K. (Peter), Noordam, R. (Raymond), Marioni, R.E. (Riccardo), Hwang, S.-J. (Shih-Jen), Musani, S.K. (Solomon K.), Schminke, U. (Ulf), Palmas, W. (Walter), Isaacs, A.J. (Aaron), Correa, D.D., Zonderman, A.B., Hofman, A. (Albert), Teumer, A. (Alexander), Cox, A.J. (Amanda J.), Uitterlinden, A.G. (André), Wong, A. (Andrew), Smit, A.J. (Andries), Newman, A.B. (Anne B.), Britton, A.R., Ruusalepp, A. (Arno), Sennblad, B. (Bengt), Hedblad, B. (Bo), Pasaniuc, B. (Bogdan), Penninx, B.W.J.H. (Brenda), Langefeld, C.D. (Carl D.), Wassel, C.L. (Christina), Tzourio, C. (Christophe), Fava, C. (Cristiano), Baldassarre, D. (Damiano), O’Leary, D.H. (Daniel H.), Teupser, D. (Daniel), Kuh, D. (Diana), Tremoli, E. (Elena), Mannarino, E. (Elmo), Grossi, E. (Enzo), Boerwinkle, E.A. (Eric), Schadt, E.E. (Eric E.), Ingelsson, E. (Erik), Veglia, F. (Fabrizio), Rivadeneira Ramirez, F. (Fernando), Beutner, F. (Frank), Chauhan, G. (Ganesh), Heiss, G. (Gerardo), Snieder, H. (Harold), Campbell, H. (Harry), Völzke, H. (Henry), Markus, H.S. (Hugh), Deary, I.J. (Ian), Jukema, J.W. (Jan Wouter), Graaf, J. (Jacqueline) de, Price, J. (Jacqueline), Pott, J. (Janne), Hopewell, J., Liang, J. (Jingjing), Thiery, J.P. (Joachim), Engmann, J. (Jorgen), Gertow, K. (Karl), Rice, K.M. (Kenneth), Taylor, K.D. (Kent), Dhana, K. (Klodian), Kiemeney, L.A.L.M. (Lambertus A. L. M.), Kao, W.H.L. (Wen), Raffield, L.M. (Laura M.), Launer, L.J. (Lenore), Holdt, L.M. (Lesca), Dörr, M. (Marcus), Kubisch, C. (Christian), Traylor, M. (Matthew), Sitzer, M. (Matthias), Kumari, M. (Meena), Kivimaki, M. (Mika), Nalls, M.A. (Michael), Melander, O. (Olle), Raitakari, O. (Olli), Franco, O.H. (Oscar), Rueda-Ochoa, O.L. (Oscar), Roussos, A. (Alexandra), Whincup, P.H. (Peter), Amouyel, P. (Philippe), Giral, P. (Philippe), Anugu, P. (Pramod), Wong, Q. (Quenna), Malik, R. (Rainer), Rauramaa, R. (Rainer), Burkhardt, R. (Ralph), Hardy, R. (Rebecca), Schmidt, R. (Reinhold), Mutsert, R. (Reneé) de, Strawbridge, R.J. (Rona), Wannamethee, S.G. (Goya), Hägg, S. (Sara), Shah, S. (Sonia), McLachlan, S. (Stela), Trompet, S. (Stella), Seshadri, S. (Sudha), Kurl, S. (Sudhir), Heckbert, S.R. (Susan), Ring, S.M. (Susan), Harris, T.B. (Tamara B.), Lehtimäki, T. (Terho), Galesloot, T.E. (Tessel), Shah, T. (Tina), Faire, U. (Ulf) de, Plagnol, V. (Vincent), Rosamond, W.D. (Wayne), Post, W.S. (Wendy S.), Zhu, X. (Xiaofeng), Zhang, X. (Xiaoling), Guo, X. (Xiuqing), Saba, Y. (Yasaman), Okada, Y. (Yukinori), Mishra, A. (Aniket), Rutten-Jacobs, L. (Loes), Giese, A.-K. (Anne-Katrin), van der Laan, S.W. (Sander W.), Gretarsdottir, S. (Solveig), Anderson, C.D. (Christopher D.), Chong, M. (Michael), Adams, H.H.H. (Hieab), Ago, T. (Tetsuro), Almgren, P. (Peter), Ay, H. (Hakan), Bartz, T.M. (Traci M.), Benavente, O.R. (Oscar R.), Bevan, S. (Steve), Boncoraglio, G. (Giorgio Battista), Brown, R.D. (Robert D.), Butterworth, A.S. (Adam S.), Carrera, C. (Caty), Carty, C.L. (Cara L.), Chasman, D.I. (Daniel), Chen, W-M., Cole, J.W. (John W.), Cotlarciuc, I. (Ioana), Cruchaga, C. (Carlos), Danesh, J. (John), Bakker, P.I.W. (Paul) de, DeStefano, A.L. (Anita), Hoed, M. (Marcel) den, Duan, Q. (Qing), Engelter, S.T. (Stefan), Falcone, G.J. (Guido J.), Gottesman, R.F. (Rebecca), Grewal, R.P. (Raji P.), Gustafsson, S. (Stefan), Haessler, J. (Jeff), Harris, T.B. (Tamara), Hassan, A. (Ahamad), Havulinna, A.S. (Aki), Holliday, E.G. (Elizabeth), Howard, G. (George), Hsu, F.-C. (Fang-Chi), Hyacinth, H.I. (Hyacinth I.), Ikram, M.A. (Arfan), Irvin, M.R. (Marguerite R.), Jian, X. (Xueqiu), Jimenez-Conde, J. (Jordi), Johnson, J.A. (Julie A.), Jukema, J.W. (J. Wouter), Kanai, M. (Masahiro), Keene, K.L. (Keith), Kissela, B.M. (Brett M.), Kleindorfer, D.O. (Dawn O.), Kooperberg, C. (Charles), Kubo, M. (Michiaki), Lange, L.A. (Leslie), Langefeld, C.D. (Carl), Langenberg, C. (Claudia), Lee, J.-M. (Jin-Moo), Lemmens, R. (Robin), Leys, D. (Didier), Lewis, C.M. (Cathryn), Lin, W.-Y. (Wei-Yu), Lindgren, A.G. (Arne G.), Lorentzen, E. (Erik), Magnusson, P.K. (Patrik), Maguire, J.M. (Jane), Manichaikul, A. (Ani), McArdle, P.F. (Patrick), Meschia, J.F. (James F.), Mosley, T.H. (Thomas H.), Ninomiya, T. (Toshiharu), O’Donnell, M.J. (Martin J.), Pulit, S.L. (Sara), Rannikmäe, K. (Kristiina), Reiner, A.P. (Alexander P.), Rexrode, K. (Kathryn), Rich, S.S. (Stephen), Ridker, P.M. (Paul), Rost, N.S. (Natalia), Rothwell, P.M. (Peter), Rundek, T. (Tatjana), Muir, K.W. (Keith), Sakaue, S. (Saori), Sale, M.M. (Michele M.), Salomaa, V. (Veikko), Sapkota, B.R. (Bishwa R.), Schmidt, C.O. (Carsten O.), Sharma, P. (Pankaj), Slowik, A. (Agnieszka), Sudlow, C. (Cathie), Tanislav, C. (Christian), Tatlisumak, T. (Turgut), Thijs, V. (Vincent), Thorleifsson, G. (Gudmar), Thorsteinsdottir, U. (Unnur), Tiedt, S. (Steffen), Walters, M. (Matthew), Wareham, N.J. (Nick), Wassertheil-Smoller, S. (Sylvia), Wiggins, K.L. (Kerri), Yang, Q. (Qiong Fang), Yusuf, S. (Salim), Pastinen, T. (Tomi), Schadt, E.E. (Eric), Koplev, S. (Simon), Codoni, V. (Veronica), Civelek, M. (Mete), Smith, N.L. (Nicholas), Tregouet, D.-A. (David-Alexandre), Christophersen, I.E. (Ingrid E.), Roselli, C. (Carolina), Lubitz, S.A. (Steven A.), Ellinor, P.T. (Patrick), Tai, E.S. (E. Shyong), Kooner, J.S. (Jaspal S.), Kato, N. (Norihiro), He, J. (Jiang), Harst, P. (Pim) van der, Elliott, P. (Paul), Chambers, J.C. (John C.), Takeuchi, F. (Fumihiko), Johnson, A.D. (Andrew), Sanghera, D.K. (Dharambir K.), Jern, C. (Christina), Strbian, D. (Daniel), Fernandez-Cadenas, I. (Israel), Longstreth Jr, W.T., Rolfs, A. (Arndt), Hata, J. (Jun), Woo, D. (Daniel), Rosand, J. (Jonathan), Pare, G. (Guillame), Saleheen, D. (Danish), Zwart, J-A. (John-Anker), Worrall, B.B. (Bradford B.), Kittner, T. (Thomas), Howson, J.M.M. (Joanna M. M.), Kamatani, Y. (Yoichiro), Dehghan, A. (Abbas), Seldenrijk, K.A. (Kees), Morrison, A.C. (Alanna), Hamsten, A. (Anders), Psaty, B.M. (Bruce), Duijn, C.M. (Cornelia) van, Lawlor, D.A. (Debbie), Mook-Kanamori, D.O. (Dennis O.), Bowden, D.W. (Donald), Schmidt, H. (Helena), Wilson, J.F. (James F.), Wilson, J.F. (James), Rotter, J.I. (Jerome I.), Wardlaw, J.M. (J.), Deanfield, J. (John), Halcox, J. (Julian), Lyytikäinen, L.-P. (Leo-Pekka), Loeffler, M. (Markus), Evans, M.K. (Michele), Debette, S. (Stéphanie), Humphries, S.E. (Steve), Völker, U. (Uwe), Gudnason, V. (Vilmundur), Hingorani, A. (Aroon), Björkegren, J.L.M. (Johan L.M.), Casas, J.P. (Juan), Ódonnell, C.J. (Christopher), and Morris, R.W. (Richard)

Abstract

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.

Published
2018
Full Text
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12. Sensitive Monogenic Noninvasive Prenatal Diagnosis by Targeted Haplotyping

Author

Vermeulen, C. Geeven, G. de Wit, E. Verstegen, M.J.A.M. Jansen, R.P.M. van Kranenburg, M. de Bruijn, E. Pulit, S.L. Kruisselbrink, E. Shahsavari, Z. Omrani, D. Zeinali, F. Najmabadi, H. Katsila, T. Vrettou, C. Patrinos, G.P. Traeger-Synodinos, J. Splinter, E. Beekman, J.M. Kheradmand Kia, S. te Meerman, G.J. Ploos van Amstel, H.K. de Laat, W.

Abstract

During pregnancy, cell-free DNA (cfDNA) in maternal blood encompasses a small percentage of cell-free fetal DNA (cffDNA), an easily accessible source for determination of fetal disease status in risk families through non-invasive procedures. In case of monogenic heritable disease, background maternal cfDNA prohibits direct observation of the maternally inherited allele. Non-invasive prenatal diagnostics (NIPD) of monogenic diseases therefore relies on parental haplotyping and statistical assessment of inherited alleles from cffDNA, techniques currently unavailable for routine clinical practice. Here, we present monogenic NIPD (MG-NIPD), which requires a blood sample from both parents, for targeted locus amplification (TLA)-based phasing of heterozygous variants selectively at a gene of interest. Capture probes-based targeted sequencing of cfDNA from the pregnant mother and a tailored statistical analysis enables predicting fetal gene inheritance. MG-NIPD was validated for 18 pregnancies, focusing on CFTR, CYP21A2, and HBB. In all cases we could predict the inherited alleles with >98% confidence, even at relatively early stages (8 weeks) of pregnancy. This prediction and the accuracy of parental haplotyping was confirmed by sequencing of fetal material obtained by parallel invasive procedures. MG-NIPD is a robust method that requires standard instrumentation and can be implemented in any clinic to provide families carrying a severe monogenic disease with a prenatal diagnostic test based on a simple blood draw. © 2017 The Authors

Published
2017

13. Deciphering the four-letter code : The genetic basis of complex traits and common disease

Author

Pulit, S.L., Bakker, P.I.W. de, and University Utrecht

Subjects
heritable traits, genomics, genetics, variation, common disease
Abstract

Deoxyribonucleic acid (DNA) is made up of four bases: adenine (A), cytosine (C), guanine (G), and thymine (T). Assembled in a strategic fashion, these bases code for the unique genomes of all walks of life, from viruses, to rodents, to primates. The human genome, mapped completely for the first time in April of 2003, is 3 billion bases long and contains approximately 20,000 genes. The genome of a randomly selected individual, checked base by base, will be approximately 99.9% identical to the reference map of the human genome. The other 0.1% (roughly 3 million bases total) will contain changes in the DNA that do not match to the canonical reference genome. These changes, or genetic variants, can have biological consequence, as they can impact the shape and function of the proteins for which genes code. Genetic variation accounts for much of the visible (phenotypic) diversity – such as eye color or height – that can be observed in humans today. Such variation also plays a role in susceptibility to disease in humans. In the last ten years, a major breakthrough in identifying the genetic changes that increase risk of disease has been genome-wide association studies (GWAS). In these studies, genetic variants (called single-nucleotide polymorphisms, or SNPs) observed in individuals with a particular trait or disorder (affected individuals) are compared to genetic variants observed in healthy (unaffected) individuals. SNPs that are observed more often in affected individuals than in unaffected individuals are associated to increased disease risk. They mark regions (called “loci”, singular “locus”) of the genome that can contain clues about a disease. Knowing which genes in a locus, when mutated, can increase risk of disease is a crucial first step in understanding why certain people are susceptible to disease while others are not. To date, GWAS have identified more than 7,000 loci that influence risk of disease. The primary goal of the work in this thesis is to identify genetic variants associated to risk of common disease. Finding such mutations can help identify disease-causing genes, potentially improving our ability to prevent, properly diagnose or treat illness in humans.

Published
2016

14. Low-frequency and common genetic variation in ischemic stroke : the METASTROKE collaboration

Author

Malik, R., Traylor, M., Pulit, S.L., Bevan, S., Hopewell, J.C., Holliday, E.G., Zhao, W., Abrantes, P., Amouyel, P., Attia, J.R., Battey, T.W., Berger, K., Boncoraglio, G.B., Chauhan, G., Cheng, Y.C., Chen, W.M., Clarke, R., Cotlarciuc, I., Debette, S., Falcone, G.J., Ferro, J.M., Gamble, D.M., Ilinca, A., Kittner, S.J., Kourkoulis, C.E., Lemmens, R., Levi, C.R., Lichtner, P., Lindgren, A., Liu, J., Meschia, J.F., Mitchell, B.D., Oliveira, S.A., Pera, J., Reiner, A.P., Rothwell, P.M., Sharma, P., Slowik, A., Sudlow, C.L., Tatlisumak, T., Thijs, V., Vicente, A.M., Woo, D., Seshadri, S., Saleheen, D., Rosand, J., Markus, H.S., Worrall, B.B., Dichgans, M., ISGC Analysis Group, METASTROKE collaboration, Wellcome Trust Case Control Consortium 2 (WTCCC2), and NINDS Stroke Genetics Network (SiGN)

Subjects
0301 basic medicine, medicine.medical_specialty, Genome-wide association study, Polymorphism, Single Nucleotide, Gastroenterology, Article, Brain Ischemia, Doenças Cardio e Cérebro-vasculares, 03 medical and health sciences, 0302 clinical medicine, Missing heritability problem, Internal medicine, ABO blood group system, Genetic variation, Humans, Medicine, Cooperative Behavior, 1000 Genomes Project, Allele frequency, Stroke, Ischemic Stroke, Genetic association, Genetics, business.industry, Genetic Variation, Correction, medicine.disease, 030104 developmental biology, Case-Control Studies, Ischemic stroke, Cardiology, Neurology (clinical), business, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Erratum in: Low-frequency and common genetic variation in ischemic stroke: The METASTROKE collaboration. [Neurology. 2016] Objective: To investigate the influence of common and low-frequency genetic variants on the risk of ischemic stroke (all IS) and etiologic stroke subtypes. Methods: We meta-analyzed 12 individual genome-wide association studies comprising 10,307 cases and 19,326 controls imputed to the 1000 Genomes (1 KG) phase I reference panel. We selected variants showing the highest degree of association (p , 1E-5) in the discovery phase for replication in Caucasian (13,435 cases and 29,269 controls) and South Asian (2,385 cases and 5,193 controls) samples followed by a transethnic meta-analysis. We further investigated the p value distribution for different bins of allele frequencies for all IS and stroke subtypes. Results: We showed genome-wide significance for 4 loci: ABO for all IS, HDAC9 for large vessel disease (LVD), and both PITX2 and ZFHX3 for cardioembolic stroke (CE). We further refined the association peaks for ABO and PITX2. Analyzing different allele frequency bins, we showed significant enrichment in low-frequency variants (allele frequency ,5%) for both LVD and small vessel disease, and an enrichment of higher frequency variants (allele frequency 10% and 30%) for CE (all p , 1E-5). Conclusions: Our findings suggest that the missing heritability in IS subtypes can in part be attributed to low-frequency and rare variants. Larger sample sizes are needed to identify the variants associated with all IS and stroke subtypes.

Published
2016

15. Genome-wide patterns and properties of de novo mutations in humans

Author

Francioli, L.C., Polak, P.P., Koren, A., Menelaou, A., Chun, S., Renkens, I., van Duijn, C.M., Swertz, M.A., Wijmenga, C., van Ommen, G.J., Slagboom, P.E., Boomsma, D.I., Ye, K., Guryev, V., Arndt, P.F., Kloosterman, W.P., Bakker, P.I.W., Sunyaev, S.R., Dijk, F., Neerincx, P.B.T., Pulit, S.L., Deelen, P., Elbers, C.C., Palamara, P.F., Pe'er, I., Abdellaoui, A., van Oven, M., Vermaat, M., Li, M., Laros, J.F.J., Stoneking, M., de Knijff, P., Kayser, M., Veldink, J.H., Van den Berg, L.H., Byelas, H., den Dunnen, J.T., Dijkstra, M., Amin, N., van der Velde, K.J., Hottenga, J.J., van Setten, J., van Leeuwen, E.M., Kanterakis, A., Kattenberg, V.M., Karssen, L.C., van Schaik, B.D.C., Bot, J., Nijman, I.J., van Enckevort, D., Mei, H., Koval, V., Estrada, K., Medina-Gomez, C., Lameijer, E.W., Moed, M.H., Hehir-Kwa, J.Y., Handsaker, R.E., McCarroll, S.A., Vuzman, D., Sohail, M., Hormozdiari, F., Marschall, T., Schönhuth, A., Beekman, M., de Craen, A.J., Suchiman, H.E.D., Hofman, A., Oostra, B., Isaacs, A., Rivadeneira, F., Uitterlinden, A.G., Willemsen, G., Platteel, M., Pitts, S.J., Potluri, S., Sundar, P., Cox, D.R., Li, Q., Li, Y., Du, Y., Chen, R., Cao, H., Li, N., Cao, S., Wang, J., Bovenberg, J.A., Brandsma, M., Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Stem Cell Aging Leukemia and Lymphoma (SALL), Groningen Research Institute for Asthma and COPD (GRIAC), Biological Psychology, Culture, Organization and Management, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, Epidemiology, and Pharmacy

Subjects
Male, Netherlands Twin Register (NTR), Mutation rate, Population genetics, Twin Study, DISEASE, Nucleotide diversity, 0302 clinical medicine, Mutation Rate, ELEMENTS, Non-U.S. Gov't, POPULATION, Genetics, 0303 health sciences, education.field_of_study, Research Support, Non-U.S. Gov't, SUBSTITUTION, Mutation (genetic algorithm), Female, Pan troglodytes, Population, DNA-SEQUENCING DATA, Mutagenesis (molecular biology technique), Biology, Research Support, Article, Paternal Age, N.I.H, Evolution, Molecular, 03 medical and health sciences, Germline mutation, SDG 3 - Good Health and Well-being, Research Support, N.I.H., Extramural, Journal Article, Animals, Humans, education, Germ-Line Mutation, 030304 developmental biology, Models, Genetic, Genome, Human, Extramural, FRAMEWORK, POLYMORPHISM, RECOMBINATION RATES, RESOLUTION, RADIATION, Human genome, 030217 neurology & neurosurgery
Abstract

Mutations create variation in the population, fuel evolution and cause genetic diseases. Current knowledge about de novo mutations is incomplete and mostly indirect(1-10). Here we analyze 11,020 de novo mutations from the whole genomes of 250 families. We show that de novo mutations in the offspring of older fathers are not only more numerous(11-13) but also occur more frequently in early-replicating, genic regions. Functional regions exhibit higher mutation rates due to CpG dinucleotides and show signatures of transcriptioncoupled repair, whereas mutation clusters with a unique signature point to a new mutational mechanism. Mutation and recombination rates independently associate with nucleotide diversity, and regional variation in human-chimpanzee divergence is only partly explained by heterogeneity in mutation rate. Finally, we provide a genome-wide mutation rate map for medical and population genetics applications. Our results provide new insights and refine long-standing hypotheses about human mutagenesis.

Published
2015
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16. No association between gluten sensitivity and amyotrophic lateral sclerosis

Author

Visser, A.E., Pazoki, R., Pulit, S.L., Rheenen, W. van, Raaphorst, J., Kooi, A.J. van der, Ricano-Ponce, I., Wijmenga, C., Otten, H.G., Veldink, J.H., Berg, L.H. van den, Visser, A.E., Pazoki, R., Pulit, S.L., Rheenen, W. van, Raaphorst, J., Kooi, A.J. van der, Ricano-Ponce, I., Wijmenga, C., Otten, H.G., Veldink, J.H., and Berg, L.H. van den

Abstract

Contains fulltext : 170399.pdf (publisher's version ) (Open Access), To examine evidence for a role of gluten sensitivity (GS) or celiac disease (CD) in ALS etiology, we included participants from a population-based case-control study in The Netherlands between January 2006 and December 2015. We compared levels and seroprevalence of IgA antibodies to tissue transglutaminase 6 (TG6) in 359 ALS patients and 359 controls, and to transglutaminase 2 (TG2) and endomysium (EMA) in 199 ALS patients and 199 controls. Questionnaire data on 1829 ALS patients and 3920 controls were examined for CD or gluten-free diets (GFD). Genetic correlation and HLA allele frequencies were analyzed using two genome-wide association studies: one on ALS (12,577 cases, 23,475 controls), and one on CD (4533 cases, 10,750 controls). We found one patient with TG6, TG2 and EMA antibodies who had typical ALS and no symptoms of GS. TG6 antibody concentrations and positivity, CD prevalence and adherence to a GFD were similar in patients and controls (p > 0.66) and in these patients disease progression was compatible with typical ALS. CD and ALS were not found to be genetically correlated (p > 0.37). CD-associated HLA allele frequencies were similar in patients and controls (p > 0.28). In conclusion, we found no serological evidence for involvement of gluten-related antibodies in ALS etiology nor did we observe an association between CD and ALS in medical history or genetic data, indicating that there is no evidence in our data for an association between the two diseases. Hence, a role for a GFD in the ALS treatment seems unlikely.

Published
2017

17. More than 25 years of genetic studies of clozapine-induced agranulocytosis

Author

With, S.A.J. de, Pulit, S.L., Staal, W.G., Kahn, R.S., Ophoff, R.A., With, S.A.J. de, Pulit, S.L., Staal, W.G., Kahn, R.S., and Ophoff, R.A.

Abstract

Item does not contain fulltext, Clozapine is one of the most effective atypical antipsychotic drugs prescribed to patients with treatment-resistant schizophrenia. Approximately 1% of patients experience potential life-threatening adverse effects in the form of agranulocytosis, greatly hindering its applicability in clinical practice. The etiology of clozapine-induced agranulocytosis (CIA) remains unclear, but is thought to be a heritable trait. We reviewed the genetic studies of CIA published thus far. One recurrent finding from early candidate gene study to more recent genome-wide analysis is that of the involvement of human leukocyte antigen locus. We conclude that CIA is most likely a complex, polygenic trait, which may hamper efforts to the development of a genetic predictor test with clinical relevance. To decipher the genetic architecture of CIA, it is necessary to apply more rigorous standards of phenotyping and study much larger sample sizes.

Published
2017

18. Genetic variation at 16q24.2 is associated with small vessel stroke

Author

Traylor, M. (Matthew), Malik, R. (Rainer), Nalls, M.A. (Michael), Cotlarciuc, I. (Ioana), Radmanesh, F. (Farid), Thorleifsson, G. (Gudmar), Hanscombe, K.B. (Ken B.), Langefeld, C.D. (Carl), Saleheen, D. (Danish), Rost, N.S. (Natalia), Yet, I. (Idil), Spector, T.D. (Timothy), Bell, J.T. (Jordana), Hannon, E. (Eilis), Mill, J. (Jonathan), Chauhan, G. (Ganesh), Debette, S. (Stéphanie), Bis, J.C. (Joshua), Longstreth Jr, W.T., Ikram, M.K. (Kamran), Launer, L.J. (Lenore), Seshadri, S. (Sudha), Hamilton-Bruce, M.A. (Monica Anne), Jimenez-Conde, J. (Jordi), Cole, J.W. (John W.), Schmidt, R. (Reinhold), Slowik, A. (Agnieszka), Lemmens, R. (Robin), Lindgren, A.G. (Arne G.), Melander, O. (Olle), Grewal, R.P. (Raji P.), Sacco, R.L. (Ralph), Rundek, T. (Tatjana), Rexrode, K. (Kathryn), Arnett, D.K. (Donna), Johnson, J.A. (Julie A.), Benavente, O.R. (Oscar R.), Wasssertheil-Smoller, S. (Sylvia), Lee, J.-M. (Jin-Moo), Pulit, S.L. (Sara), Wong, Q. (Quenna), Rich, S.S. (Stephen), Bakker, P.I.W. (Paul) de, McArdle, P.F. (Patrick), Woo, D. (Daniel), Anderson, C.D. (Christopher D.), Xu, H. (Huichun), Heitsch, L. (Laura), Fornage, M. (Myriam), Jern, C. (Christina), Zwart, J-A. (John-Anker), Thorsteinsdottir, U. (Unnur), Gretarsdottir, S. (Solveig), Lewis, C.M. (Cathryn), Sharma, P. (Pankaj), Sudlow, C. (Cathie), Rothwell, P.M. (Peter), Boncoraglio, G. (Giorgio Battista), Thijs, V. (Vincent), Levi, C. (Christopher), Meschia, J.F. (James F.), Rosand, J. (Jonathan), Kittner, T. (Thomas), Mitchell, B.D. (Braxton), Kubisch, C. (Christian), Worrall, B.B. (Bradford B.), Markus, H.S. (Hugh), Traylor, M. (Matthew), Malik, R. (Rainer), Nalls, M.A. (Michael), Cotlarciuc, I. (Ioana), Radmanesh, F. (Farid), Thorleifsson, G. (Gudmar), Hanscombe, K.B. (Ken B.), Langefeld, C.D. (Carl), Saleheen, D. (Danish), Rost, N.S. (Natalia), Yet, I. (Idil), Spector, T.D. (Timothy), Bell, J.T. (Jordana), Hannon, E. (Eilis), Mill, J. (Jonathan), Chauhan, G. (Ganesh), Debette, S. (Stéphanie), Bis, J.C. (Joshua), Longstreth Jr, W.T., Ikram, M.K. (Kamran), Launer, L.J. (Lenore), Seshadri, S. (Sudha), Hamilton-Bruce, M.A. (Monica Anne), Jimenez-Conde, J. (Jordi), Cole, J.W. (John W.), Schmidt, R. (Reinhold), Slowik, A. (Agnieszka), Lemmens, R. (Robin), Lindgren, A.G. (Arne G.), Melander, O. (Olle), Grewal, R.P. (Raji P.), Sacco, R.L. (Ralph), Rundek, T. (Tatjana), Rexrode, K. (Kathryn), Arnett, D.K. (Donna), Johnson, J.A. (Julie A.), Benavente, O.R. (Oscar R.), Wasssertheil-Smoller, S. (Sylvia), Lee, J.-M. (Jin-Moo), Pulit, S.L. (Sara), Wong, Q. (Quenna), Rich, S.S. (Stephen), Bakker, P.I.W. (Paul) de, McArdle, P.F. (Patrick), Woo, D. (Daniel), Anderson, C.D. (Christopher D.), Xu, H. (Huichun), Heitsch, L. (Laura), Fornage, M. (Myriam), Jern, C. (Christina), Zwart, J-A. (John-Anker), Thorsteinsdottir, U. (Unnur), Gretarsdottir, S. (Solveig), Lewis, C.M. (Cathryn), Sharma, P. (Pankaj), Sudlow, C. (Cathie), Rothwell, P.M. (Peter), Boncoraglio, G. (Giorgio Battista), Thijs, V. (Vincent), Levi, C. (Christopher), Meschia, J.F. (James F.), Rosand, J. (Jonathan), Kittner, T. (Thomas), Mitchell, B.D. (Braxton), Kubisch, C. (Christian), Worrall, B.B. (Bradford B.), and Markus, H.S. (Hugh)

Abstract

Objective: Genome-wide association studies (GWAS) have been successful at identifying associations with stroke and stroke subtypes, but have not yet identified any associations solely with small vessel stroke (SVS). SVS comprises one quarter of all ischemic stroke and is a major manifestation of cerebral small vessel disease, the primary cause of vascular cognitive impairment. Studies across neurological traits have shown that younger-onset cases have an increased genetic burden. We leveraged this increased genetic burden by performing an age-at-onset informed GWAS meta-analysis, including a large younger-onset SVS population, to identify novel associations with stroke. Methods: We used a three-stage age-at-onset informed GWAS to identify novel genetic variants associated with stroke. On identifying a novel locus associated with SVS, we assessed its influence on other small vessel disease phenotypes, as well as on messenger RNA (mRNA) expression of nearby genes, and on DNA methylation of nearby CpG sites in whole blood and in the fetal brain. Results: We identified an association with SVS in 4,203 cases and 50,728 controls on chromosome 16q24.2 (odds ratio [OR; 95% confidence interval {CI}] = 1.16 [1.10–1.22]; p = 3.2 × 10−9). The lead single-nucleotide polymorphism (rs12445022) was also associated with cerebral white matter hyperintensities (OR [95% CI] = 1.10 [1.05–1.16]; p = 5.3 × 10−5; N = 3,670), but not intracerebral hemorrhage (OR [95% CI] = 0.97 [0.84–1.12]; p = 0.71; 1,545 cases, 1,481 controls). rs12445022 is associated with mRNA expression of ZCCHC14 in arterial tissues (p = 9.4 × 10−7) and DNA methylation at probe cg16596957

Published
2017
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19. A replication study of genetic risk loci for ischemic stroke in a Dutch population: A case-control study

Author

Hauer, A.J. (Allard J.), Pulit, S.L. (Sara), Berg, L.H. (Leonard) van den, Bakker, P.I.W. (Paul) de, Veldink, J.H. (Jan), Ruigrok, Y.M. (Ynte), Klijn, C.J.M. (Catharina J.M.), Algra, A. (Ale), Dijk, E.J. (Ewoud) van, Koudstaal, P.J. (Peter), Luijckx, G.-J. (Gert-Jan), Nederkoorn, P.J. (Paul), Oostenbrugge, R.J. (Robert) van, Visser, M.C. (Marieke), Wermer, M.J.H. (Marieke), Kappelle, L.J. (Jaap), Hauer, A.J. (Allard J.), Pulit, S.L. (Sara), Berg, L.H. (Leonard) van den, Bakker, P.I.W. (Paul) de, Veldink, J.H. (Jan), Ruigrok, Y.M. (Ynte), Klijn, C.J.M. (Catharina J.M.), Algra, A. (Ale), Dijk, E.J. (Ewoud) van, Koudstaal, P.J. (Peter), Luijckx, G.-J. (Gert-Jan), Nederkoorn, P.J. (Paul), Oostenbrugge, R.J. (Robert) van, Visser, M.C. (Marieke), Wermer, M.J.H. (Marieke), and Kappelle, L.J. (Jaap)

Abstract

We aimed to replicate reported associations of 10 SNPs at eight distinct loci with overall ischemic stroke (IS) and its subtypes in an independent cohort of Dutch IS patients. We included 1,375 IS patients enrolled in a prospective multicenter hospital-based cohort in the Netherlands, and 1,533 population-level controls of Dutch descent. We tested these SNPs for association with overall IS and its subtypes (large artery atherosclerosis, small vessel disease and cardioembolic stroke (CE), as classified by TOAST) using an additive multivariable logistic regression model, adjusting for age and sex. We obtained odds ratios (OR) with 95% confidence intervals (95% CI) for the risk allele of each SNP analyzed and exact p-values by permutation. We confirmed the association at 4q25 (PITX2) (OR 1.43; 95% CI, 1.13-1.81, p = 0.029) and 16q22 (ZFHX3) (OR 1.62; 95% CI, 1.26-2.07, p = 0.001) as risk loci for CE. Locus 16q22 was also associated with overall IS (OR 1.24; 95% CI, 1.08-1.42, p = 0.016). Other loci previously associated with IS and/or its subtypes were not confirmed. In conclusion, we validated two loci (4q25, 16q22) associated with CE. In addition, our study may suggest that the association of locus 16q22 may not be limited to CE, but also includes overall IS.

Published
2017
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20. Prioritization and burden analysis of rare variants in 208 candidate genes suggest they do not play a major role in CAKUT

Author

Nicolaou, N., Pulit, S.L., Nijman, IJ, Monroe, G.R., Feitz, W.F.J., Schreuder, M.F., Eerde, A.M. van, Jong, T.P. de, Giltay, J.C., Zwaag, B. van der, Havenith, M.R., Zwakenberg, S., Zanden, L.F.M. van der, Poelmans, G.J.V., Cornelissen, E.A.M., Lilien, M.R., Franke, B., Roeleveld, N., Rooij, I.A.L.M. van, Cuppen, E., Bongers, E.M.H.F., Giles, R.H., Knoers, N.V.A.M., Renkema, K.Y., Nicolaou, N., Pulit, S.L., Nijman, IJ, Monroe, G.R., Feitz, W.F.J., Schreuder, M.F., Eerde, A.M. van, Jong, T.P. de, Giltay, J.C., Zwaag, B. van der, Havenith, M.R., Zwakenberg, S., Zanden, L.F.M. van der, Poelmans, G.J.V., Cornelissen, E.A.M., Lilien, M.R., Franke, B., Roeleveld, N., Rooij, I.A.L.M. van, Cuppen, E., Bongers, E.M.H.F., Giles, R.H., Knoers, N.V.A.M., and Renkema, K.Y.

Abstract

Item does not contain fulltext, The leading cause of end-stage renal disease in children is attributed to congenital anomalies of the kidney and urinary tract (CAKUT). Familial clustering and mouse models support the presence of monogenic causes. Genetic testing is insufficient as it mainly focuses on HNF1B and PAX2 mutations that are thought to explain CAKUT in 5-15% of patients. To identify novel, potentially pathogenic variants in additional genes, we designed a panel of genes identified from studies on familial forms of isolated or syndromic CAKUT and genes suggested by in vitro and in vivo CAKUT models. The coding exons of 208 genes were analyzed in 453 patients with CAKUT using next-generation sequencing. Rare truncating, splice-site variants, and non-synonymous variants, predicted to be deleterious and conserved, were prioritized as the most promising variants to have an effect on CAKUT. Previously reported disease-causing mutations were detected, but only five were fully penetrant causal mutations that improved diagnosis. We prioritized 148 candidate variants in 151 patients, found in 82 genes, for follow-up studies. Using a burden test, no significant excess of rare variants in any of the genes in our cohort compared with controls was found. Thus, in a study representing the largest set of genes analyzed in CAKUT patients to date, the contribution of previously implicated genes to CAKUT risk was significantly smaller than expected, and the disease may be more complex than previously assumed.

Published
2016

22. Genome of the Netherlands population-specific imputations identify an ABCA6 variant associated with cholesterol levels

Author

Leeuwen, E.M. van, Karssen, L.C., Deelen, J., Isaacs, A., Medina-Gomez, C., Mbarek, H., Kanterakis, A., Trompet, S., Postmus, I., Verweij, N., Enckevort, D.J. van, Huffman, J.E., White, C.C., Feitosa, M.F., Bartz, T.M., Manichaikul, A., Joshi, P.K., Peloso, G.M., Deelen, P., Dijk, F. van, Willemsen, G., Geus, E.J. de, Milaneschi, Y., Penninx, B.W., Francioli, L.C., Menelaou, A., Pulit, S.L., Rivadeneira, F., Hofman, A., Oostra, B.A., Franco, O.H., Leach, I. Mateo, Beekman, M., Craen, A.J. de, Uh, H.W., Trochet, H., Hocking, L.J., Porteous, D.J., Sattar, N., Packard, C.J., Buckley, B.M., Brody, J.A., Bis, J.C., Rotter, J.I., Mychaleckyj, J.C., Campbell, H., Duan, Q., Lange, L.A., Wilson, J.F., Hayward, C., Polasek, O., Vitart, V., Rudan, I., Wright, A.F., Rich, S.S., Psaty, B.M., Borecki, I.B., Kearney, P.M., Stott, D.J., Cupples, L. Adrienne, Consortium, G.o.t.N., Jukema, J.W., Harst, P. van der, Sijbrands, E.J., Hottenga, J.J., Uitterlinden, A.G., Swertz, M.A., Ommen, G.J. van, Bakker, P.I. de, Slagboom, P., Boomsma, D.I., Wijmenga, C., Duijn, C.M. van, Hehir-Kwa, J.Y., et al., Leeuwen, E.M. van, Karssen, L.C., Deelen, J., Isaacs, A., Medina-Gomez, C., Mbarek, H., Kanterakis, A., Trompet, S., Postmus, I., Verweij, N., Enckevort, D.J. van, Huffman, J.E., White, C.C., Feitosa, M.F., Bartz, T.M., Manichaikul, A., Joshi, P.K., Peloso, G.M., Deelen, P., Dijk, F. van, Willemsen, G., Geus, E.J. de, Milaneschi, Y., Penninx, B.W., Francioli, L.C., Menelaou, A., Pulit, S.L., Rivadeneira, F., Hofman, A., Oostra, B.A., Franco, O.H., Leach, I. Mateo, Beekman, M., Craen, A.J. de, Uh, H.W., Trochet, H., Hocking, L.J., Porteous, D.J., Sattar, N., Packard, C.J., Buckley, B.M., Brody, J.A., Bis, J.C., Rotter, J.I., Mychaleckyj, J.C., Campbell, H., Duan, Q., Lange, L.A., Wilson, J.F., Hayward, C., Polasek, O., Vitart, V., Rudan, I., Wright, A.F., Rich, S.S., Psaty, B.M., Borecki, I.B., Kearney, P.M., Stott, D.J., Cupples, L. Adrienne, Consortium, G.o.t.N., Jukema, J.W., Harst, P. van der, Sijbrands, E.J., Hottenga, J.J., Uitterlinden, A.G., Swertz, M.A., Ommen, G.J. van, Bakker, P.I. de, Slagboom, P., Boomsma, D.I., Wijmenga, C., Duijn, C.M. van, Hehir-Kwa, J.Y., and et al.

Abstract

Contains fulltext : 155355.pdf (publisher's version ) (Open Access)

Published
2015

25. Whole-genome sequence variation, population structure and demographic history of the Dutch population

Author

Francioli, L.C., Menelaou, A., Pulit, S.L., Dijk, F. van, Palamara, P.F., Elbers, C.C., Neerincx, P.B., Ye, K., Guryev, V., Kloosterman, W.P., Deelen, P., Abdellaoui, A., Leeuwen, E.M. van, Oven, M. van, Vermaat, M., Li, M., Laros, J.F., Karssen, L.C., Kanterakis, A., Amin, N., Hottenga, J.J., Lameijer, E.W., Kattenberg, M., Dijkstra, M., Byelas, H., Setten, J. van, Schaik, B.D. van, Bot, J., Nijman, I.J., Renkens, I., Marschall, T., Schönhuth, A., Hehir-Kwa, J.Y., Handsaker, R.E., Polak, P., Sohail, M., Vuzman, D., Hormozdiari, F., Enckevort, D. van, Mei, H., Koval, V., Moed, M.H., Velde, K.J. van der, Rivadeneira, F., Estrada, K., Medina-Gomez, C., Isaacs, A., McCarroll, S.A., Beekman, M., Craen, A.J. de, Suchiman, H.E., Hofman, A., Oostra, B., Uitterlinden, A.G., Willemsen, G., Platteel, M., Veldink, J.H., Berg, L.H. van den, Pitts, S.J., Potluri, S., Sundar, P., Cox, D.R., Sunyaev, S.R., Dunnen, J.T. den, Stoneking, M., Knijff, P. de, Kayser, M., Li, Q., Li, Y., Du, Y., Chen, R., Cao, H., Li, N., Cao, S., Wang, J, Bovenberg, J.A., Pe'er, I., Slagboom, P.E., Duijn, C.M. van, Boomsma, D.I., Ommen, G.J. van, Bakker, P.I. de, Swertz, M.A., Wijmenga, C., Francioli, L.C., Menelaou, A., Pulit, S.L., Dijk, F. van, Palamara, P.F., Elbers, C.C., Neerincx, P.B., Ye, K., Guryev, V., Kloosterman, W.P., Deelen, P., Abdellaoui, A., Leeuwen, E.M. van, Oven, M. van, Vermaat, M., Li, M., Laros, J.F., Karssen, L.C., Kanterakis, A., Amin, N., Hottenga, J.J., Lameijer, E.W., Kattenberg, M., Dijkstra, M., Byelas, H., Setten, J. van, Schaik, B.D. van, Bot, J., Nijman, I.J., Renkens, I., Marschall, T., Schönhuth, A., Hehir-Kwa, J.Y., Handsaker, R.E., Polak, P., Sohail, M., Vuzman, D., Hormozdiari, F., Enckevort, D. van, Mei, H., Koval, V., Moed, M.H., Velde, K.J. van der, Rivadeneira, F., Estrada, K., Medina-Gomez, C., Isaacs, A., McCarroll, S.A., Beekman, M., Craen, A.J. de, Suchiman, H.E., Hofman, A., Oostra, B., Uitterlinden, A.G., Willemsen, G., Platteel, M., Veldink, J.H., Berg, L.H. van den, Pitts, S.J., Potluri, S., Sundar, P., Cox, D.R., Sunyaev, S.R., Dunnen, J.T. den, Stoneking, M., Knijff, P. de, Kayser, M., Li, Q., Li, Y., Du, Y., Chen, R., Cao, H., Li, N., Cao, S., Wang, J, Bovenberg, J.A., Pe'er, I., Slagboom, P.E., Duijn, C.M. van, Boomsma, D.I., Ommen, G.J. van, Bakker, P.I. de, Swertz, M.A., and Wijmenga, C.

Abstract

Contains fulltext : 137213.pdf (publisher's version ) (Closed access), Whole-genome sequencing enables complete characterization of genetic variation, but geographic clustering of rare alleles demands many diverse populations be studied. Here we describe the Genome of the Netherlands (GoNL) Project, in which we sequenced the whole genomes of 250 Dutch parent-offspring families and constructed a haplotype map of 20.4 million single-nucleotide variants and 1.2 million insertions and deletions. The intermediate coverage ( approximately 13x) and trio design enabled extensive characterization of structural variation, including midsize events (30-500 bp) previously poorly catalogued and de novo mutations. We demonstrate that the quality of the haplotypes boosts imputation accuracy in independent samples, especially for lower frequency alleles. Population genetic analyses demonstrate fine-scale structure across the country and support multiple ancient migrations, consistent with historical changes in sea level and flooding. The GoNL Project illustrates how single-population whole-genome sequencing can provide detailed characterization of genetic variation and may guide the design of future population studies.

Published
2014

26. A genome-wide association study identifies a functional ERAP2 haplotype associated with birdshot chorioretinopathy

Author

Kuiper, J.J., Setten, J. van, Ripke, S., Van, T.S.R., Mulder, F., Missotten, T., Baarsma, G.S., Francioli, L.C., Pulit, S.L., Kovel, C.G.F. de, Dam-van Loon, N. ten, Hollander, A.I. den, Veld, P. Huis in het, Hoyng, C.B., Cordero-Coma, M., Martin, J., Llorenc, V., Arya, B., Thomas, D, Bakker, S.C., Ophoff, R.A., Rothova, A., Bakker, P.I. de, Mutis, T, Koeleman, B.P., Kuiper, J.J., Setten, J. van, Ripke, S., Van, T.S.R., Mulder, F., Missotten, T., Baarsma, G.S., Francioli, L.C., Pulit, S.L., Kovel, C.G.F. de, Dam-van Loon, N. ten, Hollander, A.I. den, Veld, P. Huis in het, Hoyng, C.B., Cordero-Coma, M., Martin, J., Llorenc, V., Arya, B., Thomas, D, Bakker, S.C., Ophoff, R.A., Rothova, A., Bakker, P.I. de, Mutis, T, and Koeleman, B.P.

Abstract

Item does not contain fulltext, Birdshot chorioretinopathy (BSCR) is a rare form of autoimmune uveitis that can lead to severe visual impairment. Intriguingly, >95% of cases carry the HLA-A29 allele, which defines the strongest documented HLA association for a human disease. We have conducted a genome-wide association study in 96 Dutch and 27 Spanish cases, and 398 unrelated Dutch and 380 Spanish controls. Fine-mapping the primary MHC association through high-resolution imputation at classical HLA loci, identified HLA-A*29:02 as the principal MHC association (odds ratio (OR) = 157.5, 95% CI 91.6-272.6, P = 6.6 x 10(-74)). We also identified two novel susceptibility loci at 5q15 near ERAP2 (rs7705093; OR = 2.3, 95% CI 1.7-3.1, for the T allele, P = 8.6 x 10(-8)) and at 14q32.31 in the TECPR2 gene (rs150571175; OR = 6.1, 95% CI 3.2-11.7, for the A allele, P = 3.2 x 10(-8)). The association near ERAP2 was confirmed in an independent British case-control samples (combined meta-analysis P = 1.7 x 10(-9)). Functional analyses revealed that the risk allele of the polymorphism near ERAP2 is strongly associated with high mRNA and protein expression of ERAP2 in B cells. This study further defined an extremely strong MHC risk component in BSCR, and detected evidence for a novel disease mechanism that affects peptide processing in the endoplasmic reticulum.

Published
2014

27. Common variation in fatty acid metabolic genes and risk of incident sudden cardiac arrest

Author

Lemaitre, R.N. (Rozenn ), Johnson, C.O. (Catherine), Hesselson, S. (Stephanie), Sotoodhenia, N. (Nona), McKnight, B. (Barbara), Sitlani, C.M. (Colleen), Rea, D. (Dan), King, I.B. (Irena), Kwok, P.-Y. (Pui-Yan), Mak, A. (Angel), Li, G. (Guo), Brody, J.A. (Jennifer A.), Larson, E.B. (Eric), Mozaffarian, D. (Dariush), Psaty, B.M. (Bruce), Huertas-Vazquez, A. (Adriana), Tardif, J.-C. (Jean-Claude), Albert, C.M. (Christine), Lyytikäinen, L.-P. (Leo-Pekka), Arking, D.E. (Dan), Kääb, S. (Stefan), Huikuri, H.V. (Heikki), Krijthe, B.P. (Bouwe), Eijgelsheim, M. (Mark), Wang, Y.A. (Ying), Reinier, K. (Kyndaron), Lehtimäki, T. (Terho), Pulit, S.L. (Sara), Brugada, R. (Ramon), Müller-Nurasyid, M. (Martina), Newton-Cheh, C. (Christopher), Karhunen, P.J. (Pekka), Stricker, B.H.Ch. (Bruno), Goyette, P. (Philippe), Rotter, J.I. (Jerome), Chugh, S.S. (Sumeet), Chakravarti, A. (Aravinda), Jouven, X. (Xavier), Siscovick, D.S. (David), Lemaitre, R.N. (Rozenn ), Johnson, C.O. (Catherine), Hesselson, S. (Stephanie), Sotoodhenia, N. (Nona), McKnight, B. (Barbara), Sitlani, C.M. (Colleen), Rea, D. (Dan), King, I.B. (Irena), Kwok, P.-Y. (Pui-Yan), Mak, A. (Angel), Li, G. (Guo), Brody, J.A. (Jennifer A.), Larson, E.B. (Eric), Mozaffarian, D. (Dariush), Psaty, B.M. (Bruce), Huertas-Vazquez, A. (Adriana), Tardif, J.-C. (Jean-Claude), Albert, C.M. (Christine), Lyytikäinen, L.-P. (Leo-Pekka), Arking, D.E. (Dan), Kääb, S. (Stefan), Huikuri, H.V. (Heikki), Krijthe, B.P. (Bouwe), Eijgelsheim, M. (Mark), Wang, Y.A. (Ying), Reinier, K. (Kyndaron), Lehtimäki, T. (Terho), Pulit, S.L. (Sara), Brugada, R. (Ramon), Müller-Nurasyid, M. (Martina), Newton-Cheh, C. (Christopher), Karhunen, P.J. (Pekka), Stricker, B.H.Ch. (Bruno), Goyette, P. (Philippe), Rotter, J.I. (Jerome), Chugh, S.S. (Sumeet), Chakravarti, A. (Aravinda), Jouven, X. (Xavier), and Siscovick, D.S. (David)

Abstract

Background There is limited information on genetic factors associated with sudden cardiac arrest (SCA). Objective To assess the association of common variation in genes in fatty acid pathways with SCA risk. Methods We selected 85 candidate genes and 1155 single nucleotide polymorphisms (SNPs) tagging common variation in each gene. We investigated the SNP associations with SCA in a population-based case-control study. Cases (n = 2160) were from a repository of SCA in the greater Seattle area. Controls (n = 2615), frequency-matched on age and sex, were from the same area. We used linear logistic regression to examine SNP associations with SCA. We performed permutation-based p-min tests to account for multiple comparisons within each gene. The SNP associations with a corrected P value of <.05 were then examined in a meta-analysis of these SNP associations in 9 replication studies totaling 2129 SCA cases and 23,833 noncases. Results Eight SNPs in or near 8 genes were associated with SCA risk in the discovery study, one of which was nominally significant in the replication phase (rs7737692, minor allele frequency 36%, near the LPCAT1 gene). For each copy of the minor allele, rs7737692 was associated with 13% lower SCA risk (95% confidence interval -21% to -5%) in the discovery phase and 9% lo

Published
2014
Full Text
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28. A genome-wide association study identifies a functional ERAP2 haplotype associated with birdshot chorioretinopathy

Author

Kuiper, J.J.W. (Jonas), Setten, J. (Jessica) van, Ripke, S. (Stephan), Slot, R. (Ruben) van 't, Mulder, F. (Flip), Missotten, T. (Tom), Baarsma, G.S. (Seerp), Francioli, L.C. (Laurent), Pulit, S.L. (Sara), Kovel, C.G.F. (Carolien) de, Dam-Van Loon, N.T. (Ninette Ten), Hollander, A.I. (Anneke), Huis in het Veld, P. (Paulien), Hoyng, C.B. (Carel), Cordero-Coma, M. (Miguel), Martín, J. (Javier), Llorenç, V. (Victor), Arya, B. (Bharti), Thomas, D. (Dhanes), Bakker, S.C. (Steven), Ophoff, R.A. (Roel), Rothová, A. (Aniki), Bakker, P.I.W. (Paul) de, Mutis, T. (Tuna), Koeleman, B.P.C. (Bobby), Kuiper, J.J.W. (Jonas), Setten, J. (Jessica) van, Ripke, S. (Stephan), Slot, R. (Ruben) van 't, Mulder, F. (Flip), Missotten, T. (Tom), Baarsma, G.S. (Seerp), Francioli, L.C. (Laurent), Pulit, S.L. (Sara), Kovel, C.G.F. (Carolien) de, Dam-Van Loon, N.T. (Ninette Ten), Hollander, A.I. (Anneke), Huis in het Veld, P. (Paulien), Hoyng, C.B. (Carel), Cordero-Coma, M. (Miguel), Martín, J. (Javier), Llorenç, V. (Victor), Arya, B. (Bharti), Thomas, D. (Dhanes), Bakker, S.C. (Steven), Ophoff, R.A. (Roel), Rothová, A. (Aniki), Bakker, P.I.W. (Paul) de, Mutis, T. (Tuna), and Koeleman, B.P.C. (Bobby)

Abstract

Birdshot chorioretinopathy (BSCR) is a rare form of autoimmune uveitis that can lead to severe visual impairment. Intriguingly, >95% of cases carry the HLA-A29 allele, which defines the strongest documented HLA association for a human disease. We have conducted a genome-wide association study in 96 Dutch and 27 Spanish cases, and 398 unrelated Dutch and 380 Spanish controls. Fine-mapping the primary MHC association through high-resolution imputation at classicalHLA loci, identified HLA-A*29:02 as the principalMHCassociation (odds ratio (OR) 5 157.5, 95% CI 91.6-272.6, P = 6.6 × 10-74). We also identified two novel susceptibility loci at 5q15 nearERAP2 (rs7705093;OR 5 2.3,95%CI 1.7-3.1, for the T allele,P = 8.6 × 10-8) and at 14q32.31 in theTECPR2 gene (rs150571175;OR 5 6.1,95%CI 3.2-11.7, for theAallele,P = 3.2 × 10-8). The association nearERAP2was confirmed in an independent British case-control samples (combined meta-analysis P = 1.7 × 10-9). Functional analyses revealed that the risk allele of the polymorphism near ERAP2 is strongly associated with high mRNA and protein expression of ERAP2 in B cells. This study further defined an extremely strong MHC risk component in BSCR, and detected evidence for a novel disease mechanism that affects peptide processing in the endoplasmic re

Published
2014
Full Text
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29. Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization

Author

Arking, D.E. (Dan), Pulit, S.L. (Sara), Crotti, L. (Lia), Harst, P. (Pim) van der, Munroe, P. (Patricia), Koopmann, T.T. (Tamara), Sotoodehnia, N. (Nona), Rossin, E. (Elizabeth), Morley, M. (Michael), Wang, X. (Xinchen), Johnson, A.D. (Andrew), Lundby, A. (Alicia), Gudbjartsson, D.F. (Daniel), Noseworthy, P.A. (Peter), Eijgelsheim, M. (Mark), Bradford, Y. (Yuki), Tarasov, K.V. (Kirill), Dörr, M. (Marcus), Müller-Nurasyid, M. (Martina), Lahtinen, A.M. (Annukka), Nolte, I.M. (Ilja), Smith, A.V. (Davey), Bis, J.C. (Joshua), Isaacs, A.J. (Aaron), Newhouse, S.J. (Stephen), Evans, D.S. (Daniel), Post, W.S. (Wendy S.), Waggott, D. (Daryl), Lyytikäinen, L.-P. (Leo-Pekka), Hicks, A.A. (Andrew), Eisele, L. (Lewin), Ellinghaus, D. (David), Hayward, C. (Caroline), Navarro, P. (Pau), Ulivi, S. (Shelia), Tanaka, T. (Toshiko), Tester, D.J. (David), Chatel, S. (Stéphanie), Gustafsson, S. (Stefan), Kumari, M. (Meena), Morris, R.W. (Richard), Naluai, A.T. (Asa), Padmanabhan, S. (Sandosh), Kluttig, A. (Alexander), Strohmer, B. (Bernhard), Panayiotou, A.G. (Andrie), Torres, M. (Maria), Knoflach, M. (Michael), Hubacek, J.A. (Jaroslav A.), Slowikowski, K. (Kamil), Raychaudhuri, S. (Soumya), Kumar, R.D. (Runjun), Harris, T.B. (Tamara), Launer, L.J. (Lenore), Shuldiner, A.R. (Alan), Alonso, A. (Alvaro), Bader, J.S. (Joel), Ehret, G.B. (Georg), Huang, H. (Hailiang), Kao, W.H.L. (Wen), Strait, J.B. (James), Macfarlane, P.W. (Peter), Brown, M.J. (Morris), Caulfield, M. (Mark), Samani, N.J. (Nilesh), Kronenberg, F. (Florian), Willeit, J. (Johann), Smith, J.G. (J. Gustav), Greiser, K.H. (Karin Halina), Zu Schwabedissen, H.M. (Henriette Meyer), Werdan, K. (Karl), Carella, C. (Cintia), Zelante, L. (Leopoldo), Heckbert, S.R. (Susan), Psaty, B.M. (Bruce), Rotter, J.I. (Jerome), Kolcic, I. (Ivana), Polasek, O. (Ozren), Wright, A.F. (Alan), Griffin, M. (Maura), Daly, M.J. (Mark), Arnar, D.O. (David), Hólm, H. (Hilma), Thorsteinsdottir, U. (Unnur), Denny, J.C. (Joshua), Roden, D.M. (Dan), Zuvich, R.L. (Rebecca), Emilsson, V. (Valur), Plump, A.S. (Andrew), Larson, M.G. (Martin), O'Donnell, C.J. (Christopher), Yin, X. (Xiaoyan), Bobbo, M. (Marco), Adamo, P. (Pio) d', Iorio, A. (Annamaria), Sinagra, G. (Gianfranco), Carracedo, A. (Angel), Cummings, S.R. (Steven), Nalls, M.A. (Michael), Jula, A. (Antti), Kontula, K.K. (Kimmo), Marjamaa, A. (Annukka), Oikarinen, L. (Lasse), Perola, M. (Markus), Porthan, K. (Kimmo), Erbel, R. (Raimund), Hoffmann, P. (Per), Jöckel, K.-H. (Karl-Heinz), Kälsch, H. (Hagen), Nöthen, M.M. (Markus), Hoed, M. (Marcel) den, Loos, R.J.F. (Ruth), Thelle, D.S. (Dag), Gieger, C. (Christian), Meitinger, T. (Thomas), Perz, S. (Siegfried), Peters, A. (Annette), Prucha, H. (Hanna), Sinner, M.F. (Moritz), Waldenberger, M. (Melanie), Boer, R.A. (Rudolf) de, Franke, L. (Lude), Vleuten, P.A. (Pieter) van der, Beckmann, B.M. (Britt), Martens, E. (Eimo), Bardai, A. (Abdennasser), Hofman, N. (Nynke), Wilde, A.A.M. (Arthur), Behr, E.R. (Elijah), Dalageorgou, C. (Chrysoula), Giudicessi, J.R. (John), Medeiros-Domingo, A. (Argelia), Barc, J. (Julien), Kyndt, F. (Florence), Probst, V. (Vincent), Ghidoni, A. (Alice), Insolia, R. (Roberto), Hamilton, R.M. (Robert), Scherer, S.W. (Stephen), Brandimarto, J. (Jeffrey), Margulies, K. (Kenneth), Moravec, C.E. (Christine), Del Greco, F. (Fabiola), Fuchsberger, C. (Christian), O'Connell, J.R. (Jeffery), Lee, W.K. (Wai), Watt, G.C.M. (Graham), Campbell, H. (Harry), Wild, S.H. (Sarah), El Mokhtari, N.E. (Nour), Frey, N. (Norbert), Asselbergs, F.W. (Folkert), Leach, I.M. (Irene Mateo), Navis, G. (Gerjan), Berg, M.P. (Maarten) van den, Veldhuisen, D.J. (Dirk) van, Kellis, M. (Manolis), Krijthe, B.P. (Bouwe), Franco, O.H. (Oscar), Hofman, A. (Albert), Kors, J.A. (Jan), Uitterlinden, A.G. (André), Witteman, J.C.M. (Jacqueline), Kedenko, L. (Lyudmyla), Lamina, C. (Claudia), Oostra, B.A. (Ben), Abecasis, G.R. (Gonçalo), Lakatta, E. (Edward), Mulas, A. (Antonella), Orrù, M. (Marco), Schlessinger, D. (David), Uda, M. (Manuela), Markus, M.R.P. (Marcello R. P.), Völker, U. (Uwe), Snieder, H. (Harold), Spector, T.D. (Timothy), Ärnlöv, J. (Johan), Lind, L. (Lars), Sundstrom, J. (Johan), Syvanen, A.C., Kivimaki, M. (Mika), Kähönen, M. (Mika), Mononen, K. (Kari), Raitakari, O. (Olli), Viikari, J. (Jorma), Adamkova, V. (Vera), Kiechl, S. (Stefan), Brion, M.-J. (Maria), Nicolaides, A.N. (Andrew), Paulweber, B. (Bernhard), Haerting, J. (Johannes), Dominiczak, A. (Anna), Nyberg, F. (Fredrik), Whincup, P.H. (Peter), Hingorani, A. (Aroon), Schott, J.-J. (Jean-Jacques), Bezzina, C.R. (Connie), Ingelsson, E. (Erik), Ferrucci, L. (Luigi), Gasparini, P. (Paolo), Wilson, J.F. (James), Rudan, I. (Igor), Franke, A. (Andre), Mühleisen, T.W. (Thomas), Pramstaller, P.P. (Peter Paul), Lehtimäki, T. (Terho), Paterson, A.D. (Andrew), Parsa, A. (Afshin), Liu, Y. (YongMei), Duijn, C.M. (Cornelia) van, Siscovick, D.S. (David), Gudnason, V. (Vilmundur), Jamshidi, Y. (Yalda), Salomaa, V. (Veikko), Felix, S.B. (Stephan), Sanna, S. (Serena), Ritchie, M.D. (Marylyn), Stricker, B.H.Ch. (Bruno), Zwart, J-A. (John-Anker), Boyer, L.A. (Laurie), Cappola, T.P. (Thomas), Olsen, J.V. (Jesper), Lage, P. (Pedro), Schwartz, P.J. (Peter), Kääb, S. (Stefan), Chakravarti, A. (Aravinda), Ackerman, M. (Margaret), Pfeufer, A. (Arne), Bakker, P.I.W. (Paul) de, Newton-Cheh, C. (Christopher), Arking, D.E. (Dan), Pulit, S.L. (Sara), Crotti, L. (Lia), Harst, P. (Pim) van der, Munroe, P. (Patricia), Koopmann, T.T. (Tamara), Sotoodehnia, N. (Nona), Rossin, E. (Elizabeth), Morley, M. (Michael), Wang, X. (Xinchen), Johnson, A.D. (Andrew), Lundby, A. (Alicia), Gudbjartsson, D.F. (Daniel), Noseworthy, P.A. (Peter), Eijgelsheim, M. (Mark), Bradford, Y. (Yuki), Tarasov, K.V. (Kirill), Dörr, M. (Marcus), Müller-Nurasyid, M. (Martina), Lahtinen, A.M. (Annukka), Nolte, I.M. (Ilja), Smith, A.V. (Davey), Bis, J.C. (Joshua), Isaacs, A.J. (Aaron), Newhouse, S.J. (Stephen), Evans, D.S. (Daniel), Post, W.S. (Wendy S.), Waggott, D. (Daryl), Lyytikäinen, L.-P. (Leo-Pekka), Hicks, A.A. (Andrew), Eisele, L. (Lewin), Ellinghaus, D. (David), Hayward, C. (Caroline), Navarro, P. (Pau), Ulivi, S. (Shelia), Tanaka, T. (Toshiko), Tester, D.J. (David), Chatel, S. (Stéphanie), Gustafsson, S. (Stefan), Kumari, M. (Meena), Morris, R.W. (Richard), Naluai, A.T. (Asa), Padmanabhan, S. (Sandosh), Kluttig, A. (Alexander), Strohmer, B. (Bernhard), Panayiotou, A.G. (Andrie), Torres, M. (Maria), Knoflach, M. (Michael), Hubacek, J.A. (Jaroslav A.), Slowikowski, K. (Kamil), Raychaudhuri, S. (Soumya), Kumar, R.D. (Runjun), Harris, T.B. (Tamara), Launer, L.J. (Lenore), Shuldiner, A.R. (Alan), Alonso, A. (Alvaro), Bader, J.S. (Joel), Ehret, G.B. (Georg), Huang, H. (Hailiang), Kao, W.H.L. (Wen), Strait, J.B. (James), Macfarlane, P.W. (Peter), Brown, M.J. (Morris), Caulfield, M. (Mark), Samani, N.J. (Nilesh), Kronenberg, F. (Florian), Willeit, J. (Johann), Smith, J.G. (J. Gustav), Greiser, K.H. (Karin Halina), Zu Schwabedissen, H.M. (Henriette Meyer), Werdan, K. (Karl), Carella, C. (Cintia), Zelante, L. (Leopoldo), Heckbert, S.R. (Susan), Psaty, B.M. (Bruce), Rotter, J.I. (Jerome), Kolcic, I. (Ivana), Polasek, O. (Ozren), Wright, A.F. (Alan), Griffin, M. (Maura), Daly, M.J. (Mark), Arnar, D.O. (David), Hólm, H. (Hilma), Thorsteinsdottir, U. (Unnur), Denny, J.C. (Joshua), Roden, D.M. (Dan), Zuvich, R.L. (Rebecca), Emilsson, V. (Valur), Plump, A.S. (Andrew), Larson, M.G. (Martin), O'Donnell, C.J. (Christopher), Yin, X. (Xiaoyan), Bobbo, M. (Marco), Adamo, P. (Pio) d', Iorio, A. (Annamaria), Sinagra, G. (Gianfranco), Carracedo, A. (Angel), Cummings, S.R. (Steven), Nalls, M.A. (Michael), Jula, A. (Antti), Kontula, K.K. (Kimmo), Marjamaa, A. (Annukka), Oikarinen, L. (Lasse), Perola, M. (Markus), Porthan, K. (Kimmo), Erbel, R. (Raimund), Hoffmann, P. (Per), Jöckel, K.-H. (Karl-Heinz), Kälsch, H. (Hagen), Nöthen, M.M. (Markus), Hoed, M. (Marcel) den, Loos, R.J.F. (Ruth), Thelle, D.S. (Dag), Gieger, C. (Christian), Meitinger, T. (Thomas), Perz, S. (Siegfried), Peters, A. (Annette), Prucha, H. (Hanna), Sinner, M.F. (Moritz), Waldenberger, M. (Melanie), Boer, R.A. (Rudolf) de, Franke, L. (Lude), Vleuten, P.A. (Pieter) van der, Beckmann, B.M. (Britt), Martens, E. (Eimo), Bardai, A. (Abdennasser), Hofman, N. (Nynke), Wilde, A.A.M. (Arthur), Behr, E.R. (Elijah), Dalageorgou, C. (Chrysoula), Giudicessi, J.R. (John), Medeiros-Domingo, A. (Argelia), Barc, J. (Julien), Kyndt, F. (Florence), Probst, V. (Vincent), Ghidoni, A. (Alice), Insolia, R. (Roberto), Hamilton, R.M. (Robert), Scherer, S.W. (Stephen), Brandimarto, J. (Jeffrey), Margulies, K. (Kenneth), Moravec, C.E. (Christine), Del Greco, F. (Fabiola), Fuchsberger, C. (Christian), O'Connell, J.R. (Jeffery), Lee, W.K. (Wai), Watt, G.C.M. (Graham), Campbell, H. (Harry), Wild, S.H. (Sarah), El Mokhtari, N.E. (Nour), Frey, N. (Norbert), Asselbergs, F.W. (Folkert), Leach, I.M. (Irene Mateo), Navis, G. (Gerjan), Berg, M.P. (Maarten) van den, Veldhuisen, D.J. (Dirk) van, Kellis, M. (Manolis), Krijthe, B.P. (Bouwe), Franco, O.H. (Oscar), Hofman, A. (Albert), Kors, J.A. (Jan), Uitterlinden, A.G. (André), Witteman, J.C.M. (Jacqueline), Kedenko, L. (Lyudmyla), Lamina, C. (Claudia), Oostra, B.A. (Ben), Abecasis, G.R. (Gonçalo), Lakatta, E. (Edward), Mulas, A. (Antonella), Orrù, M. (Marco), Schlessinger, D. (David), Uda, M. (Manuela), Markus, M.R.P. (Marcello R. P.), Völker, U. (Uwe), Snieder, H. (Harold), Spector, T.D. (Timothy), Ärnlöv, J. (Johan), Lind, L. (Lars), Sundstrom, J. (Johan), Syvanen, A.C., Kivimaki, M. (Mika), Kähönen, M. (Mika), Mononen, K. (Kari), Raitakari, O. (Olli), Viikari, J. (Jorma), Adamkova, V. (Vera), Kiechl, S. (Stefan), Brion, M.-J. (Maria), Nicolaides, A.N. (Andrew), Paulweber, B. (Bernhard), Haerting, J. (Johannes), Dominiczak, A. (Anna), Nyberg, F. (Fredrik), Whincup, P.H. (Peter), Hingorani, A. (Aroon), Schott, J.-J. (Jean-Jacques), Bezzina, C.R. (Connie), Ingelsson, E. (Erik), Ferrucci, L. (Luigi), Gasparini, P. (Paolo), Wilson, J.F. (James), Rudan, I. (Igor), Franke, A. (Andre), Mühleisen, T.W. (Thomas), Pramstaller, P.P. (Peter Paul), Lehtimäki, T. (Terho), Paterson, A.D. (Andrew), Parsa, A. (Afshin), Liu, Y. (YongMei), Duijn, C.M. (Cornelia) van, Siscovick, D.S. (David), Gudnason, V. (Vilmundur), Jamshidi, Y. (Yalda), Salomaa, V. (Veikko), Felix, S.B. (Stephan), Sanna, S. (Serena), Ritchie, M.D. (Marylyn), Stricker, B.H.Ch. (Bruno), Zwart, J-A. (John-Anker), Boyer, L.A. (Laurie), Cappola, T.P. (Thomas), Olsen, J.V. (Jesper), Lage, P. (Pedro), Schwartz, P.J. (Peter), Kääb, S. (Stefan), Chakravarti, A. (Aravinda), Ackerman, M. (Margaret), Pfeufer, A. (Arne), Bakker, P.I.W. (Paul) de, and Newton-Cheh, C. (Christopher)

Abstract

The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼ 8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD.

Published
2014
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30. The Genome of the Netherlands: Design, and project goals

Author

Boomsma, D.I. (Dorret), Wijmenga, C. (Cisca), Slagboom, P.E. (Eline), Swertz, M. (Morris), Karssen, L.C. (Lennart), Abdellaoui, A. (Abdel), Ye, K. (Kai), Guryev, V. (Victor), Vermaat, J.S. (Joost), Dijk, F. (Freerk) van, Francioli, L.C. (Laurent), Hottenga, J.J. (Jouke Jan), Laros, J.F.J. (Jeroen F.), Li, Q. (Qibin), Li, Y. (Yingrui), Cao, H. (Hongzhi), Chen, R. (Ruoyan), Du, Y. (Yangchun), Li, N. (Ning), Cao, S. (Sherry), Setten, J. (Jessica) van, Menelaou, A. (Androniki), Pulit, S.L. (Sara), Hehir-Kwa, J. (Jayne), Beekman, M. (Marian), Elbers, C.C. (Clara), Byelas, H. (Heorhiy), Craen, A.J. (Anton) de, Deelen, P. (Patrick), Dijkstra, M. (Martijn), Dunnen, J.T. (Johan) den, Knijff, P. (Peter) de, Houwing-Duistermaat, J.J. (Jeanine), Koval, V. (Vyacheslav), Estrada Gil, K. (Karol), Hofman, A. (Albert), Kanterakis, A. (Alexandros), Enckevort, D. (David) van, Mai, H. (Hailiang), Kattenberg, V.M. (Mathijs), Leeuwen, E.M. (Elisa) van, Neerincx, P.B.T. (Pieter B T), Oostra, B.A. (Ben), Rivadeneira Ramirez, F. (Fernando), Suchiman, H.E.D. (Eka), Uitterlinden, A.G. (André), Willemsen, G.A.H.M. (Gonneke), Wolffenbuttel, B.H.R. (Bruce), Wang, J. (Jinxia), Bakker, P.I.W. (Paul) de, Ommen, G.J. (Gert) van, Duijn, C.M. (Cornelia) van, Boomsma, D.I. (Dorret), Wijmenga, C. (Cisca), Slagboom, P.E. (Eline), Swertz, M. (Morris), Karssen, L.C. (Lennart), Abdellaoui, A. (Abdel), Ye, K. (Kai), Guryev, V. (Victor), Vermaat, J.S. (Joost), Dijk, F. (Freerk) van, Francioli, L.C. (Laurent), Hottenga, J.J. (Jouke Jan), Laros, J.F.J. (Jeroen F.), Li, Q. (Qibin), Li, Y. (Yingrui), Cao, H. (Hongzhi), Chen, R. (Ruoyan), Du, Y. (Yangchun), Li, N. (Ning), Cao, S. (Sherry), Setten, J. (Jessica) van, Menelaou, A. (Androniki), Pulit, S.L. (Sara), Hehir-Kwa, J. (Jayne), Beekman, M. (Marian), Elbers, C.C. (Clara), Byelas, H. (Heorhiy), Craen, A.J. (Anton) de, Deelen, P. (Patrick), Dijkstra, M. (Martijn), Dunnen, J.T. (Johan) den, Knijff, P. (Peter) de, Houwing-Duistermaat, J.J. (Jeanine), Koval, V. (Vyacheslav), Estrada Gil, K. (Karol), Hofman, A. (Albert), Kanterakis, A. (Alexandros), Enckevort, D. (David) van, Mai, H. (Hailiang), Kattenberg, V.M. (Mathijs), Leeuwen, E.M. (Elisa) van, Neerincx, P.B.T. (Pieter B T), Oostra, B.A. (Ben), Rivadeneira Ramirez, F. (Fernando), Suchiman, H.E.D. (Eka), Uitterlinden, A.G. (André), Willemsen, G.A.H.M. (Gonneke), Wolffenbuttel, B.H.R. (Bruce), Wang, J. (Jinxia), Bakker, P.I.W. (Paul) de, Ommen, G.J. (Gert) van, and Duijn, C.M. (Cornelia) van

Abstract

Within the Netherlands a national network of biobanks has been established (Biobanking and Biomolecular Research Infrastructure-Netherlands (BBMRI-NL)) as a national node of the European BBMRI. One of the aims of BBMRI-NL is to enrich biobanks with different types of molecular and phenotype data. Here, we describe the Genome of the Netherlands (GoNL), one of the projects within BBMRI-NL. GoNL is a whole-genome-sequencing project in a representative sample consisting of 250 trio-families from all provinces in the Netherlands, which aims to characterize DNA sequence variation in the Dutch population. The parent-offspring trios include adult individuals ranging in age from 19 to 87 years (mean=53 years; SD=16 years) from birth cohorts 1910-1994. Sequencing was done on blood-derived DNA from uncultured cells and accomplished coverage was 14-15x. The family-based design represents a unique resource to assess the frequency of regional variants, accurately reconstruct haplotypes by family-based phasing, characterize short indels and complex structural variants, and establish the rate of de novo mutational events. GoNL will also serve as a reference panel for imputation in the available genome-wide association studies in Dutch and other cohorts to refine association signals and uncover population-specific variants. GoNL will create a catalog of human genetic variation in this sample that is uniquely characterized with respect to micro-geographic location and a wide range of phenotypes. The resource will be made available to the research and medical community to guide the interpretation of sequencing projects. The present paper summarizes the global characteristics of the project.

Published
2014
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31. Deleterious Alleles in the Human Genome Are on Average Younger Than Neutral Alleles of the Same Frequency

Author

Kiezun, A. (Adam), Pulit, S.L. (Sara), Francioli, L.C. (Laurent), Dijk, F. (Freerk) van, Swertz, M. (Morris), Boomsma, D.I. (Dorret), Duijn, C.M. (Cornelia) van, Slagboom, P.E. (Eline), Ommen, G.J. (Gert) van, Wijmenga, C. (Cisca), Bakker, P.I.W. (Paul) de, Sunyaev, S.R. (Shamil), Kiezun, A. (Adam), Pulit, S.L. (Sara), Francioli, L.C. (Laurent), Dijk, F. (Freerk) van, Swertz, M. (Morris), Boomsma, D.I. (Dorret), Duijn, C.M. (Cornelia) van, Slagboom, P.E. (Eline), Ommen, G.J. (Gert) van, Wijmenga, C. (Cisca), Bakker, P.I.W. (Paul) de, and Sunyaev, S.R. (Shamil)

Abstract

Large-scale population sequencing studies provide a complete picture of human genetic variation within the studied populations. A key challenge is to identify, among the myriad alleles, those variants that have an effect on molecular function, phenotypes, and reproductive fitness. Most non-neutral variation consists of deleterious alleles segregating at low population frequency due to incessant mutation. To date, studies characterizing selection against deleterious alleles have been based on allele frequency (testing for a relative excess of rare alleles) or ratio of polymorphism to divergence (testing for a relative increase in the number of polymorphic alleles). Here, starting from Maruyama's theoretical prediction (Maruyama T (1974), Am J Hum Genet USA 6:669-673) that a (slightly) deleterious allele is, on average, younger than a neutral allele segregating at the same frequency, we devised an approach to characterize selection based on allelic age. Unlike existing methods, it compares sets of neutral and deleterious sequence variants at the same allele frequency. When applied to human sequence data from the Genome of the Netherlands Project, our approach distinguishes low-frequency coding non-synonymous variants from synonymous and non-coding variants at the same allele frequency and discriminates between sets of variants independently predicted to be benign or damaging for protein structure and function. The results confirm the abundance of slightly deleterious coding variation in humans.

Published
2013
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32. The major genetic determinants of HIV-1 control affect HLA class I peptide presentation

Author

Pereyra, F., Jia, X., McLaren, P.J., Telenti, A., de Bakker, P.I.W., Walker, B.D., Ripke, S., Brumme, C.J., Pulit, S.L., Carrington, M., Kadie, C.M., Carlson, J.M., Heckerman, D., Graham, R.R., Plenge, R.M., Deeks, S.G., Gianniny, L., Crawford, G., Sullivan, J., Gonzalez, E., Davies, L., Camargo, A., Moore, J.M, Beattie, N., Gupta, S., Crenshaw, A., Burtt, N.P., Guiducci, C., Gupta, N., Gao, X., Qi, Y., Yuki, Y., Piechocka-Trocha, A., Cutrell, E., Rosenberg, R., Moss, K.L., Lemay, P., O'Leary, J., Schaefer, T., Verma, P., Tóth, I., Block, B., Baker, B., Rothchild, A., Lian, J., Proudfoot, J., Alvino, D.M.L., Vine, S., Addo, M.M., Allen, T.M., Altfeld, M., Henn, M.R., Le Gall, S., Streeck, H., Haas, D.W., Kuritzkes, D.R., Robbins, G.K., Shafer, R.W., Gulick, R.M., Shikuma, C.M., Haubrich, R., Riddler, S., Sax, P.E., Daar, E.S., Ribaudo, H.J., Agan, B., Agarwal, S., Ahern, R.L., Allen, B.L., Altidor, S., Altschuler, E.L., Ambardar, S., Anastos, K., Anderson, B., Anderson, V., Andrady, U., Antoniskis, D., Bangsberg, D., Barbaro, D., Barrie, W., Bartczak, J., Barton, S., Basden, P., Basgoz, N., Bazner, S., Bellos, N.C., Benson, A.M., Berger, J., Bernard, N.F., Bernard, A.M., Birch, C., Bodner, S.J., Bolan, R.K., Boudreaux, E.T., Bradley, M., Braun, J.F., Brndjar, J.E., Brown, S.J., Brown, K., Brown, S.T., Burack, J., Bush, L.M., Cafaro, V., Campbell, O., Campbell, J., Carlson, R.H., Carmichael, J.K., Casey, K.K., Cavacuiti, C., Celestin, G., Chambers, S.T., Chez, N., Chirch, L.M., Cimoch, P.J., Cohen, D., Cohn, L.E., Conway, B., Cooper, D.A., Cornelson, B., Cox, D.T., Cristofano, M.V., Cuchural, G., Czartoski, J.L., Dahman, J.M., Daly, J.S., Davis, B.T., Davis, K., Davod, S.M., DeJesus, E., Dietz, C.A., Dunham, E., Dunn, M.E., Ellerin, T.B., Eron, J.J., Fangman, J.J.W., Farel, C.E., Ferlazzo, H., Fidler, S., Fleenor-Ford, A., Frankel, R., Freedberg, K.A., French, N.K., Fuchs, J.D., Fuller, J.D., Gaberman, J., Gallant, J.E., Gandhi, R.T., García, E., Garmon, D., Gathe, J.C., Gaultier, C.R., Gebre, W., Gilman, F.D., Gilson, I., Goepfert, P.A., Gottlieb, M.S., Goulston, C., Groger, R.K., Gurley, T.D., Haber, S., Hardwicke, R., Hardy, W.D., Harrigan, P.R., Hawkins, T.N., Heath, S., Hecht, F.M., Henry, W.K., Hladek, M., Hoffman, R.P., Horton, J.M., Hsu, R.K., Huhn, G.D., Hunt, P., Hupert, M.J., Illeman, M.L., Jaeger, H., Jellinger, R.M., John, M., Johnson, J.A., Johnson, K.L., Johnson, H., Johnson, K., Joly, J., Jordan, W.C., Kauffman, C.A., Khanlou, H., Killian, R.K., Kim, A.Y., Kim, D.D., Kinder, C.A., Kirchner, J.T., Kogelman, L., Kojic, E.M., Korthuis, P.T., Kurisu, W., Kwon, D.S., LaMar, M., Lampiris, H., Lanzafame, M., Lederman, M.M., Lee, D.M., Lee, J.M.L., Lee, M.J., Lee, E.T.Y., Lemoine, J., Levy, J.A., Llibre, J.M., Liguori, M.A., Little, S.J., Liu, A.Y., Lopez, A.J., Loutfy, M.R., Loy, D., Mohammed, D.Y., Man, A., Mansour, M.K., Marconi, V.C., Markowitz, M., Marques, R., Martin, J.N., Martin, H.L., Mayer, K.H., McElrath, M.J., McGhee, T.A., McGovern, B.H., McGowan, K., McIntyre, D., Mcleod, G.X., Menezes, P., Mesa, G., Metroka, C.E., Meyer-Olson, D., Miller, A.O., Montgomery, K., Mounzer, K.C., Nagami, E.H., Nagin, I., Nahass, R.G., Nelson, M.O., Nielsen, C., Norene, D.L., O'Connor, D.H., Ojikutu, B.O., Okulicz, J., Oladehin, O.O., Oldfield, E.C., Olender, S.A., Ostrowski, M., Owen, W.F., Pae, E., Parsonnet, J., Pavlatos, A.M., Perlmutter, A.M., Pierce, M.N., Pincus, J.M., Pisani, L., Price, L.J., Proia, L., Prokesch, R.C., Pujet, H.C., Ramgopal, M., Rathod, A., Rausch, M., Ravishankar, J., Rhame, F.S., Richards, C.S., Richman, D.D., Rodes, B., Rodriguez, M., Rose, R.C., Rosenberg, E.S., Rosenthal, D., Ross, P.E., Rubin, D.S., Rumbaugh, E., Saenz, L., Salvaggio, M.R., Sanchez, W.C., Sanjana, V.M., Santiago, S., Schmidt, W., Schuitemaker, H., Sestak, P.M., Shalit, P., Shay, W., Shirvani, V.N., Silebi, V.I., Sizemore, J.M., Skolnik, P.R., Sokol-Anderson, M., Sosman, J.M., Stabile, P., Stapleton, J.T., Starrett, S., Stein, F., Stellbrink, H-J, Sterman, F.L., Stone, V.E., Stone, D.R., Tambussi, G., Taplitz, R.A., Tedaldi, E.M., Theisen, W., Torres, R., Tosiello, L., Tremblay, C., Tribble, M.A., Trinh, P.D., Tsao, A., Ueda, P., Vaccaro, A., Valadas, E., Vanig, T.J., Vecino, I., Vega, V.M., Veikley, W., Wade, B.H., Walworth, C., Wanidworanun, C., Ward, D.J., Warner, D.A., Weber, R.D., Webster, D., Weis, S., Wheeler, D.A., White, D.J., Wilkins, E., Winston, A., Wlodaver, C.G., van't Wout, A., Wright, D.P., Yang, O.O., Yurdin, D.L., Zabukovic, B.W., Zachary, K.C., Zeeman, B., Zhao, M., Pereyra, F., Jia, X., McLaren, P.J., Telenti, A., de Bakker, P.I.W., Walker, B.D., Ripke, S., Brumme, C.J., Pulit, S.L., Carrington, M., Kadie, C.M., Carlson, J.M., Heckerman, D., Graham, R.R., Plenge, R.M., Deeks, S.G., Gianniny, L., Crawford, G., Sullivan, J., Gonzalez, E., Davies, L., Camargo, A., Moore, J.M, Beattie, N., Gupta, S., Crenshaw, A., Burtt, N.P., Guiducci, C., Gupta, N., Gao, X., Qi, Y., Yuki, Y., Piechocka-Trocha, A., Cutrell, E., Rosenberg, R., Moss, K.L., Lemay, P., O'Leary, J., Schaefer, T., Verma, P., Tóth, I., Block, B., Baker, B., Rothchild, A., Lian, J., Proudfoot, J., Alvino, D.M.L., Vine, S., Addo, M.M., Allen, T.M., Altfeld, M., Henn, M.R., Le Gall, S., Streeck, H., Haas, D.W., Kuritzkes, D.R., Robbins, G.K., Shafer, R.W., Gulick, R.M., Shikuma, C.M., Haubrich, R., Riddler, S., Sax, P.E., Daar, E.S., Ribaudo, H.J., Agan, B., Agarwal, S., Ahern, R.L., Allen, B.L., Altidor, S., Altschuler, E.L., Ambardar, S., Anastos, K., Anderson, B., Anderson, V., Andrady, U., Antoniskis, D., Bangsberg, D., Barbaro, D., Barrie, W., Bartczak, J., Barton, S., Basden, P., Basgoz, N., Bazner, S., Bellos, N.C., Benson, A.M., Berger, J., Bernard, N.F., Bernard, A.M., Birch, C., Bodner, S.J., Bolan, R.K., Boudreaux, E.T., Bradley, M., Braun, J.F., Brndjar, J.E., Brown, S.J., Brown, K., Brown, S.T., Burack, J., Bush, L.M., Cafaro, V., Campbell, O., Campbell, J., Carlson, R.H., Carmichael, J.K., Casey, K.K., Cavacuiti, C., Celestin, G., Chambers, S.T., Chez, N., Chirch, L.M., Cimoch, P.J., Cohen, D., Cohn, L.E., Conway, B., Cooper, D.A., Cornelson, B., Cox, D.T., Cristofano, M.V., Cuchural, G., Czartoski, J.L., Dahman, J.M., Daly, J.S., Davis, B.T., Davis, K., Davod, S.M., DeJesus, E., Dietz, C.A., Dunham, E., Dunn, M.E., Ellerin, T.B., Eron, J.J., Fangman, J.J.W., Farel, C.E., Ferlazzo, H., Fidler, S., Fleenor-Ford, A., Frankel, R., Freedberg, K.A., French, N.K., Fuchs, J.D., Fuller, J.D., Gaberman, J., Gallant, J.E., Gandhi, R.T., García, E., Garmon, D., Gathe, J.C., Gaultier, C.R., Gebre, W., Gilman, F.D., Gilson, I., Goepfert, P.A., Gottlieb, M.S., Goulston, C., Groger, R.K., Gurley, T.D., Haber, S., Hardwicke, R., Hardy, W.D., Harrigan, P.R., Hawkins, T.N., Heath, S., Hecht, F.M., Henry, W.K., Hladek, M., Hoffman, R.P., Horton, J.M., Hsu, R.K., Huhn, G.D., Hunt, P., Hupert, M.J., Illeman, M.L., Jaeger, H., Jellinger, R.M., John, M., Johnson, J.A., Johnson, K.L., 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D.J., Wilkins, E., Winston, A., Wlodaver, C.G., van't Wout, A., Wright, D.P., Yang, O.O., Yurdin, D.L., Zabukovic, B.W., Zachary, K.C., Zeeman, B., and Zhao, M.

Abstract

Infectious and inflammatory diseases have repeatedly shown strong genetic associations within the major histocompatibility complex (MHC); however, the basis for these associations remains elusive. To define host genetic effects on the outcome of a chronic viral infection, we performed genome-wide association analysis in a multiethnic cohort of HIV-1 controllers and progressors, and we analyzed the effects of individual amino acids within the classical human leukocyte antigen (HLA) proteins. We identified >300 genome-wide significant single-nucleotide polymorphisms (SNPs) within the MHC and none elsewhere. Specific amino acids in the HLA-B peptide binding groove, as well as an independent HLA-C effect, explain the SNP associations and reconcile both protective and risk HLA alleles. These results implicate the nature of the HLA-viral peptide interaction as the major factor modulating durable control of HIV infection.

Published
2010

33. HLA-B*13:01and the Dapsone Hypersensitivity Syndrome

Author

Zhang, F.-R., primary, Liu, H., additional, Irwanto, A., additional, Fu, X.-A., additional, Li, Y., additional, Yu, G.-Q., additional, Yu, Y.-X., additional, Chen, M.-F., additional, Low, H.-Q., additional, Li, J.-H., additional, Bao, F.-F., additional, Foo, J.-N., additional, Bei, J.-X., additional, Jia, X.-M., additional, Liu, J., additional, Liany, H., additional, Wang, N., additional, Niu, G.-Y., additional, Wang, Z.-Z., additional, Shi, B.-Q., additional, Tian, H.-Q., additional, Liu, H.-X., additional, Ma, S.-S., additional, Zhou, Y., additional, You, J.-B., additional, Yang, Q., additional, Wang, C., additional, Chu, T.-S., additional, Liu, D.-C., additional, Yu, X.-L., additional, Sun, Y.-H., additional, Ning, Y., additional, Wei, Z.-H., additional, Chen, S.-L., additional, Chen, X.-C., additional, Zhang, Z.-X., additional, Liu, Y.-X., additional, Pulit, S.L., additional, Wu, W.-B., additional, Zheng, Z.-Y., additional, Yang, R.-D., additional, Long, H., additional, Liu, Z.-S., additional, Wang, J.-Q., additional, Li, M., additional, Zhang, L.-H., additional, Wang, H., additional, Wang, L.-M., additional, Xiao, P., additional, Li, J.-L., additional, Huang, Z.-M., additional, Huang, J.-X., additional, Li, Z., additional, Xiong, L., additional, Yang, J., additional, Wang, X.-D., additional, Yu, D.-B., additional, Lu, X.-M., additional, Zhou, G.-Z., additional, Yan, L.-B., additional, Shen, J.-P., additional, Zhang, G.-C., additional, Zeng, Y.-X., additional, de Bakker, P.I.W., additional, Chen, S.-M., additional, and Liu, J.-J., additional

Published
2013
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34. An Enhancer Polymorphism at the Cardiomyocyte Intercalated Disc Protein NOS1AP Locus Is a Major Regulator of the QT Interval

Author

Kapoor, A., Sekar, R.B., Hansen, N.F., Fox-Talbot, K., Morley, M., Pihur, V., Chatterjee, S., Brandimarto, J., Moravec, C.S., Pulit, S.L., QT Interval International GWAS Consortium (), Pfeufer, A., Mullikin, J.C., Ross, M., Green, E.D., Bentley, D., Newton-Cheh, C., Boerwinkle, E., Tomaselli, G.F., Cappola, T.P., Arking, D.E., Halushka, M.K., and Chakravarti, A.

Subjects
Genotype, Long QT syndrome, Quantitative Trait Loci, Population, Locus (genetics), Genome-wide association study, Quantitative trait locus, Biology, Polymorphism, Single Nucleotide, QT interval, Article, Cohort Studies, Electrocardiography, Mice, NOS1AP, Genetics, medicine, Animals, Humans, Genetics(clinical), Myocytes, Cardiac, education, Zebrafish, Genetics (clinical), Adaptor Proteins, Signal Transducing, education.field_of_study, Lentivirus, medicine.disease, Long QT Syndrome, HEK293 Cells, Phenotype, medicine.anatomical_structure, Gene Expression Regulation, Intercalated disc, Genome-Wide Association Study
Abstract

QT interval variation is assumed to arise from variation in repolarization as evidenced from rare Na- and K-channel mutations in Mendelian QT prolongation syndromes. However, in the general population, common noncoding variants at a chromosome 1q locus are the most common genetic regulators of QT interval variation. In this study, we use multiple human genetic, molecular genetic, and cellular assays to identify a functional variant underlying trait association: a noncoding polymorphism (rs7539120) that maps within an enhancer of NOS1AP and affects cardiac function by increasing NOS1AP transcript expression. We further localized NOS1AP to cardiomyocyte intercalated discs (IDs) and demonstrate that overexpression of NOS1AP in cardiomyocytes leads to altered cellular electrophysiology. We advance the hypothesis that NOS1AP affects cardiac electrical conductance and coupling and thereby regulates the QT interval through propagation defects. As further evidence of an important role for propagation variation affecting QT interval in humans, we show that common polymorphisms mapping near a specific set of 170 genes encoding ID proteins are significantly enriched for association with the QT interval, as compared to genome-wide markers. These results suggest that focused studies of proteins within the cardiomyocyte ID are likely to provide insights into QT prolongation and its associated disorders.

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