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1. GWAS of blood cell traits identifies novel associated loci and epistatic interactions in Caucasian and African-American children.

Author

Li J, Glessner JT, Zhang H, Hou C, Wei Z, Bradfield JP, Mentch FD, Guo Y, Kim C, Xia Q, Chiavacci RM, Thomas KA, Qiu H, Grant SF, Furth SL, Hakonarson H, and Sleiman PM

Subjects
Anemia, Iron-Deficiency blood, Anemia, Iron-Deficiency ethnology, Erythrocyte Indices, Erythrocytes metabolism, Genetic Loci, Genetic Predisposition to Disease, Genotype, Guanine Nucleotide Exchange Factors genetics, Humans, Polymorphism, Single Nucleotide, Rho Guanine Nucleotide Exchange Factors, alpha-Globins genetics, Black or African American genetics, Anemia, Iron-Deficiency genetics, Epistasis, Genetic, Genome-Wide Association Study, White People genetics
Abstract

Hematological traits are important clinical indicators, the genetic determinants of which have not been fully investigated. Common measures of hematological traits include red blood cell (RBC) count, hemoglobin concentration (HGB), hematocrit (HCT), mean corpuscular hemoglobin (MCH), MCH concentration (MCHC), mean corpuscular volume (MCV), platelet count (PLT) and white blood cell (WBC) count. We carried out a genome-wide association study of the eight common hematological traits among 7943 African-American children and 6234 Caucasian children. In African Americans, we report five novel associations of HBE1 variants with HCT and MCHC, the alpha-globin gene cluster variants with RBC and MCHC, and a variant at the ARHGEF3 locus with PLT, as well as replication of four previously reported loci at genome-wide significance. In Caucasians, we report a novel association of variants at the COPZ1 locus with PLT as well as replication of four previously reported loci at genome-wide significance. Extended analysis of an association observed between MCH and the alpha-globin gene cluster variants demonstrated independent effects and epistatic interaction at the locus, impacting the risk of iron deficiency anemia in African Americans with specific genotype states. In summary, we extend the understanding of genetic variants underlying hematological traits based on analyses in African-American children.

Published
2013
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2. The role of height-associated loci identified in genome wide association studies in the determination of pediatric stature.

Author

Zhao J, Li M, Bradfield JP, Zhang H, Mentch FD, Wang K, Sleiman PM, Kim CE, Glessner JT, Hou C, Keating BJ, Thomas KA, Garris ML, Deliard S, Frackelton EC, Otieno FG, Chiavacci RM, Berkowitz RI, Hakonarson H, and Grant SF

Subjects
Adult, Child, Chromosome Structures, Diabetes Mellitus, Type 2 genetics, Genome, Growth genetics, Growth Differentiation Factor 5, HMGA2 Protein genetics, Humans, Research, White People genetics, Genome-Wide Association Study, Genotype, Polymorphism, Single Nucleotide
Abstract

Background: Human height is considered highly heritable and correlated with certain disorders, such as type 2 diabetes and cancer. Despite environmental influences, genetic factors are known to play an important role in stature determination. A number of genetic determinants of adult height have already been established through genome wide association studies., Methods: To examine 51 single nucleotide polymorphisms (SNPs) corresponding to the 46 previously reported genomic loci for height in 8,184 European American children with height measurements. We leveraged genotyping data from our ongoing GWA study of height variation in children in order to query the 51 SNPs in this pediatric cohort., Results: Sixteen of these SNPs yielded at least nominally significant association to height, representing fifteen different loci including EFEMP1-PNPT1, GPR126, C6orf173, SPAG17, Histone class 1, HLA class III and GDF5-UQCC. Other loci revealed no evidence for association, including HMGA1 and HMGA2. For the 16 associated variants, the genotype score explained 1.64% of the total variation for height z-score., Conclusion: Among 46 loci that have been reported to associate with adult height to date, at least 15 also contribute to the determination of height in childhood.

Published
2010
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3. Examination of all type 2 diabetes GWAS loci reveals HHEX-IDE as a locus influencing pediatric BMI.

Author

Zhao J, Bradfield JP, Zhang H, Annaiah K, Wang K, Kim CE, Glessner JT, Frackelton EC, Otieno FG, Doran J, Thomas KA, Garris M, Hou C, Chiavacci RM, Li M, Berkowitz RI, Hakonarson H, and Grant SF

Subjects
Adolescent, Child, Child, Preschool, Female, Genetic Predisposition to Disease, Genetic Variation, Humans, Hyperglycemia genetics, Male, Polymorphism, Single Nucleotide, Risk Factors, Body Mass Index, Diabetes Mellitus, Type 2 epidemiology, Diabetes Mellitus, Type 2 genetics, Genome-Wide Association Study, Homeodomain Proteins genetics, Insulysin genetics, Transcription Factors genetics
Abstract

Objective: A number of studies have found that BMI in early life influences the risk of developing type 2 diabetes later in life. Our goal was to investigate if any type 2 diabetes variants uncovered through genome-wide association studies (GWAS) impact BMI in childhood., Research Design and Methods: Using data from an ongoing GWAS of pediatric BMI in our cohort, we investigated the association of pediatric BMI with 20 single nucleotide polymorphisms at 18 type 2 diabetes loci uncovered through GWAS, consisting of ADAMTS9, CDC123-CAMK1D, CDKAL1, CDKN2A/B, EXT2, FTO, HHEX-IDE, IGF2BP2, the intragenic region on 11p12, JAZF1, KCNQ1, LOC387761, MTNR1B, NOTCH2, SLC30A8, TCF7L2, THADA, and TSPAN8-LGR5. We randomly partitioned our cohort exactly in half in order to have a discovery cohort (n = 3,592) and a replication cohort (n = 3,592)., Results: Our data show that the major type 2 diabetes risk-conferring G allele of rs7923837 at the HHEX-IDE locus was associated with higher pediatric BMI in both the discovery (P = 0.0013 and survived correction for 20 tests) and replication (P = 0.023) sets (combined P = 1.01 x 10(-4)). Association was not detected with any other known type 2 diabetes loci uncovered to date through GWAS except for the well-established FTO., Conclusions: Our data show that the same genetic HHEX-IDE variant, which is associated with type 2 diabetes from previous studies, also influences pediatric BMI.

Published
2010
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4. Variants of DENND1B associated with asthma in children.

Author

Sleiman PM, Flory J, Imielinski M, Bradfield JP, Annaiah K, Willis-Owen SA, Wang K, Rafaels NM, Michel S, Bonnelykke K, Zhang H, Kim CE, Frackelton EC, Glessner JT, Hou C, Otieno FG, Santa E, Thomas K, Smith RM, Glaberson WR, Garris M, Chiavacci RM, Beaty TH, Ruczinski I, Orange JS, Allen J, Spergel JM, Grundmeier R, Mathias RA, Christie JD, von Mutius E, Cookson WO, Kabesch M, Moffatt MF, Grunstein MM, Barnes KC, Devoto M, Magnusson M, Li H, Grant SF, Bisgaard H, and Hakonarson H

Subjects
Black People genetics, Case-Control Studies, Child, Chromosomes, Human, Pair 17, Female, Humans, Male, Meta-Analysis as Topic, North America, Odds Ratio, Receptors, Tumor Necrosis Factor metabolism, Asthma genetics, Chromosomes, Human, Pair 1, Death Domain Receptor Signaling Adaptor Proteins genetics, Genetic Predisposition to Disease, Genome-Wide Association Study, Guanine Nucleotide Exchange Factors genetics, Polymorphism, Single Nucleotide, White People genetics
Abstract

Background: Asthma is a complex disease that has genetic and environmental causes. The genetic factors associated with susceptibility to asthma remain largely unknown., Methods: We carried out a genomewide association study involving children with asthma. The sample included 793 North American children of European ancestry with persistent asthma who required daily inhaled glucocorticoid therapy and 1988 matched controls (the discovery set). We also tested for genomewide association in an independent cohort of 917 persons of European ancestry who had asthma and 1546 matched controls (the replication set). Finally, we tested for an association between 20 single-nucleotide polymorphisms (SNPs) at chromosome 1q31 and asthma in 1667 North American children of African ancestry who had asthma and 2045 ancestrally matched controls., Results: In our meta-analysis of all samples from persons of European ancestry, we observed an association, with genomewide significance, between asthma and SNPs at the previously reported locus on 17q21 and an additional eight SNPs at a novel locus on 1q31. The SNP most strongly associated with asthma was rs2786098 (P=8.55x10(-9)). We observed replication of the association of asthma with SNP rs2786098 in the independent series of persons of European ancestry (combined P=9.3x10(-11)). The alternative allele of each of the eight SNPs on chromosome 1q31 was strongly associated with asthma in the children of African ancestry (P=1.6x10(-13) for the comparison across all samples). The 1q31 locus contains the 1q31 locus contains DENND1B, a gene expressed by natural killer cells and dendritic cells. DENND1B protein is predicted to interact with the tumor necrosis factor α receptor [corrected]., Conclusions: We have identified a locus containing DENND1B on chromosome 1q31.3 that is associated with susceptibility to asthma., (2010 Massachusetts Medical Society)

Published
2010
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5. Follow-up analysis of genome-wide association data identifies novel loci for type 1 diabetes.

Author

Grant SF, Qu HQ, Bradfield JP, Marchand L, Kim CE, Glessner JT, Grabs R, Taback SP, Frackelton EC, Eckert AW, Annaiah K, Lawson ML, Otieno FG, Santa E, Shaner JL, Smith RM, Skraban R, Imielinski M, Chiavacci RM, Grundmeier RW, Stanley CA, Kirsch SE, Waggott D, Paterson AD, Monos DS, Polychronakos C, and Hakonarson H

Subjects
Adolescent, Adult, Canada, Child, Child, Preschool, Cohort Studies, Genotype, Humans, Infant, Meta-Analysis as Topic, United States, Young Adult, Diabetes Mellitus, Type 1 genetics, Genetic Predisposition to Disease genetics, Genome-Wide Association Study methods, Polymorphism, Single Nucleotide
Abstract

Objective: Two recent genome-wide association (GWA) studies have revealed novel loci for type 1 diabetes, a common multifactorial disease with a strong genetic component. To fully utilize the GWA data that we had obtained by genotyping 563 type 1 diabetes probands and 1,146 control subjects, as well as 483 case subject-parent trios, using the Illumina HumanHap550 BeadChip, we designed a full stage 2 study to capture other possible association signals., Research Design and Methods: From our existing datasets, we selected 982 markers with P < 0.05 in both GWA cohorts. Genotyping these in an independent set of 636 nuclear families with 974 affected offspring revealed 75 markers that also had P < 0.05 in this third cohort. Among these, six single nucleotide polymorphisms in five novel loci also had P < 0.05 in the Wellcome Trust Case-Control Consortium dataset and were further tested in 1,303 type 1 diabetes probands from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) plus 1,673 control subjects., Results: Two markers (rs9976767 and rs3757247) remained significant after adjusting for the number of tests in this last cohort; they reside in UBASH3A (OR 1.16; combined P = 2.33 x 10(-8)) and BACH2 (1.13; combined P = 1.25 x 10(-6))., Conclusions: Evaluation of a large number of statistical GWA candidates in several independent cohorts has revealed additional loci that are associated with type 1 diabetes. The two genes at these respective loci, UBASH3A and BACH2, are both biologically relevant to autoimmunity.

Published
2009
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6. Common variants at 12q15 and 12q24 are associated with infant head circumference

Author

Taal, H Rob, Pourcain, Beate St, Geller, Frank, Davis, Oliver S P, Elliott, Paul, Evans, David M, Feenstra, Bjarke, Flexeder, Claudia, Frayling, Tim, Freathy, Rachel M, Gaillard, Romy, Groen-Blokhuis, Maria, Guxens, Mònica, Goh, Liang-Kee, Haworth, Claire M A, Hadley, Dexter, Hedebrand, Johannes, Hinney, Anke, Hirschhorn, Joel N, Holloway, John W, Holst, Claus, Hottenga, Jouke Jan, Cousminer, Diana L, Horikoshi, Momoko, Huikari, Ville, Hypponen, Elina, Iñiguez, Carmen, Kaakinen, Marika, Kilpeläinen, Tuomas O, Kirin, Mirna, Kowgier, Matthew, Lakka, Hanna-Maaria, Lange, Leslie A, Kerkhof, Marjan, Lawlor, Debbie A, Lehtimäki, Terho, Lewin, Alex, Lindgren, Cecilia, Lindi, Virpi, Maggi, Reedik, Marsh, Julie, Middeldorp, Christel, Millwood, Iona, Mook-Kanamori, Dennis O, Timpson, Nicholas J, Murray, Jeffrey C, Nivard, Michel, Nohr, Ellen Aagaard, Ntalla, Ioanna, Oken, Emily, O'Reilly, Paul F, Palmer, Lyle J, Panoutsopoulou, Kalliope, Pararajasingham, Jennifer, Prokopenko, Inga, Ikram, M Arfan, Rodriguez, Alina, Salem, Rany M, Sebert, Sylvain, Siitonen, Niina, Sovio, Ulla, St Pourcain, Beate, Strachan, David P, Sunyer, Jordi, Teo, Yik-Ying, Beilin, Lawrence J, Thiering, Elisabeth, Tiesler, Carla, Uitterlinden, Andre G, Valcárcel, Beatriz, Warrington, Nicole M, White, Scott, Willemsen, Gonneke, Yaghootkar, Hanieh, Zeggini, Eleftheria, Boomsma, Dorret I, Bønnelykke, Klaus, Cooper, Cyrus, Estivill, Xavier, Gillman, Matthew, Grant, Struan F A, Hakonarson, Hakon, Hattersley, Andrew T, Heinrich, Joachim, Hocher, Berthold, Jaddoe, Vincent W V, Jarvelin, Marjo-Riitta, Buxton, Jessica L, Lakka, Timo A, McCarthy, Mark I, Melbye, Mads, Mohlke, Karen L, Dedoussis, George V, Ong, Ken K, Pearson, Ewan R, Pennell, Craig E, Price, Thomas S, Power, Chris, Charoen, Pimphen, Raitakari, Olli T, Saw, Seang-Mei, Scherag, Andre, Simell, Olli, Sørensen, Thorkild I A, Widen, Elisabeth, Wilson, James F, Ang, Wei, van Beijsterveldt, Toos, Chawes, Bo Lund Krogsgaard, Bergen, Nienke, Benke, Kelly, Berry, Diane, Bradfield, Jonathan P, Coin, Lachlan, Das, Shikta, Eriksson, Johan, Hofman, Albert, Standl, Marie, Kemp, John P, Kim, Cecilia E, Klopp, Norman, Fornage, Myriam, Smith, Albert V, Seshadri, Sudha, Schmidt, Reinhold, Debette, Stéphanie, Vrooman, Henri A, Ropele, Stefan, Sigurdsson, Sigurdur, Lahti, Jari, Coker, Laura H, Longstreth, W. T., Niessen, Wiro J, DeStefano, Anita L, Beiser, Alexa, Zijdenbos, Alex P, Struchalin, Maksim, Jack, Clifford R, Nalls, Mike A, Au, Rhoda, Lye, Stephen J, Gudnason, Haukur, van der Lugt, Aad, Harris, Tamara B, Meeks, William M, Vernooij, Meike W, van Buchem, Mark A, Catellier, Diane, Gudnason, Vilmundur, Windham, B Gwen, McMahon, George, Wolf, Philip A, van Duijn, Cornelia M, Mosley, Thomas H, Schmidt, Helena, Launer, Lenore J, Breteler, Monique M B, DeCarli, Charles, Mentch, Frank D, Müller, Martina, Rivadeneira, Fernando, Steegers, Eric A P, Epidemiology, Cohorts for Heart and Aging Research in Genetic, Debette, Stephanie, Epidemiology, Early Genetics & Lifecourse, Blakemore, Alexandra If, Chiavacci, Rosetta M, Fernandez-Benet, Julio, Hartikainen, Anna-Liisa, van der Heijden, Albert J, Lathrop, Mark, McArdle, Wendy L, Mølgaard, Anne, Newnham, John P, Palotie, Aarno, Pouta, Annneli, Ring, Susan M, Kreiner-Møller, Eskil, Wichmann, H-Erich, Vissing, Nadja Hawwa, Koppelman, Gerard H, Bisgaard, Hans, Smith, George Davey, Genetics, Early Growth, Adair, Linda S, Atalay, Mustafa, Faculteit Medische Wetenschappen/UMCG, Groningen Research Institute for Asthma and COPD (GRIAC), Biological Psychology, Neuroscience Campus Amsterdam - Brain Imaging, EMGO+ - Mental Health, Epidemiology, Erasmus MC other, Internal Medicine, Obstetrics & Gynecology, Radiology & Nuclear Medicine, Pediatrics, Early Genetics & Lifecourse Epidemiology (EAGLE) Consortium, Heart and Aging Research in Genetic Epidemiology (CHARGE) Consortium, Early Growth Genetics (EGG) Consortium, Taal, H Rob, St Pourcain, Beate, Thiering, Elisabeth, Das, Shikta, Jaddo, Vincent WV, and Hypponen, Elina

Subjects
Embaràs -- Complicacions, Netherlands Twin Register (NTR), Male, Medizin, pathology [Head], Physiology, PROTEIN, Genome-wide association study, INTELLIGENCE, Bioinformatics, 0302 clinical medicine, PARKINSONS-DISEASE, Polymorphism (computer science), Pregnancy, infant head circumference, chromosome 12q24, Cap -- Malalties, health care economics and organizations, Cap -- Creixement, 0303 health sciences, 3. Good health, genetics [European Continental Ancestry Group], genetics [Chromosomes, Human, Pair 12], genetics [Polymorphism, Single Nucleotide], Medical genetics, Female, chromosome 12q15, BRAIN-DEVELOPMENT, Genetic Markers, medicine.medical_specialty, DISORDERS, Single-nucleotide polymorphism, Biology, etiology [Pregnancy Complications], Polymorphism, Single Nucleotide, White People, Article, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Meta-Analysis as Topic, ddc:570, Genetics, medicine, Humans, GENOME-WIDE ASSOCIATION, Institut für Biochemie und Biologie, 030304 developmental biology, Genetic association, Cromosomes humans, pathology [Pregnancy Complications], Chromosomes, Human, Pair 12, IDENTIFICATION, growth & development [Head], MUTATIONS, Polimorfisme genètic, Chromosome, Infant, ta3121, medicine.disease, brain growth, GENE, Pregnancy Complications, Genetic marker, Genetic Loci, FETAL-GROWTH, Head, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

To identify genetic variants associated with head circumference in infancy, we performed a meta-analysis of seven genome-wide association studies (GWAS) (N = 10,768 individuals of European ancestry enrolled in pregnancy and/or birth cohorts) and followed up three lead signals in six replication studies (combined N = 19,089). rs7980687 on chromosome 12q24 (P = 8.1 × 10(-9)) and rs1042725 on chromosome 12q15 (P = 2.8 × 10(-10)) were robustly associated with head circumference in infancy. Although these loci have previously been associated with adult height, their effects on infant head circumference were largely independent of height (P = 3.8 × 10(-7) for rs7980687 and P = 1.3 × 10(-7) for rs1042725 after adjustment for infant height). A third signal, rs11655470 on chromosome 17q21, showed suggestive evidence of association with head circumference (P = 3.9 × 10(-6)). SNPs correlated to the 17q21 signal have shown genome-wide association with adult intracranial volume, Parkinson's disease and other neurodegenerative diseases, indicating that a common genetic variant in this region might link early brain growth with neurological disease in later life. Major funding for the research in this paper is as follows: Academy of Finland (project grants 104781, 120315, 129269, 1114194 and Center of Excellence in Complex Disease Genetics); Canadian Institutes of Health Research (grant MOP 82893); The European Community’s Seventh Framework Programme (FP7/2007-2013), ENGAGE project, grant agreement HEALTH-F4-2007-201413; Instituto de Salud Carlos III (FIS PI081151, and PS09/00432); Medical Research Council UK (G0500539, G0600331, PrevMetSyn/Salve/MRC, G0600705); National Health and Medical Research Council of Australia (ID 403981 and ID 003209); Netherlands Organisation for Scientific Research (NOW)/Netherlands Organisation for Health Reseacrh and Development (ZonMw) (grants SPI 56-464-14192, 904-61-090, 904-61-193, 480-04-004, 400-05-717); NHLBI (grant 5R01HL087679-02 through the STAMPEED program (1RL1MH083268-01)); NIH (grant 1R01HD056465-01A1); University of Leipzig; Wellcome Trust (project grant GR069224); Western Australian DNA Bank; Western Australian Genetic Epidemiology Resource; ZonMW (grant 21000074). Personal funding is as follows: H.R.T by the Dutch Kidney Foundation (C08.2251) , S.D. by the Medical Research Council UK (G0500539, PrevMetSyn, and PS0476), R.M.F by a Sir Henry Wellcome Postdoctoral Fellowship (Wellcome Trust grant: 085541/Z/08/Z), D.M.E. by a Medical Research Council New Investigator Award (MRC G0800582 to D.M.E.), J.P.K. by a Wellcome Trust 4-year PhD studentship (WT083431MA), I.P. and J.F.B. in part supported by the European Community’s ENGAGE grant HEALTH-F4-2007-201413. A.T.H. is employed as a core member of the Peninsula NIHR Clinical Research Facility, V.W.V.J by the Netherlands Organization for Health Research (ZonMw 90700303, 916.10159)

Published
2012
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7. A genome-wide association study of anorexia nervosa suggests a risk locus implicated in dysregulated leptin signaling

Author

Dong, Li, Chang, Xiao, Connolly, John J., Tian, Lifeng, Liu, Yichuan, Bhoj, Elizabeth J., Robinson, Nora, Abrams, Debra, Yun R., Li, Bradfield, Jonathan P., Kim, Cecilia E., Jin, Li, Wang, Fengxiang, Snyder, James, Lemma, Maria, Hou, Cuiping, Wei, Zhi, Guo, Yiran, Qiu, Haijun, Mentch, Frank D., Thomas, Kelly A., Chiavacci, Rosetta M., Cone, Roger, Bingshan, Li, Sleiman, Patrick A., Hakonarson, Hakon, Perica, Vesna Boraska, Franklin, Christopher S., Floyd, James A. B., Thornton, Laura M., Huckins, Laura M., Southam, Lorraine, Rayner, N. William, Tachmazidou, Ioanna, Schmidt, Ulrike, Tozzi, Federica, Kiezebrink, Kirsty, Hebebrand, Johannes, Gorwood, Philip, Adan, Roger A. H., Kas, Martien J. H., Favaro, Angela, Santonastaso, Paolo, Fernánde Aranda, Fernando, Gratacos, Monica, Rybakowski, Filip, Dmitrzak Weglarz, Monika, Kaprio, Jaakko, Keski Rahkonen, Anna, Raevuori Helkamaa, Anu, Furth, Eric F. Van, Slof Opt Landt, Margarita C. T., Hudson, James I., Reichborn Kjennerud, Ted, Knudsen, Gun Peggy S., Monteleone, Palmiero, Karwautz, Andreas, Berrettini, Wade H., Schork, Nicholas J., Ando, Tetsuya, Inoko, Hidetoshi, Esko, Toã±u, Fischer, Krista, Mã¤nnik, Katrin, Metspalu, Andres, Baker, Jessica H., Desocio, Janiece E., Hilliard, Christopher E., O'Toole, Julie K., Pantel, Jacques, Szatkiewicz, Jin P., Zerwas, Stephanie, Davis, Oliver S. P., Helder, Sietske, Bã¼hren, Katharina, Burghardt, Roland, De Zwaan, Martina, Egberts, Karin, Ehrlich, Stefan, Herpertz Dahlmann, Beate, Herzog, Wolfgang, Imgart, Hartmut, Scherag, Andrã, Zipfel, Stephan, Boni, Claudette, Ramoz, Nicolas, Versini, Audrey, Danner, Unna N., Hendriks, Judith, Koeleman, Bobby P. C., Ophoff, Roel A., Strengman, Eric, Van Elburg, Annemarie A., Bruson, Alice, Clementi, Maurizio, Degortes, Daniela, Forzan, Monica, Tenconi, Elena, Docampo, Elisa, Escaramã­s, Geã²rgia, Jiménez Murcia, Susana, Lissowska, Jolanta, Rajewski, Andrzej, Szeszenia Dabrowska, Neonila, Slopien, Agnieszka, Hauser, Joanna, Karhunen, Leila, Meulenbelt, Ingrid, Slagboom, P. Eline, Tortorella, Alfonso Antonio Vincenzo, Maj, Mario, Dedoussis, George, Dikeos, Dimitris, Gonidakis, Fragiskos, Tziouvas, Konstantinos, Tsitsika, Artemis, Papezova, Hana, Slachtova, Lenka, Martaskova, Debora, Kennedy, James L., Levitan, Robert D., Yilmaz, Zeynep, Huemer, Julia, Koubek, Doris, Merl, Elisabeth, Wagner, Gudrun, Lichtenstein, Paul, Breen, Gerome, Cohen Woods, Sarah, Farmer, Anne, Mcguffin, Peter, Cichon, Sven, Giegling, Ina, Herms, Stefan, Rujescu, Dan, Schreiber, Stefan, Wichmann, H. Erich, Dina, Christian, Sladek, Rob, Gambaro, Giovanni, Soranzo, Nicole, Julia, Antonio, Marsal, Sara, Rabionet, Raquel, Gaborieau, Valerie, Dick, Danielle M., Palotie, Aarno, Ripatti, Samuli, Widã©n, Elisabeth, Andreassen, Ole A., Espeseth, Thomas, Lundervold, Astri, Reinvang, Ivar, Steen, Vidar M., Le Hellard, Stephanie, Mattingsdal, Morten, Ntalla, Ioanna, Bencko, Vladimir, Foretova, Lenka, Janout, Vladimir, Navratilova, Marie, Gallinger, Steven, Pinto, Dalila, Scherer, Stephen W., Aschauer, Harald, Carlberg, Laura, Schosser, Alexandra, Alfredsson, Lars, Ding, Bo, Klareskog, Lars, Padyukov, Leonid, Finan, Chris, Kalsi, Gursharan, Roberts, Marion, Barrett, Jeff C., Estivill, Xavier, Hinney, Anke, Sullivan, Patrick F., Zeggini, Eleftheria, Bulik, Cynthia M., Brandt, Harry, Crawford, Steve, Crow, Scott, Fichter, Manfred M., Halmi, Katherine A., Johnson, Craig, Kaplan, Allan S., La Via, Maria C., Mitchell, James, Strober, Michael, Rotondo, Alessandro, Treasure, Janet, Woodside, D. Blake, Keel, Pamela K., Klump, Kelly L., Lilenfeld, Lisa, Bergen, Andrew W., Kaye, Walter, Magistretti, Pierre, Universitat de Barcelona, Centre of Excellence in Complex Disease Genetics, Aarno Palotie / Principal Investigator, Institute for Molecular Medicine Finland, Department of Public Health, Clinicum, Samuli Olli Ripatti / Principal Investigator, Biostatistics Helsinki, HUS Children and Adolescents, Complex Disease Genetics, Genomics of Neurological and Neuropsychiatric Disorders, Genetic Epidemiology, Kas lab, School of Medicine / Clinical Nutrition, Li, Dong, Chang, Xiao, Connolly, John J., Tian, Lifeng, Liu, Yichuan, Bhoj, Elizabeth J., Robinson, Nora, Abrams, Debra, Li, Yun R., Bradfield, Jonathan P., Kim, Cecilia E., Li, Jin, Wang, Fengxiang, Snyder, Jame, Lemma, Maria, Hou, Cuiping, Wei, Zhi, Guo, Yiran, Qiu, Haijun, Mentch, Frank D., Thomas, Kelly A., Chiavacci, Rosetta M., Cone, Roger, Li, Bingshan, Sleiman, Patrick A., Hakonarson, Hakon, Perica, Vesna Boraska, Franklin, Christopher S., Floyd, James A. B., Thornton, Laura M., Huckins, Laura M., Southam, Lorraine, Rayner, N. William, Tachmazidou, Ioanna, Schmidt, Ulrike, Tozzi, Federica, Kiezebrink, Kirsty, Hebebrand, Johanne, Gorwood, Philip, Adan, Roger A. H., Kas, Martien J. H., Favaro, Angela, Santonastaso, Paolo, Fernánde-Aranda, Fernando, Gratacos, Monica, Rybakowski, Filip, Dmitrzak-Weglarz, Monika, Kaprio, Jaakko, Keski-Rahkonen, Anna, Raevuori-Helkamaa, Anu, Furth, Eric F. Van, Slof-Opt Landt, Margarita C. T., Hudson, James I., Reichborn-Kjennerud, Ted, Knudsen, Gun Peggy S., Monteleone, Palmiero, Karwautz, Andrea, Berrettini, Wade H., Schork, Nicholas J., Ando, Tetsuya, Inoko, Hidetoshi, Esko, Toã±u, Fischer, Krista, Mã¤nnik, Katrin, Metspalu, Andre, Baker, Jessica H., Desocio, Janiece E., Hilliard, Christopher E., O'Toole, Julie K., Pantel, Jacque, Szatkiewicz, Jin P., Zerwas, Stephanie, Davis, Oliver S. P., Helder, Sietske, Bã¼hren, Katharina, Burghardt, Roland, De Zwaan, Martina, Egberts, Karin, Ehrlich, Stefan, Herpertz-Dahlmann, Beate, Herzog, Wolfgang, Imgart, Hartmut, Scherag, Andrã©, Zipfel, Stephan, Boni, Claudette, Ramoz, Nicola, Versini, Audrey, Danner, Unna N., Hendriks, Judith, Koeleman, Bobby P. C., Ophoff, Roel A., Strengman, Eric, Van Elburg, Annemarie A., Bruson, Alice, Clementi, Maurizio, Degortes, Daniela, Forzan, Monica, Tenconi, Elena, Docampo, Elisa, Escaramã­s, Geã²rgia, Jiménez-Murcia, Susana, Lissowska, Jolanta, Rajewski, Andrzej, Szeszenia-Dabrowska, Neonila, Slopien, Agnieszka, Hauser, Joanna, Karhunen, Leila, Meulenbelt, Ingrid, Slagboom, P. Eline, Tortorella, Alfonso, Maj, Mario, Dedoussis, George, Dikeos, Dimitri, Gonidakis, Fragisko, Tziouvas, Konstantino, Tsitsika, Artemi, Papezova, Hana, Slachtova, Lenka, Martaskova, Debora, Kennedy, James L., Levitan, Robert D., Yilmaz, Zeynep, Huemer, Julia, Koubek, Dori, Merl, Elisabeth, Wagner, Gudrun, Lichtenstein, Paul, Breen, Gerome, Cohen-Woods, Sarah, Farmer, Anne, Mcguffin, Peter, Cichon, Sven, Giegling, Ina, Herms, Stefan, Rujescu, Dan, Schreiber, Stefan, Wichmann, H-Erich, Dina, Christian, Sladek, Rob, Gambaro, Giovanni, Soranzo, Nicole, Julia, Antonio, Marsal, Sara, Rabionet, Raquel, Gaborieau, Valerie, Dick, Danielle M., Palotie, Aarno, Ripatti, Samuli, Widã©n, Elisabeth, Andreassen, Ole A., Espeseth, Thoma, Lundervold, Astri, Reinvang, Ivar, Steen, Vidar M., Le Hellard, Stephanie, Mattingsdal, Morten, Ntalla, Ioanna, Bencko, Vladimir, Foretova, Lenka, Janout, Vladimir, Navratilova, Marie, Gallinger, Steven, Pinto, Dalila, Scherer, Stephen W., Aschauer, Harald, Carlberg, Laura, Schosser, Alexandra, Alfredsson, Lar, Ding, Bo, Klareskog, Lar, Padyukov, Leonid, Finan, Chri, Kalsi, Gursharan, Roberts, Marion, Barrett, Jeff C., Estivill, Xavier, Hinney, Anke, Sullivan, Patrick F., Zeggini, Eleftheria, Bulik, Cynthia M., Brandt, Harry, Crawford, Steve, Crow, Scott, Fichter, Manfred M., Halmi, Katherine A., Johnson, Craig, Kaplan, Allan S., La Via, Maria C., Mitchell, Jame, Strober, Michael, Rotondo, Alessandro, Treasure, Janet, Woodside, D. Blake, Keel, Pamela K., Klump, Kelly L., Lilenfeld, Lisa, Bergen, Andrew W., Kaye, Walter, Magistretti, Pierre, Guo, Yiran [0000-0002-6549-8589], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Leptin signaling, Eating Disorders, Medizin, Genome-wide association study, CHILDREN, VARIANTS, Bioinformatics, 3124 Neurology and psychiatry, 0302 clinical medicine, B-CELL-FACTOR, Eating Disorders Working Group of the Psychiatric Genomics Consortium, 2.1 Biological and endogenous factors, Aetiology, Genetics, Multidisciplinary, Anorèxia nerviosa, Genomics, Phenotype, Price Foundation Collaborative Group, 3142 Public health care science, environmental and occupational health, Anorexia, Eating disorders, Mental Health, Behavioural genetics, Medicine, Erratum, GENETICS, Science, Locus (genetics), Single-nucleotide polymorphism, Biology, PRESSURE, PARAMETERS, 03 medical and health sciences, medicine, Journal Article, General, EBF1, Prevention, Human Genome, EATING-DISORDERS, Settore MED/13 - ENDOCRINOLOGIA, OBSESSIVE-COMPULSIVE DISORDER, Anorexia nervosa, medicine.disease, Confidence interval, 030227 psychiatry, Genòmica, 030104 developmental biology, Risk factors
Abstract

We conducted a genome-wide association study (GWAS) of anorexia nervosa (AN) using a stringently defined phenotype. Analysis of phenotypic variability led to the identification of a specific genetic risk factor that approached genome-wide significance (rs929626 in EBF1 (Early B-Cell Factor 1); P = 2.04 × 10−7; OR = 0.7; 95% confidence interval (CI) = 0.61–0.8) with independent replication (P = 0.04), suggesting a variant-mediated dysregulation of leptin signaling may play a role in AN. Multiple SNPs in LD with the variant support the nominal association. This demonstrates that although the clinical and etiologic heterogeneity of AN is universally recognized, further careful sub-typing of cases may provide more precise genomic signals. In this study, through a refinement of the phenotype spectrum of AN, we present a replicable GWAS signal that is nominally associated with AN, highlighting a potentially important candidate locus for further investigation., published version, peerReviewed

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8. Genetic sharing and heritability of paediatric age of onset autoimmune diseases

Author

Jin Li, Patrick M. A. Sleiman, Rosetta M. Chiavacci, Dimitri S. Monos, Fengxiang Wang, Zhi Wei, Jane E Munro, Edward M. Behrens, Carol Wise, Kathleen E. Sullivan, Jack Satsangi, Jordan S. Orange, Sihai Dave Zhao, Subramaniam Kugathasan, Maede Mohebnasab, Vito Annese, Elena S. Resnick, Charlotte Cunningham-Rundles, Eline T. Luning Prak, Constantin Polychronakos, Christopher J. Cardinale, Haijun Qui, Kelly A. Thomas, David C. Wilson, Cecilia E. Kim, Yiran Guo, Marina Bakay, Julie Kobie, Brendan J. Keating, Elena E. Perez, Frank D. Mentch, Marla Dubinsky, Richard K Russell, Hakon Hakonarson, Stephen L. Guthery, Berit Flatø, Justine A. Ellis, Susan D. Thompson, Struan F.A. Grant, Øystein Førre, James Snyder, Benedicte A. Lie, Marilynn Punaro, Erasmo Miele, Yun Li, Mara L. Becker, Debra J. Abrams, S. Melkorka Maggadottir, Annamaria Staiano, Caterina Strisciuglio, Lee A. Denson, Terri H. Finkel, John Connolly, Dong Li, Hongzhe Li, Helen Chapel, Robert N. Baldassano, Anne M. Griffiths, Anna Latiano, Mark S. Silverberg, Jonathan P. Bradfield, Laura Steel, Joseph T. Glessner, Li, Yun R., Zhao, Sihai D., Li, Jin, Bradfield, Jonathan P., Mohebnasab, Maede, Steel, Laura, Kobie, Julie, Abrams, Debra J., Mentch, Frank D., Glessner, Joseph T., Guo, Yiran, Wei, Zhi, Connolly, John J., Cardinale, Christopher J., Bakay, Marina, Li, Dong, Maggadottir, S. Melkorka, Thomas, Kelly A., Qui, Haijun, Chiavacci, Rosetta M., Kim, Cecilia E., Wang, Fengxiang, Snyder, Jame, Flatø, Berit, Førre, Oystein, Denson, Lee A., Thompson, Susan D., Becker, Mara L., Guthery, Stephen L., Latiano, Anna, Perez, Elena, Resnick, Elena, Strisciuglio, Caterina, Staiano, Annamaria, Miele, Erasmo, Silverberg, Mark S., Lie, Benedicte A., Punaro, Marilynn, Russell, Richard K., Wilson, David C., Dubinsky, Marla C., Monos, Dimitri S., Annese, Vito, Munro, Jane E., Wise, Carol, Chapel, Helen, Cunningham Rundles, Charlotte, Orange, Jordan S., Behrens, Edward M., Sullivan, Kathleen E., Kugathasan, Subra, Griffiths, Anne M., Satsangi, Jack, Grant, Struan F. A., Sleiman, Patrick M. A., Finkel, Terri H., Polychronakos, Constantin, Baldassano, Robert N., Luning Prak, Eline T., Ellis, Justine A., Li, Hongzhe, Keating, Brendan J., and Hakonarson, Hakon

Subjects
Male, Adolescent, Population, European Continental Ancestry Group, General Physics and Astronomy, Genome-wide association study, Biology, Major histocompatibility complex, Inflammatory bowel disease, Autoimmune Disease, Polymorphism, Single Nucleotide, General Biochemistry, Genetics and Molecular Biology, White People, Article, Autoimmune Diseases, 03 medical and health sciences, Physics and Astronomy (all), 0302 clinical medicine, medicine, Humans, Genetic Predisposition to Disease, Age of Onset, education, Child, 030304 developmental biology, 030203 arthritis & rheumatology, Genetics, 0303 health sciences, education.field_of_study, Multidisciplinary, Biochemistry, Genetics and Molecular Biology (all), Chemistry (all), Case-control study, General Chemistry, Heritability, medicine.disease, 3. Good health, Rheumatoid arthritis, Case-Control Studies, Child, Preschool, biology.protein, Female, Age of onset, Case-Control Studie, Genome-Wide Association Study, Human
Abstract

Autoimmune diseases (AIDs) are polygenic diseases affecting 7–10% of the population in the Western Hemisphere with few effective therapies. Here, we quantify the heritability of paediatric AIDs (pAIDs), including JIA, SLE, CEL, T1D, UC, CD, PS, SPA and CVID, attributable to common genomic variations (SNP-h2). SNP-h2 estimates are most significant for T1D (0.863±s.e. 0.07) and JIA (0.727±s.e. 0.037), more modest for UC (0.386±s.e. 0.04) and CD (0.454±0.025), largely consistent with population estimates and are generally greater than that previously reported by adult GWAS. On pairwise analysis, we observed that the diseases UC-CD (0.69±s.e. 0.07) and JIA-CVID (0.343±s.e. 0.13) are the most strongly correlated. Variations across the MHC strongly contribute to SNP-h2 in T1D and JIA, but does not significantly contribute to the pairwise rG. Together, our results partition contributions of shared versus disease-specific genomic variations to pAID heritability, identifying pAIDs with unexpected risk sharing, while recapitulating known associations between autoimmune diseases previously reported in adult cohorts., Autoimmune diseases are genetically complex disorders that affect up to 10% of the Western population. Here Li et al. quantify the heritability of a range of autoimmune diseases in the largest paediatric cohort examined to date, illustrating that genetic and non-genetic components variably contribute to the susceptibility of each disease.

Published
2015
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9. Meta-analysis of shared genetic architecture across ten pediatric autoimmune diseases

Author

Marina Bakay, Diana Chang, Kelly A. Thomas, Jack Satsangi, Sihai Dave Zhao, Cuiping Hou, Carol Wise, Dong Li, Feng Gao, Anne M. Griffiths, Brendan J. Keating, Jane E Munro, Jin Li, Berit Flatø, Øystein Førre, Marla Dubinsky, Benedicte A. Lie, Charlotte Cunningham-Rundles, Erasmo Miele, Debra J. Abrams, Elena S. Resnick, Edward M. Behrens, Haijun Qiu, Marilynn Punaro, Anna Latiano, Alon Keinan, David C. Wilson, Christopher J. Cardinale, John Connolly, Lee A. Denson, Mark S. Silverberg, Subra Kugathasan, Jonathan P. Bradfield, Dimitri S. Monos, Fengxiang Wang, Richard K Russell, Annamaria Staiano, Hakon Hakonarson, Caterina Strisciuglio, Justine A. Ellis, Stephen L. Guthery, Hongzhe Li, Terri H. Finkel, Helen Chapel, Marylyn D Richie, James Snyder, S. Melkorka Maggadottir, Elena E. Perez, Rosetta M. Chiavacci, Kathleen E. Sullivan, Struan F.A. Grant, Robert N. Baldassano, Jordan S. Orange, Eline T. Luning Prak, Vito Annese, Constantin Polychronakos, Cecilia E. Kim, Yiran Guo, Frank D. Mentch, Susan D. Thompson, Charlly Kao, Yun Li, Mara L. Becker, Zhi Wei, Joseph T. Glessner, Patrick M. A. Sleiman, Li, Yun R., Li, Jin, Zhao, Sihai D., Bradfield, Jonathan P., Mentch, Frank D., Maggadottir, S. Melkorka, Hou, Cuiping, Abrams, Debra J., Chang, Diana, Gao, Feng, Guo, Yiran, Wei, Zhi, Connolly, John J., Cardinale, Christopher J., Bakay, Marina, Glessner, Joseph T., Li, Dong, Kao, Charlly, Thomas, Kelly A., Qiu, Haijun, Chiavacci, Rosetta M., Kim, Cecilia E., Wang, Fengxiang, Snyder, Jame, Richie, Marylyn D., Flatø, Berit, Førre, Øystein, Denson, Lee A., Thompson, Susan D., Becker, Mara L., Guthery, Stephen L., Latiano, Anna, Perez, Elena, Resnick, Elena, Russell, Richard K., Wilson, David C., Silverberg, Mark S., Annese, Vito, Lie, Benedicte A., Punaro, Marilynn, Dubinsky, Marla C., Monos, Dimitri S., Strisciuglio, Caterina, Staiano, Annamaria, Miele, Erasmo, Kugathasan, Subra, Ellis, Justine A., Munro, Jane E., Sullivan, Kathleen E., Wise, Carol A., Chapel, Helen, Cunningham Rundles, Charlotte, Grant, Struan F. A., Orange, Jordan S., Sleiman, Patrick M. A., Behrens, Edward M., Griffiths, Anne M., Satsangi, Jack, Finkel, Terri H., Keinan, Alon, Prak, Eline T. Luning, Polychronakos, Constantin, Baldassano, Robert N., Li, Hongzhe, Keating, Brendan J., and Hakonarson, Hakon

Subjects
Candidate gene, Population, Quantitative Trait Loci, Single-nucleotide polymorphism, Genome-wide association study, Quantitative trait locus, Autoimmune Disease, Polymorphism, Single Nucleotide, General Biochemistry, Genetics and Molecular Biology, Autoimmune Diseases, Risk Factors, Humans, Medicine, education, Child, Genetic association, Genetics, education.field_of_study, Biochemistry, Genetics and Molecular Biology (all), business.industry, Risk Factor, Medicine (all), General Medicine, Genetic architecture, Expression quantitative trait loci, Immunology, business, Genome-Wide Association Study, Human
Abstract

Genome-wide association studies (GWASs) have identified hundreds of susceptibility genes, including shared associations across clinically distinct autoimmune diseases. We performed an inverse χ(2) meta-analysis across ten pediatric-age-of-onset autoimmune diseases (pAIDs) in a case-control study including more than 6,035 cases and 10,718 shared population-based controls. We identified 27 genome-wide significant loci associated with one or more pAIDs, mapping to in silico-replicated autoimmune-associated genes (including IL2RA) and new candidate loci with established immunoregulatory functions such as ADGRL2, TENM3, ANKRD30A, ADCY7 and CD40LG. The pAID-associated single-nucleotide polymorphisms (SNPs) were functionally enriched for deoxyribonuclease (DNase)-hypersensitivity sites, expression quantitative trait loci (eQTLs), microRNA (miRNA)-binding sites and coding variants. We also identified biologically correlated, pAID-associated candidate gene sets on the basis of immune cell expression profiling and found evidence of genetic sharing. Network and protein-interaction analyses demonstrated converging roles for the signaling pathways of type 1, 2 and 17 helper T cells (TH1, TH2 and TH17), JAK-STAT, interferon and interleukin in multiple autoimmune diseases.

Published
2015
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