DOCSLIB.ORG

Significant Locus and Metabolic Genetic Correlations Revealed In

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Significant Locus and Metabolic Genetic Correlations Revealed In ARTICLES Significant Locus and Metabolic Genetic Correlations Revealed in Genome-Wide Association Study of Anorexia Nervosa Laramie Duncan, Ph.D., Zeynep Yilmaz, Ph.D., Helena Gaspar, Ph.D., Raymond Walters, Ph.D., Jackie Goldstein, Ph.D., Verneri Anttila, Ph.D., Brendan Bulik-Sullivan, Ph.D., Stephan Ripke, M.D., Ph.D., Eating Disorders Working Group of the Psychiatric Genomics Consortium, Laura Thornton, Ph.D., Anke Hinney, Ph.D., MarkDaly,Ph.D.,PatrickF.Sullivan,M.D.,F.R.A.N.Z.C.P.,EleftheriaZeggini,Ph.D.,GeromeBreen,Ph.D., Cynthia M. Bulik, Ph.D. Objective: The authors conducted a genome-wide associ- fraction of the twin-based heritability arises from common ation study of anorexia nervosa and calculated genetic genetic variation. The authors identified one genome-wide correlations with a series of psychiatric, educational, and significant locus on chromosome 12 (rs4622308) in a region metabolic phenotypes. harboring a previously reported type 1 diabetes and auto- immune disorder locus. Significant positive genetic cor- Method: Following uniform quality control and imputation relations were observed between anorexia nervosa and procedures using the 1000 Genomes Project (phase 3) schizophrenia, neuroticism, educational attainment, and in 12 case-control cohorts comprising 3,495 anorexia high-density lipoprotein cholesterol, and significant negative nervosa cases and 10,982 controls, the authors performed genetic correlations were observed between anorexia standard association analysis followed by a meta-analysis nervosa and body mass index, insulin, glucose, and lipid across cohorts. Linkage disequilibrium score regression phenotypes. was used to calculate genome-wide common variant heritability (single-nucleotide polymorphism [SNP]-based Conclusions: Anorexia nervosa is a complex heritable phe- 2 heritability [h SNP]), partitioned heritability, and genetic notype for which this study has uncovered the first genome- correlations [rg]) between anorexia nervosa and 159 other wide significant locus. Anorexia nervosa also has large and phenotypes. significant genetic correlations with both psychiatric phe- notypes and metabolic traits. The study results encourage a Results: Results were obtained for 10,641,224 SNPs and reconceptualization of this frequently lethal disorder as one insertion-deletion variants with minor allele frequencies .1% with both psychiatric and metabolic etiology. 2 and imputation quality scores .0.6. The h SNP of anorexia nervosa was 0.20 (SE=0.02), suggesting that a substantial Am J Psychiatry 2017; 00:1–9; doi: 10.1176/appi.ajp.2017.16121402 Anorexia nervosa is a serious eating disorder character- Our aim in the present study was to combine existing ized by restriction of energy intake relative to require- samples to conduct a more powerful GWAS of anorexia ments, resulting in abnormally low body weight. It has a nervosa. To further characterize the nature of the illness, we lifetime prevalence of approximately 1% and dispropor- applied linkage disequilibrium (LD) score regression (8) to tionately affects females (1, 2), and no well-replicated calculate genome-wide common variant heritability (single- 2 evidence of effective pharmacological or psychological nucleotide polymorphism [SNP]-based heritability [h SNP]), treatments for it have been identified, despite high mor- partitioned heritability, and genetic correlations (rg) between bidity and mortality (3, 4). Twin studies consistently anorexia nervosa and other phenotypes. These include the support a genetic basis for the observed familial aggre- other major psychiatric disorders with large GWASs, namely gation in anorexia nervosa, with heritability estimates in schizophrenia, bipolar disorder, major depressive disorder, the range of 48%–74% (5). Although initial genome-wide autism, and attention deficit hyperactivity disorder (ADHD), association studies (GWASs) were underpowered (6, 7), as well as medical, educational, and personality phenotypes. the available evidence strongly suggested that signals for We then used rg estimates between anorexia nervosa and anorexia nervosa would be detected with increased 159 additional phenotypes to characterize the phenome-wide sample size (6). genetic architecture of anorexia nervosa. Am J Psychiatry 00:0, nn 2017 ajp.psychiatryonline.org 1 SIGNIFICANT LOCUS AND METABOLIC CORRELATIONS IN GWAS OF ANOREXIA NERVOSA METHOD combining the U.S. and Canadian cases, we included 11 GCAN/WTCCC3–based data sets plus the CHOP/PFCG Cases and Controls data set in our analyses. For the nine data sets requiring new Our sample included 3,495 anorexia nervosa cases and 10,982 controls, we first evaluated diverse control data sets from controls. Case definition required a lifetime diagnosis of Psychiatric Genomics Consortium collaborators for po- anorexia nervosa (restricting or binge-purge subtype) or tentially suitable controls based on geographic location and fi lifetime eating disorder not otherwise speci ed, anorexia Illumina genotyping. We then performed quality control nervosa subtype (i.e., exhibiting the core features of anorexia steps (see below; additional details are provided in the nervosa). A lifetime history of bulimia nervosa was allowed, data supplement), using visual inspection of principal given the frequency of diagnostic crossover (9). Amenorrhea component plots (comparing cases to controls) as well as was not required, because it does not increase diagnostic quantile-quantile (QQ) and Manhattan plots (for evidence of fi speci city (10) (and it was removed as a diagnostic criterion systematic bias) to identify suitably matched controls. All in DSM-5 [11]). Extensive information on diagnostic and samples in the present study are of European ancestry. As consensus procedures for the samples included in the Child- shown in Figure S1 in the data supplement, all of the data sets ’ ren s Hospital of Philadelphia/Price Foundation Collabo- (except the one from Finland) form a gradient of clusters rative Group (CHOP/PFCG) cohort are available elsewhere when visualized in a scatterplot of the first two principal (7). The cases included from the Genetic Consortium for components, as expected based on known population genetic – Anorexia Nervosa/Wellcome Trust Case Control Consortium 3 features (15). (GCAN/WTCCC3) GWAS came from 12 previously collected clinical or population cohorts. Given that these were archived Quality Control and Analysis samples, the calculation of reliability statistics on diagnoses After uniform quality control and imputation using the was not possible. Mitigating that concern, however, is that 1000 Genomes Project (phase 3) (16) in the anorexia nervosa anorexia nervosa is a highly homogeneous phenotype with case-control cohorts, we performed association analysis with an high interrater agreement for diagnosis (typical kappa values additivemodelusingthedosage(theexpectedcountofoneof range from 0.81 to 0.97 [12]). Moreover, the approach taken the alleles) for each genotype for each individual for each co- here is consistent with successful GWAS meta-analysis ef- hort. After adjustment for unbalanced case and control numbers forts across psychiatric diagnoses, in which larger samples across our 12 strata (see reference 17), our summed effective are used to detect the modest effects of typical single common balanced sample size was 5,082 cases and 5,082 controls. Ac- genetic risk variants. cordingly,ourpowerwas83.1%foragenotyperelativeriskof 2 Individuals with schizophrenia, intellectual disability, and 1.25,atanallelefrequencyof0.2atp,5310 8 (http://zzz.bwh. medical or neurological conditions causing weight loss were harvard.edu/gpc). Analysis within data sets was performed in excluded, as in previous studies (6, 7). All sites had docu- PLINK with the first 10 principal components as covariates. mented permission from local ethical committees, and all METAL (17) was used to conduct fixed-effects meta-analysis participants provided informed consent. across the 12 data sets using inverse-variance weighting. Consistent with procedures established by the Psychiatric Results were obtained for 10,641,224 SNPs and insertion- Genomics Consortium (13, 14), we collected individual-level deletion variants with minor allele frequencies .1% and genotype (GWAS array) and phenotype (binary case-control imputation quality scores .0.6 (for the QQ plot, see Figure status) data from contributing previous GWAS consortia and S2 in the data supplement). The GWAS statistic inflation groups (for a description, see Table S1 in the data supplement factor (l) was 1.080, with a sample-size-adjusted l1000 of that accompanies the online edition of this article). In par- 1.008, consistent with minimal population stratification or ticular, the previous reports on anorexia nervosa GWASs other systematic biases. Plotting was performed in R (18) from CHOP/PFCG data (7) and the GCAN/WTCCC3 (6) and with LocusZoom (19). See the data supplement for provide further details about cohort ascertainment and additional methods and quality control details, and Table S1 participant characteristics not described below or in the for individual study details. online data supplement. Although most of the cases included in the published Statistical Significance anorexia nervosa GWASs were included in this analysis, The primary analysis in this study is the GWAS, which an- many of the controls used in previous GWASs could not be alyzes each SNP for association with phenotype. The in- 2 used for subsequent analyses. To summarize, our analysis ternational standard
Load more

Recommended publications
  • (12) United States Patent (10) Patent No.: US 7,592,444 B2 Khvorova Et Al
    USOO7592444B2 (12) United States Patent (10) Patent No.: US 7,592,444 B2 KhVOrOVa et al. (45) Date of Patent: Sep. 22, 2009 (54) SIRNA TARGETING MYELOID CELL 2003/0228597 A1 12/2003 COWSert LEUKEMIA SEQUENCE 1 2004/OO29275 A1 2/2004 Brown et al. 2004.00541.55 A1 3, 2004 Woolf (75) Inventors: Anastasia Khvorova, Boulder, CO 2004-0063654. A 42004 Davis et al. (US); Angela Reynolds, Conifer, CO S.S. A. 3. Singhofer (US);O O Devin Leake, Denver, CO (US); 2004/O180357 A1 9, 2004 eich William Marshall, Boulder, CO (US); 2004/O192629 A1 9, 2004 Xu et al. Stephen Scaringe, Lafayette, CO (US); 2004/0204380 A1 10, 2004 Ackerman Steven Read, Boulder, CO (US) 2004/0219671 A1 1 1/2004 McSwiggen 2004/024.8296 A1 12/2004 Beresford (73) Assignee: Dharmacon, Inc., Lafayette, CO (US) 2004/0248299 A1 12/2004 Jayasena 2004/0259247 A1 12, 2004 TuSchlet al. (*) Notice: Subject to any disclaimer, the term of this 2005/0048529 A1 3/2005 McSwiggen patent is extended or adjusted under 35 2005/0107328 A1 5/2005 Wyatt U.S.C. 154(b) by 0 days. 2005. O130181 A1 6/2005 McSwiggen 2005/0176O25 A1 8/2005 McSwiggen (21) Appl. No.: 12/378,164 2005, 0181382 A1 8, 2005 Zamore 2005, 0186586 A1 8, 2005 Zamore 2005/0227935 A1 10/2005 McSwiggen (22) Filed: Feb. 11, 2009 2005/0239731 A1 10/2005 McSwiggen 2005.0245475 A1 11/2005 Khvorova (65) Prior Publication Data 2006/0286575 A1 12/2006 Farrell US 2009/O1637O2A1 Jun. 25, 2009 2007/0031844 A1 2/2007 Khvorova 2007,0254.850 A1 11/2007 Lieberman Related U.S.
    [Show full text]
  • Supplementary Materials
    Supplementary materials Supplementary Table S1: MGNC compound library Ingredien Molecule Caco- Mol ID MW AlogP OB (%) BBB DL FASA- HL t Name Name 2 shengdi MOL012254 campesterol 400.8 7.63 37.58 1.34 0.98 0.7 0.21 20.2 shengdi MOL000519 coniferin 314.4 3.16 31.11 0.42 -0.2 0.3 0.27 74.6 beta- shengdi MOL000359 414.8 8.08 36.91 1.32 0.99 0.8 0.23 20.2 sitosterol pachymic shengdi MOL000289 528.9 6.54 33.63 0.1 -0.6 0.8 0 9.27 acid Poricoic acid shengdi MOL000291 484.7 5.64 30.52 -0.08 -0.9 0.8 0 8.67 B Chrysanthem shengdi MOL004492 585 8.24 38.72 0.51 -1 0.6 0.3 17.5 axanthin 20- shengdi MOL011455 Hexadecano 418.6 1.91 32.7 -0.24 -0.4 0.7 0.29 104 ylingenol huanglian MOL001454 berberine 336.4 3.45 36.86 1.24 0.57 0.8 0.19 6.57 huanglian MOL013352 Obacunone 454.6 2.68 43.29 0.01 -0.4 0.8 0.31 -13 huanglian MOL002894 berberrubine 322.4 3.2 35.74 1.07 0.17 0.7 0.24 6.46 huanglian MOL002897 epiberberine 336.4 3.45 43.09 1.17 0.4 0.8 0.19 6.1 huanglian MOL002903 (R)-Canadine 339.4 3.4 55.37 1.04 0.57 0.8 0.2 6.41 huanglian MOL002904 Berlambine 351.4 2.49 36.68 0.97 0.17 0.8 0.28 7.33 Corchorosid huanglian MOL002907 404.6 1.34 105 -0.91 -1.3 0.8 0.29 6.68 e A_qt Magnogrand huanglian MOL000622 266.4 1.18 63.71 0.02 -0.2 0.2 0.3 3.17 iolide huanglian MOL000762 Palmidin A 510.5 4.52 35.36 -0.38 -1.5 0.7 0.39 33.2 huanglian MOL000785 palmatine 352.4 3.65 64.6 1.33 0.37 0.7 0.13 2.25 huanglian MOL000098 quercetin 302.3 1.5 46.43 0.05 -0.8 0.3 0.38 14.4 huanglian MOL001458 coptisine 320.3 3.25 30.67 1.21 0.32 0.9 0.26 9.33 huanglian MOL002668 Worenine
    [Show full text]
  • Identification and Subcellular Localization of Human Rab5b, a New Member of the Ras-Related Superfamily of Gtpases
    Identification and subcellular localization of human rab5b, a new member of the ras-related superfamily of GTPases. D B Wilson, M P Wilson J Clin Invest. 1992;89(3):996-1005. https://doi.org/10.1172/JCI115683. Research Article Members of the mammalian rab family of GTPases are associated with specific subcellular compartments, where these proteins are postulated to function in vesicular transport. By screening a human umbilical vein endothelial cell library with degenerate oligonucleotide probes, we have isolated a 1.6-kb cDNA clone encoding a 215-amino-acid protein belonging to the rab family of GTPases. This newly identified rab protein is 81% identical to human rab5, the canine counterpart of which has been localized to the plasma membrane and early endosomes. In light of this homology, we have named this new member of the GTPase superfamily "rab5b." Northern analysis using the rab5b cDNA as a probe revealed a 3.6-kb mRNA in a variety of cell types, including human umbilical vein endothelial cells, K562 erythroleukemia cells, U937 monoblastic cells, and HeLa cells. A fusion protein between glutathione-S-transferase (GST) and rab5b was expressed in bacteria and purified to homogeneity. The recombinant protein was shown to bind GTP and GDP. As is typical of other recombinant rab proteins, the rab5b-GST fusion protein displayed a low intrinsic rate of GTP hydrolysis (0.005/min). An antiserum to rab5b was prepared and used to determine the apparent molecular size and subcellular distribution of the protein. Western blotting with this antibody revealed a 25-kD protein in COS cells transfected with rab5b and in nontransfected HeLa cells.
    [Show full text]
  • (12) Patent Application Publication (10) Pub. No.: US 2008/0132691 A1 Khvorova Et Al
    US 2008O132691A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2008/0132691 A1 KhVOrOVa et al. (43) Pub. Date: Jun. 5, 2008 (54) SIRNA TARGETING KINASE INSERT Related U.S. Application Data DOMAIN RECEPTOR (KDR) (63) Continuation-in-part of application No. 10/940,892, filed on Sep. 14, 2004, which is a continuation of (75) Inventors: Anastasia Khvorova, Boulder, CO application No. PCT/US04/14885, filed on May 12, (US); Angela Reynolds, Conifer, 2004, Continuation-in-part of application No. 10/714, CO (US); Devin Leake, Denver, 333, filed on Nov. 14, 2003. CO (US); William Marshall, (60) Provisional application No. 60/426,137, filed on Nov. Boulder, CO (US); Steven Read, 14, 2002, provisional application No. 60/502,050, Denver, CO (US); Stephen filed on Sep. 10, 2003. Scaringe, Lafayette, CO (US) Publication Classification Correspondence Address: (51) Int. C. KALOW & SPRINGUT LLP C7H 2L/02 (2006.01) 488 MADISONAVENUE, 19TH FLOOR (52) U.S. Cl. ....................................................... 536/24.5 NEW YORK, NY 10022 (57) ABSTRACT Efficient sequence specific gene silencing is possible through (73) Assignee: DHARMACON, INC., Lafayette, the use of siRNA technology. By selecting particular siRNAs CO (US) by rational design, one can maximize the generation of an effective gene silencing reagent, as well as methods for (21) Appl. No.: 11/978,107 silencing genes. Methods, compositions, and kits generated through rational design of siRNAS are disclosed including (22) Filed: Oct. 26, 2007 those directed to nucleotide sequences for KDR. s S & 3 & SSSSSSSSSSS k kD CHC & 17O CLCa H EEA 1-> k O-Actinin-> --, -er is a set sat -100 DynII-> ..
    [Show full text]
  • Genome-Wide Association Study in Alopecia Areata Implicates Both Innate and Adaptive Immunity
    Vol 466 | 1 July 2010 | doi:10.1038/nature09114 LETTERS Genome-wide association study in alopecia areata implicates both innate and adaptive immunity Lynn Petukhova1, Madeleine Duvic2, Maria Hordinsky3, David Norris4, Vera Price5, Yutaka Shimomura1, Hyunmi Kim1, Pallavi Singh1, Annette Lee6, Wei V. Chen7, Katja C. Meyer8, Ralf Paus8,9, Colin A. B. Jahoda10, Christopher I. Amos7, Peter K. Gregersen6 & Angela M. Christiano1,11 Alopecia areata (AA) is among the most highly prevalent human multiple lines of evidence4. AA hair follicles are surrounded by an autoimmune diseases, leading to disfiguring hair loss due to the immune infiltrate with activated T-helper cells (TH cells), cytotoxic T collapse of immune privilege of the hair follicle and subsequent cells (TC cells) and natural killer (NK) cells, characterized as a TH1- autoimmune attack1,2. The genetic basis of AA is largely unknown. type inflammatory response5,6. The notion of a collapse of immune We undertook a genome-wide association study (GWAS) in a privilege is thought to be a key event in triggering AA4,7. sample of 1,054 cases and 3,278 controls and identified 139 single Evidence supporting a genetic basis for AA stems from multiple nucleotide polymorphisms that are significantly associated with AA lines of research, including the observed heritability in first-degree (P # 5 3 1027). Here we show an association with genomic regions relatives8,9, twin studies10 and, most recently, from our family-based containing several genes controlling the activation and prolifera- linkage studies11. Although a number of candidate-gene association tion of regulatory T cells (Treg cells), cytotoxic T lymphocyte- studies were performed over the past two decades, the informative- associated antigen 4 (CTLA4), interleukin (IL)-2/IL-21,IL-2 ness of these studies was inherently limited by small sample sizes and receptor A (IL-2RA; CD25)andEos (also known as Ikaros family preselection of candidate genes.
    [Show full text]
  • The ZNF76 Rs10947540 Polymorphism Associated With
    www.nature.com/scientificreports OPEN The ZNF76 rs10947540 polymorphism associated with systemic lupus erythematosus risk in Chinese populations Yuan‑yuan Qi1,4, Yan Cui1,4, Hui Lang2, Ya‑ling Zhai1, Xiao‑xue Zhang1, Xiao‑yang Wang1, Xin‑ran Liu1, Ya‑fei Zhao1, Xiang‑hui Ning3 & Zhan‑zheng Zhao1* Systemic lupus erythematosus (SLE) is a typical autoimmune disease with a strong genetic disposition. Genetic studies have revealed that single‑nucleotide polymorphisms (SNPs) in zinc fnger protein (ZNF)‑coding genes are associated with susceptibility to autoimmune diseases, including SLE. The objective of the current study was to evaluate the correlation between ZNF76 gene polymorphisms and SLE risk in Chinese populations. A total of 2801 individuals (1493 cases and 1308 controls) of Chinese Han origin were included in this two‑stage genetic association study. The expression of ZNF76 was evaluated, and integrated bioinformatic analysis was also conducted. The results showed that 28 SNPs were associated with SLE susceptibility in the GWAS cohort, and the association of rs10947540 was successfully replicated in the independent replication cohort −2 (Preplication = 1.60 × 10 , OR 1.19, 95% CI 1.03–1.37). After meta‑analysis, the association between −6 rs10947540 and SLE was pronounced (Pmeta = 9.62 × 10 , OR 1.29, 95% CI 1.15–1.44). Stratifed analysis suggested that ZNF76 rs10947540 C carriers were more likely to develop relatively high levels of serum creatinine (Scr) than noncarriers (CC + CT vs. TT, p = 9.94 × 10−4). The bioinformatic analysis revealed that ZNF76 rs10947540 was annotated as an eQTL and that rs10947540 was correlated with decreased expression of ZNF76.
    [Show full text]
  • Evidence for Two Independent Associations with Type 1 Diabetes at the 12Q13 Locus
    Genes and Immunity (2012) 13, 66–70 & 2012 Macmillan Publishers Limited All rights reserved 1466-4879/12 www.nature.com/gene ORIGINAL ARTICLE Evidence for two independent associations with type 1 diabetes at the 12q13 locus KL Keene1,2, AR Quinlan1,2,3, X Hou2,3, IM Hall1, JC Mychaleckyj2,3, S Onengut-Gumuscu2,4 and P Concannon1,2 1Department of Biochemistry and Molecular Genetics, UVA School of Medicine, University of Virginia, Charlottesville, VA, USA; 2Center for Public Health Genomics, UVA School of Medicine, University of Virginia, Charlottesville, VA, USA; 3Department of Public Health Sciences, UVA School of Medicine, University of Virginia, Charlottesville, VA, USA and 4Division of Endocrinology and Metabolism, UVA School of Medicine, University of Virginia, Charlottesville, VA, USA Genome-wide association studies have identified associations between type 1 diabetes and single-nucleotide polymorphisms (SNPs) at chromosome 12q13, surrounding the gene ERBB3. Our objective was to fine map this region to further localize causative variants. Re-sequencing identified more than 100 putative SNPs in an 80-kb region at 12q13. By genotyping 42 SNPs, spanning B214 kb, in 382 affected sibling pair type 1 diabetes families, we were able to genotype or tag 67 common SNPs (MAFX0.05) identified from HapMap CEU data and CEU data from the 1000 Genomes Project, plus additional rare coding variants identified from our re-sequencing efforts. In all, 15 SNPs provided nominal evidence for association (Pp0.05), with type 1 diabetes. The most significant associations were observed with rs2271189 (P ¼ 4.22 Â 10À5), located in exon 27 of the ERBB3 gene, and an intergenic SNP rs11171747 (P ¼ 1.70 Â 10À4).
    [Show full text]
  • Genome-Wide Association Study Reveals First Locus for Anorexia Nervosa and Metabolic Correlations
    bioRxiv preprint doi: https://doi.org/10.1101/088815; this version posted December 6, 2016. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Genome-Wide Association Study Reveals First Locus for Anorexia Nervosa and Metabolic Correlations Authors Duncan, E.L.* ... 210 additional authors Thornton, L.M. Hinney, A. Daly, M.J. Sullivan, P.F. Zeggini, E. Breen, G. Bulik, C.M.* * Corresponding authors Abstract Anorexia nervosa (AN) is a serious eating disorder characterized by restriction of energy intake relative to requirements, resulting in abnormally low body weight. It has a lifetime prevalence of approximately 1%, disproportionately affects females1,2, and has no well replicated evidence of effective pharmacological or psychological treatments despite high morbidity and mortality2. Twin studies support a genetic basis for the observed aggregation of AN in families3, with heritability estimates of 48%-74%4. Although initial genome-wide association studies (GWASs) were underpowered5,6, evidence suggested that signals for AN would be detected with increased power5. We present a GWAS of 3,495 AN cases and 10,982 controls with one genome-wide significant locus (index variant rs4622308, p=4.3x10-9) in a region (chr12:56,372,585- % 56,482,185) which includes six genes. The SNP-chip heritability (h"#$) of AN from these data is 0.20 (SE=0.02), suggesting that a substantial fraction of the twin-based heritability stems from common genetic variation.
    [Show full text]
  • Genome-Wide Association Study Reveals First Locus for Anorexia Nervosa and Metabolic Correlations
    bioRxiv preprint doi: https://doi.org/10.1101/088815; this version posted December 6, 2016. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Genome-Wide Association Study Reveals First Locus for Anorexia Nervosa and Metabolic Correlations Authors Duncan, E.L.* ... 210 additional authors Thornton, L.M. Hinney, A. Daly, M.J. Sullivan, P.F. Zeggini, E. Breen, G. Bulik, C.M.* * Corresponding authors Abstract Anorexia nervosa (AN) is a serious eating disorder characterized by restriction of energy intake relative to requirements, resulting in abnormally low body weight. It has a lifetime prevalence of approximately 1%, disproportionately affects females1,2, and has no well replicated evidence of effective pharmacological or psychological treatments despite high morbidity and mortality2. Twin studies support a genetic basis for the observed aggregation of AN in families3, with heritability estimates of 48%-74%4. Although initial genome-wide association studies (GWASs) were underpowered5,6, evidence suggested that signals for AN would be detected with increased power5. We present a GWAS of 3,495 AN cases and 10,982 controls with one genome-wide significant locus (index variant rs4622308, p=4.3x10-9) in a region (chr12:56,372,585- % 56,482,185) which includes six genes. The SNP-chip heritability (h"#$) of AN from these data is 0.20 (SE=0.02), suggesting that a substantial fraction of the twin-based heritability stems from common genetic variation.
    [Show full text]
  • Conserved Human Effector Treg Cell Transcriptomic and Epigenetic Signature in Arthritic Joint Inflammation
    ARTICLE https://doi.org/10.1038/s41467-021-22975-7 OPEN Conserved human effector Treg cell transcriptomic and epigenetic signature in arthritic joint inflammation Gerdien Mijnheer1,6, Lisanne Lutter 1,6, Michal Mokry 1,2,3, Marlot van der Wal 1, Rianne Scholman1, Veerle Fleskens4, Aridaman Pandit 1, Weiyang Tao1, Mark Wekking3, Stephin Vervoort1,5, Ceri Roberts 4, Alessandra Petrelli1, Janneke G. C. Peeters 1, Marthe Knijff1, Sytze de Roock1, Sebastiaan Vastert1, ✉ Leonie S. Taams 4, Jorg van Loosdregt1,5,7 & Femke van Wijk 1,7 1234567890():,; Treg cells are critical regulators of immune homeostasis, and environment-driven Treg cell differentiation into effector (e)Treg cells is crucial for optimal functioning. However, human Treg cell programming in inflammation is unclear. Here, we combine transcriptional and epigenetic profiling to identify a human eTreg cell signature. Inflammation-derived functional Treg cells have a transcriptional profile characterized by upregulation of both a core Treg cell (FOXP3, CTLA4, TIGIT) and effector program (GITR, BLIMP-1, BATF). We identify a specific human eTreg cell signature that includes the vitamin D receptor (VDR) as a predicted regulator in eTreg cell differentiation. H3K27ac/H3K4me1 occupancy indicates an altered (super-)enhancer landscape, including enrichment of the VDR and BATF binding motifs. The Treg cell profile has striking overlap with tumor-infiltrating Treg cells. Our data demonstrate that human inflammation-derived Treg cells acquire a conserved and specific eTreg cell profile guided by epigenetic changes, and fine-tuned by environment-specific adaptations. 1 Center for Translational Immunology, Pediatric Immunology & Rheumatology, Wilhelmina Children’s Hospital, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.
    [Show full text]
  • Lethal Congenital Contractural Syndrome Type 2 (LCCS2) Is Caused by a Mutation in ERBB3 (Her3), a Modulator of the Phosphatidylinositol-3-Kinase/Akt Pathway
    REPORT Lethal Congenital Contractural Syndrome Type 2 (LCCS2) Is Caused by a Mutation in ERBB3 (Her3), a Modulator of the Phosphatidylinositol-3-Kinase/Akt Pathway Ginat Narkis, Rivka Ofir, Esther Manor, Daniella Landau, Khalil Elbedour, and Ohad S. Birk Lethal congenital contractural syndrome type 2 (LCCS2) is an autosomal recessive neurogenic form of arthrogryposis that is associated with atrophy of the anterior horn of the spinal cord. We previously mapped LCCS2 to 6.4 Mb on chromosome 12q13 and have now narrowed the locus to 4.6 Mb. We show that the disease is caused by aberrant splicing of ERBB3, which leads to a predicted truncated protein. ERBB3 (Her3), an activator of the phosphatidylinositol-3-kinase/ Akt pathway—regulating cell survival and vesicle trafficking—is essential for the generation of precursors of Schwann cells that normally accompany peripheral axons of motor neurons. Gain-of-function mutations in members of the epidermal growth-factor tyrosine kinase–receptor family have been associated with predilection to cancer. This is the first report of a human phenotype resulting from loss of function of a member of this group. Lethal congenital contractual syndrome type 2 (LCCS2 shown). The possibility that the disease-associated locus [MIM 607598]), a neonatally lethal form of arthrogryposis is between D12S305 and D12S1072 cannot be ruled out, presenting in two Israeli-Bedouin kindreds1 (families A but it is less likely, since this would require two crossing- and B) (fig. 1), is characterized by multiple joint contrac- over events occurring in individual 61 (fig. 2). tures, anterior horn atrophy in the spinal cord, and a In an attempt to identify the specific molecular defect unique feature of a markedly distended urinary bladder.
    [Show full text]
  • Immuno-Navigator, a Batch-Corrected Coexpression Database, Reveals Cell
    Immuno-Navigator, a batch-corrected coexpression PNAS PLUS database, reveals cell type-specific gene networks in the immune system Alexis Vandenbona,1, Viet H. Dinha, Norihisa Mikamib, Yohko Kitagawab, Shunsuke Teraguchic, Naganari Ohkurab,d, and Shimon Sakaguchib,1 aImmuno-Genomics Research Unit, Immunology Frontier Research Center, Osaka University, Suita 565-0871, Japan; bLaboratory of Experimental Immunology, Immunology Frontier Research Center, Osaka University, Suita 565-0871, Japan; cQuantitative Immunology Research Unit, Immunology Frontier Research Center, Osaka University, Suita 565-0871, Japan; and dFrontier Research in Tumor Immunology, Graduate School of Medicine, Osaka University, Suita 565-0871, Japan Contributed by Shimon Sakaguchi, March 17, 2016 (sent for review October 24, 2015; reviewed by Alf Hamann and Jun Sese) High-throughput gene expression data are one of the primary of lineage-specific and cell type-specific receptor molecules, sig- resources for exploring complex intracellular dynamics in modern naling pathways, and transcriptional regulators (10, 11). However, biology. The integration of large amounts of public data may allow most existing coexpression databases do not support the analysis of us to examine general dynamical relationships between regulators cell type-specific coexpression. One notable study examined gene and target genes. However, obstacles for such analyses are study- coexpression in a several tissues separately and showed that such specific biases or batch effects in the original data. Here we present a tissue-specific approach was more efficient in predicting disease Immuno-Navigator, a batch-corrected gene expression and coexpres- genes (12). Other efforts, such as the Immunological Genome sion database for 24 cell types of the mouse immune system.
    [Show full text]