Genetic Epidemiology, Psychiatric Genetics, Asthma Genetics and Statistical Genetics Laboratories investigate the pattern of disease in families, particularly identical and non-identical twins, to assess the relative importance of genes and environment in a variety of important health problems.
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27184124
TITLE
Evidence for three genetic loci involved in both anorexia nervosa risk and variation of body mass index.
ABSTRACT
NlmCategory: UNASSIGNED
The maintenance of normal body weight is disrupted in patients with anorexia nervosa (AN) for prolonged periods of time. Prior to the onset of AN, premorbid body mass index (BMI) spans the entire range from underweight to obese. After recovery, patients have reduced rates of overweight and obesity. As such, loci involved in body weight regulation may also be relevant for AN and vice versa. Our primary analysis comprised a cross-trait analysis of the 1000 single-nucleotide polymorphisms (SNPs) with the lowest P-values in a genome-wide association meta-analysis (GWAMA) of AN (GCAN) for evidence of association in the largest published GWAMA for BMI (GIANT). Subsequently we performed sex-stratified analyses for these 1000 SNPs. Functional ex vivo studies on four genes ensued. Lastly, a look-up of GWAMA-derived BMI-related loci was performed in the AN GWAMA. We detected significant associations (P-values <5 × 10(-5), Bonferroni-corrected P<0.05) for nine SNP alleles at three independent loci. Interestingly, all AN susceptibility alleles were consistently associated with increased BMI. None of the genes (chr. 10: CTBP2, chr. 19: CCNE1, chr. 2: CARF and NBEAL1; the latter is a region with high linkage disequilibrium) nearest to these SNPs has previously been associated with AN or obesity. Sex-stratified analyses revealed that the strongest BMI signal originated predominantly from females (chr. 10 rs1561589; Poverall: 2.47 × 10(-06)/Pfemales: 3.45 × 10(-07)/Pmales: 0.043). Functional ex vivo studies in mice revealed reduced hypothalamic expression of Ctbp2 and Nbeal1 after fasting. Hypothalamic expression of Ctbp2 was increased in diet-induced obese (DIO) mice as compared with age-matched lean controls. We observed no evidence for associations for the look-up of BMI-related loci in the AN GWAMA. A cross-trait analysis of AN and BMI loci revealed variants at three chromosomal loci with potential joint impact. The chromosome 10 locus is particularly promising given that the association with obesity was primarily driven by females. In addition, the detected altered hypothalamic expression patterns of Ctbp2 and Nbeal1 as a result of fasting and DIO implicate these genes in weight regulation.Molecular Psychiatry advance online publication, 17 May 2016; doi:10.1038/mp.2016.71.
DATE PUBLISHED
2016 May 17
HISTORY
PUBSTATUS PUBSTATUSDATE
received 2015/08/28
revised 2016/02/22
accepted 2016/03/17
entrez 2016/05/18 06:00
pubmed 2016/05/18 06:00
medline 2016/05/18 06:00
AUTHORS
NAME COLLECTIVENAME LASTNAME FORENAME INITIALS AFFILIATION AFFILIATIONINFO
Hinney A Hinney A A Department of Child and Adolescent Psychiatry, Psychotherapy, and Psychosomatics, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
Kesselmeier M Kesselmeier M M Clinical Epidemiology, Integrated Research and Treatment Center, Center for Sepsis Control and Care (CSCC), Jena University Hospital, Jena, Germany.
Jall S Jall S S Division of Metabolic Diseases, Department of Medicine, Technische Universität München, Munich, Germany.
Volckmar AL Volckmar A-L AL Department of Child and Adolescent Psychiatry, Psychotherapy, and Psychosomatics, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
Föcker M Föcker M M Department of Child and Adolescent Psychiatry, Psychotherapy, and Psychosomatics, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
Antel J Antel J J Department of Child and Adolescent Psychiatry, Psychotherapy, and Psychosomatics, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
GCAN
WTCCC3
Heid IM Heid I M IM Department of Genetic Epidemiology, University of Regensburg, Regensburg, Germany.
Winkler TW Winkler T W TW Department of Genetic Epidemiology, University of Regensburg, Regensburg, Germany.
GIANT
Grant SF Grant S F A SF The Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
EGG
Guo Y Guo Y Y The Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Bergen AW Bergen A W AW BioRealm, LLC, Culver City, CA, USA.
Kaye W Kaye W W Department of Psychiatry, University of California, San Diego, San Diego, CA, USA.
Berrettini W Berrettini W W Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA.
Hakonarson H Hakonarson H H The Division of Human Genetics, Department of Pediatrics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Price Foundation Collaborative Group
Children’s Hospital of Philadelphia/Price Foundation
Herpertz-Dahlmann B Herpertz-Dahlmann B B Department of Child and Adolescent Psychiatry and Psychotherapy, University Hospital of the RWTH Aachen, Aachen, Germany.
de Zwaan M de Zwaan M M Department of Psychosomatic Medicine and Psychotherapy, Hannover Medical School, Hannover, Germany.
Herzog W Herzog W W Department of Internal Medicine II, General Internal and Psychosomatic Medicine, University of Heidelberg, Heidelberg, Germany.
Ehrlich S Ehrlich S S Translational Developmental Neuroscience Section, Department of Child and Adolescent Psychiatry, Faculty of Medicine, TU-Dresden, University Hospital Carl Gustav Carus, Dresden University of Technology, Dresden, Germany.
Zipfel S Zipfel S S Department of Psychosomatic Medicine and Psychotherapy, Medical University Hospital, Tübingen, Germany.
Egberts KM Egberts K M KM Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University of Würzburg, Würzburg, Germany.
Adan R Adan R R Altrecht Eating Disorders Rintveld, Zeist, The Netherlands.
Brandys M Brandys M M Altrecht Eating Disorders Rintveld, Zeist, The Netherlands.
van Elburg A van Elburg A A Brain Center Rudolf Magnus, Department of Translational Neuroscience, University Medical Center Utrecht, Utrecht, The Netherlands.
Boraska Perica V Boraska Perica V V University of Split School of Medicine, Split, Croatia.
Franklin CS Franklin C S CS Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.
Tschöp MH Tschöp M H MH Division of Metabolic Diseases, Department of Medicine, Technische Universität München, Munich, Germany.
Zeggini E Zeggini E E Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.
Bulik CM Bulik C M CM Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
Collier D Collier D D Eli Lilly and Company Ltd, Surrey, UK.
Scherag A Scherag A A Clinical Epidemiology, Integrated Research and Treatment Center, Center for Sepsis Control and Care (CSCC), Jena University Hospital, Jena, Germany.
Müller TD Müller T D TD Division of Metabolic Diseases, Department of Medicine, Technische Universität München, Munich, Germany.
Hebebrand J Hebebrand J J Department of Child and Adolescent Psychiatry, Psychotherapy, and Psychosomatics, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
INVESTIGATORS
LASTNAME FORENAME INITIALS AFFILIATION
Perica Vesna Boraska VB
Franklin Christopher S CS
Floyd James A B JA
Thornton Laura M LM
Huckins Laura M LM
Southam Lorraine L
Rayner N William NW
Tachmazidou Ioanna I
Klump Kelly L KL
Treasure Janet J
Lewis Cathryn M CM
Schmidt Ulrike U
Tozzi Federica F
Iezebrink Kirsty K
Hebebrand Johannes J
Gorwood Philip P
Adan Roger A H RA
Kas Martien J H MJ
Favaro Angela A
Santonastaso Paolo P
Fernández-Aranda Fernando F
Gratacos Monica M
Rybakowski Filip F
Dmitrzak-Weglarz Monika M
Kaprio Jaakko J
Keski-Rahkonen Anna A
Raevuori-Helkamaa Anu A
Van Furth Eric F EF
Slof-Op't Landt Margarita C T MC
Hudson James I JI
Reichborn-Kjennerud Ted T
Knudsen Gun Peggy S GP
Monteleone Palmiero P
Kaplan Allan S AS
Karwautz Andreas A
Hakonarson Hakon H
Berrettini Wade H WH
Guo Yiran Y
Li Dong D
Schork Nicholas J NJ
Komaki Gen G
Ando Tetsuya T
Inoko Hidetoshi H
Esko Tõnu T
Fischer Krista K
Männik Katrin K
Metspalu Andres A
Baker Jessica H JH
Cone Roger D RD
Dackor Jennifer J
DeSocio Janiece E JE
Hilliard Christopher E CE
O'Toole Julie K JK
Pantel Jacques J
Szatkiewicz Jin P JP
Taico Chrysecolla C
Zerwas Stephanie S
Trace Sara E SE
Davis Oliver S P OS
Helder Sietske S
Bühren Katharina K
Burghardt Roland R
de Zwaan Martina M
Egberts Karin K
Ehrlich Stefan S
Herpertz-Dahlmann Beate B
Herzog Wolfgang W
Imgart Hartmut H
Scherag André A
Scherag Susann S
Zipfel Stephan S
Boni Claudette C
Ramoz Nicolas N
Versini Audrey A
Brandys Marek K MK
Danner Unna N UN
de Kove Carolien C
Hendriks Judith J
Koeleman Bobby P C BP
Ophoff Roel A RA
Strengman Eric E
van Elburg Annemarie A AA
Bruson Alice A
Clementi Maurizio M
Degortes Daniela D
Forzan Monica M
Tenconi Elena E
Docampo Elisa E
Escaramí Geòrgia G
Jiménez-Murcia Susana S
Lissowska Jolanta J
Rajewski Andrzej A
Szeszenia-Dabrowska Neonila N
Slopien Agnieszka A
Hauser Joanna J
Karhunen Leila L
Meulenbelt Ingrid I
Slagboom P Eline PE
Tortorella Alfonso A
Maj Mario M
Dedoussis George G
Dikeos Dimitris D
Gonidakis Fragiskos F
Tziouvas Konstantinos K
Tsitsika Artemis A
Papezova Hana H
Slachtova Lenka L
Martaskova Debora D
Kennedy James L JL
Levitan Robert D RD
Yilmaz Zeynep Z
Huemer Julia J
Koubek Doris D
Merl Elisabeth E
Wagner Gudrun G
Lichtenstein Paul P
Breen Gerome G
Cohen-Woods Sarah S
Farmer Anne A
McGuffin Peter P
Cichon Sven S
Giegling Ina I
Herms Stefan S
Rujescu Dan D
Schreiber Stefan S
Wichmann H-Erich HE
Dina Christian C
Sladek Rob R
Gambaro Giovanni G
Soranzo Nicole N
Julia Antonio A
Marsal Sara S
Rabionet Raquel R
Gaborieau Valerie V
Dick Danielle M DM
Palotie Aarno A
Ripatti Samuli S
Widén Elisabeth E
Andreassen Ole A OA
Espeseth Thomas T
Lundervold Astri A
Reinvang Ivar I
Steen Vidar M VM
Hellard Stephanie Le SL
Mattingsdal Morten M
Ntalla Ioanna I
Bencko Vladimir V
Foretova Lenka L
Janout Vladimir V
Navratilova Marie M
Gallinger Steven S
Pinto Dalila D
Scherer Stephen W SW
Aschauer Harald H
Carlberg Laura L
Schosser Alexandra A
Alfredsson Lars L
Ding Bo B
Klareskog Lars L
Padyukov Leonid L
Finan Chris C
Kalsi Gursharan G
Roberts Marion M
Logan Darren W DW
Peltonen Leena L
Ritchie Graham R S GR
Barrett Jeff C JC
Estivill Xavier X
Hinney Anke A
Sullivan Patrick F PF
Collier David A DA
Zeggini Eleftheria E
Bulik Cynthia M CM
Anderson Carl A CA
Barrett Jeffrey C JC
Floyd James A B JA
Franklin Christopher S CS
McGinnis Ralph R
Soranzo Nicole N
Zeggini Eleftheria E
Sambrook Jennifer J
Stephens Jonathan J
Ouwehand Willem H WH
McArdle Wendy L WL
Ring Susan M SM
Strachan David P DP
Alexander Graeme G
Bulik Cynthia M CM
Collier David A DA
Conlon Peter J PJ
Dominiczak Anna A
Duncanson Audrey A
Hill Adrian A
Langford Cordelia C
Lord Graham G
Maxwell Alexander P AP
Morgan Linda L
Peltonen Leena L
Sandford Richard N RN
Sheerin Neil N
Vannberg Frederik O FO
Blackburn Hannah H
Chen Wei-Min WM
Edkins Sarah S
Gillman Mathew M
Gray Emma E
Hunt Sarah E SE
Nengut-Gumuscu Suna S
Potter Simon S
Rich Stephen S SS
Simpkin Douglas D
Whittaker Pamela P
de Bakker P P
Bültmann U U
Geleijnse M M
Harst P V PV
Koppelman G G
Rosmalen J G JG
van Rossum L L
Smidt H H
Swertz M A MA
Stolk R P RP
Alizadeh B B
de Boer R R
Boezen H M HM
Bruinenberg M M
Franke L L
van der Harst P P
Hillege H H
van der Klauw M M
Navis G G
Ormel J J
Postma D D
Rosmalen J J
Slaets J J
Snieder H H
Stolk R R
Wolffenbuttel B B
Wijmenga C C
Berg J J
Blackwood D D
Campbell H H
Cavanagh J J
Connell J J
Connor M M
Cunningham-Burley S S
Deary I I
Dominiczak A A
Ellis P P
FitzPatrick B B
Ford I I
Gertz R R
Grau A A
Haddow G G
Jackson C C
Kerr S S
Lindsay R R
McGilchrist M M
McIntyre D D
Morris A A
Morton R R
Muir W W
Murray G G
Palmer C C
Pell J J
Philp A A
Porteous D D
Porteous M M
Procter R R
Ralston S S
Reid D D
Sinnott R R
Smith B B
Clair D S DS
Sullivan F F
Sweetland M M
Ure J J
Watt G G
Wolf R R
Wright A A
Berndt S I SI
Gustafsson S S
Mägi R R
Ganna A A
Wheeler E E
Feitosa M F MF
Justice A E AE
Monda K L KL
Croteau-Chonka D C DC
Day F R FR
Esko T T
Fall T T
Ferreira T T
Gentilini D D
Jackson A U AU
Luan J J
Randall J C JC
Vedantam S S
Willer C J CJ
Winkler T W TW
Wood A R AR
Workalemahu T T
Hu Y J YJ
Lee S H SH
Liang L L
Lin D Y DY
Min J L JL
Neale B M BM
Thorleifsson G G
Yang J J
Albrecht E E
Amin N N
Bragg-Gresham J L JL
Cadby G G
den Heijer M M
Eklund N N
Fischer K K
Goel A A
Hottenga J J JJ
Huffman J E JE
Jarick I I
Johansson A A
Johnson T T
Kanoni S S
Kleber M E ME
König I R IR
Kristiansson K K
Kutalik Z Z
Lamina C C
Lecoeur C C
Li G G
Mangino M M
McArdle W L WL
Medina-Gomez C C
Müller-Nurasyid M M
Ngwa J S JS
Nolte I M IM
Paternoster L L
Pechlivanis S S
Perola M M
Peters M J MJ
Preuss M M
Rose L M LM
Shi J J
Shungin D D
Smith A V AV
Strawbridge R J RJ
Surakka I I
Teumer A A
Trip M D MD
Tyrer J J
Van Vliet-Ostaptchouk J V JV
Vandenput L L
Waite L L LL
Zhao J H JH
Absher D D
Asselbergs F W FW
Atalay M M
Attwood A P AP
Balmforth A J AJ
Basart H H
Beilby J J
Bonnycastle L L LL
Brambilla P P
Bruinenberg M M
Campbell H H
Chasman D I DI
Chines P S PS
Collins F S FS
Connell J M JM
Cookson W W
de Faire U U
de Vegt F F
Dei M M
Dimitriou M M
Edkins S S
Estrada K K
Evans D M DM
Farrall M M
Ferrario M M MM
Ferrières J J
Franke L L
Frau F F
Gejman P V PV
Grallert H H
Grönberg H H
Gudnason V V
Hall A S AS
Hall P P
Hartikainen A L AL
Hayward C C
Heard-Costa N L NL
Heath A C AC
Hebebrand J J
Homuth G G
Hu F B FB
Hunt S E SE
Hyppönen E E
Iribarren C C
Jacobs K B KB
Jansson J O JO
Jula A A
Kähönen M M
Kathiresan S S
Kee F F
Khaw K T KT
Kivimaki M M
Koenig W W
Kraja A T AT
Kumari M M
Kuulasmaa K K
Kuusisto J J
Laitinen J H JH
Lakka T A TA
Langenberg C C
Launer L J LJ
Lind L L
Lindström J J
Liu J J
Liuzzi A A
Lokki M L ML
Lorentzon M M
Madden P A PA
Magnusson P K PK
Manunta P P
Marek D D
März W W
Mateo Leach I I
McKnight B B
Medland S E SE
Mihailov E E
Milani L L
Montgomery G W GW
Mooser V V
Mühleisen T W TW
Munroe P B PB
Musk A W AW
Narisu N N
Navis G G
Nicholson G G
Nohr E A EA
Ong K K KK
Oostra B A BA
Palmer C N CN
Palotie A A
Peden J F JF
Pedersen N N
Peters A A
Polasek O O
Pouta A A
Pramstaller P P PP
Prokopenko I I
Pütter C C
Radhakrishnan A A
Raitakari O O
Rendon A A
Rivadeneira F F
Rudan I I
Saaristo T E TE
Sambrook J G JG
Sanders A R AR
Sanna S S
Saramies J J
Schipf S S
Schreiber S S
Schunkert H H
Shin S Y SY
Signorini S S
Sinisalo J J
Skrobek B B
Soranzo N N
Stancakova A A
Stark K K
Stephens J C JC
Stirrups K K
Stolk R P RP
Stumvoll M M
Swift A J AJ
Theodoraki E V EV
Thorand B B
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Tremoli E E
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van Meurs J B JB
Vermeulen S H SH
Viikari J J
Virtamo J J
Vitart V V
Waeber G G
Wang Z Z
Widen E E
Wild S H SH
Willemsen G G
Winkelmann B R BR
Witteman J C JC
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Amouyel P P
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Caulfield M J MJ
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Eriksson J G JG
Franks P W PW
Froguel P P
Gieger C C
Gyllensten U U
Hamsten A A
Harris T B TB
Hengstenberg C C
Hicks A A AA
Hingorani A A
Hinney A A
Hofman A A
Hovingh K G KG
Hveem K K
Illig T T
Jarvelin M R MR
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Keinanen-Kiukaanniemi S M SM
Kiemeney L A LA
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Lehtimäki T T
Levinson D F DF
Martin N G NG
Metspalu A A
Morris A D AD
Nieminen M S MS
Njølstad I I
Ohlsson C C
Oldehinkel A J AJ
Ouwehand W H WH
Palmer L J LJ
Penninx B B
Power C C
Province M A MA
Psaty B M BM
Qi L L
Rauramaa R R
Ridker P M PM
Ripatti S S
Salomaa V V
Samani N J NJ
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Sørensen T I TI
Spector T D TD
Stefansson K K
Tönjes A A
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Uitterlinden A G AG
Uusitupa M M
van der Harst P P
Vollenweider P P
Wallaschofski H H
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Watkins H H
Wichmann H- H
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Abecasis G R GR
Assimes T L TL
Barroso I I
Boehnke M M
Borecki I B IB
Deloukas P P
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Haritunian T T
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Kaplan R C RC
Karpe F F
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Pawitan Y Y
Schadt E E EE
Schlessinger D D
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van Duijn C M CM
Visscher P M PM
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Hofman A A
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Järvelin M R MR
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Kilpeläinen T O TO
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McArdle W L WL
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Murray S S SS
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Northstone K K
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Peacock M M
Palmer L J LJ
Palotie A A
Paré G G
Parker A N AN
Pedersen N L NL
Peltonen L L
Pennell C E CE
Pharoah P P
Polasek O O
Plump A S AS
Pouta A A
Porcu E E
Rafnar T T
Rice J P JP
Ring S M SM
Rivadeneira F F
Rudan I I
Sala C C
Salomaa V V
Sanna S S
Schlessinger D D
Schork N J NJ
Scuteri A A
Segrè A V AV
Shuldiner A R AR
Soranzo N N
Sovio U U
Srinivasan S R SR
Strachan D P DP
Tammesoo M L ML
Tikkanen E E
Toniolo D D
Tsui K K
Tryggvadottir L L
Tyrer J J
Uda M M
van Dam R M RM
van Meurs J B JB
Vollenweider P P
Waeber G G
Wareham N J NJ
Waterworth D M DM
Weedon M N MN
Wichmann H E HE
Willemsen G G
Wilson J F JF
Wright A F AF
Young L L
Zhai G G
Zhuang W V WV
Bierut L J LJ
Boyd H A HA
Crisponi L L
Demerath E W EW
van Duijn C M CM
Econs M J MJ
Harris T B TB
Hunter D J DJ
Loos R J RJ
Metspalu A A
Montgomery G W GW
Ridker P M PM
Spector T D TD
Streeten E A EA
Stefansson K K
Thorsteinsdottir U U
Uitterlinden A G AG
Widen E E
Murabito J M JM
Ong K K KK
Murray A A
Brandt Harry H
Crawford Steve S
Crow Scott S
Fichter Manfred M MM
Halmi Katherine A KA
Johnson Craig C
Kaplan Allan S AS
Via Maria La M
Mitchell James J
Strober Michael M
Rotondo Alessandro A
Treasure Janet J
Woodside D Blake DB
Bulik Cynthia M CM
Keel Pamela P
Klump Kelly L KL
Lilenfeld Lisa L
Thornton Laura M LM
Plotnicov Kathy K
Bergen Andrew W AW
Berrettini Wade W
Kaye Walter W
Magistretti Pierre P
JOURNAL
VOLUME:
ISSUE:
TITLE: Molecular psychiatry
ISOABBREVIATION: Mol. Psychiatry
YEAR: 2016
MONTH: May
DAY: 17
MEDLINEDATE:
SEASON:
CITEDMEDIUM: Internet
ISSN: 1476-5578
ISSNTYPE: Electronic
MEDLINE JOURNAL
MEDLINETA: Mol Psychiatry
COUNTRY: England
ISSNLINKING: 1359-4184
NLMUNIQUEID: 9607835
PUBLICATION TYPE
PUBLICATIONTYPE TEXT
JOURNAL ARTICLE
COMMENTS AND CORRECTIONS
GRANTS
GRANTID AGENCY COUNTRY
R01 DK075787 NIDDK NIH HHS United States
GENERAL NOTE
KEYWORDS
MESH HEADINGS
SUPPLEMENTARY MESH
GENE SYMBOLS
CHEMICALS
OTHER ID's