Journal article
Evidence for three genetic loci involved in both anorexia nervosa risk and variation of body mass index
Molecular psychiatry, Vol.22(2), pp.192-201
02/01/2017
DOI: 10.1038/mp.2016.71
PMCID: PMC5114162
PMID: 27184124
Abstract
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 Pvalues 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 <5x10(-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; P-overall: 2.47 x 10(-06)/P-females: 3.45 x 10(-07)/P-males: 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.
Details
- Title: Subtitle
- Evidence for three genetic loci involved in both anorexia nervosa risk and variation of body mass index
- Creators
- A. Hinney - University of Duisburg-EssenM. Kesselmeier - Jena University HospitalS. Jall - Deutsches Diabetes-Zentrum e.V.A-L Volckmar - University of Duisburg-EssenM. Foecker - University of Duisburg-EssenJ. Antel - University of Duisburg-EssenI. M. Heid - University of RegensburgT. W. Winkler - University of RegensburgS. F. A. Grant - Univ Penn, Dept Pediat, Philadelphia, PA 19104 USAY. Guo - Children's Hospital of PhiladelphiaA. W. Bergen - BioRealmW. Kaye - Univ Calif San Diego, Dept Psychiat, San Diego, CA 92103 USAW. Berrettini - University of PennsylvaniaH. Hakonarson - University of PennsylvaniaB. Herpertz-Dahlmann - RWTH Aachen UniversityM. de Zwaan - Medizinische Hochschule HannoverW. Herzog - Heidelberg UniversityS. Ehrlich - Technische Universität DresdenS. Zipfel - University of TübingenK. M. Egberts - University of WürzburgR. Adan - Univ Med Ctr Utrecht, Dept Translat Neurosci, Brain Ctr Rudolf Magnus, Utrecht, NetherlandsM. Brandys - Altrecht GGZA. van Elburg - Univ Med Ctr Utrecht, Dept Translat Neurosci, Brain Ctr Rudolf Magnus, Utrecht, NetherlandsV. Boraska Perica - Wellcome Sanger InstituteC. S. Franklin - Wellcome Sanger InstituteM H Tschoep - Helmholtz Zentrum MünchenE. Zeggini - Wellcome Sanger InstituteC. M. Bulik - Univ North Carolina Chapel Hill, Dept Psychiat, Chapel Hill, NC USAD. Collier - Kings Coll London, Inst Psychiat, Social Genet & Dev Psychiat Ctr, London, EnglandA. Scherag - Jena University HospitalT. D. Mueller - Helmholtz Zentrum MünchenJ. Hebebrand - University of Duisburg-EssenGenetic Consortium for AN (GCAN)Jeffrey C Murray (Contributor)
- Resource Type
- Journal article
- Publication Details
- Molecular psychiatry, Vol.22(2), pp.192-201
- DOI
- 10.1038/mp.2016.71
- PMID
- 27184124
- PMCID
- PMC5114162
- NLM abbreviation
- Mol Psychiatry
- ISSN
- 1359-4184
- eISSN
- 1476-5578
- Publisher
- Springer Nature
- Number of pages
- 10
- Grant note
- U54 RR0252204-01 / Scripps Translational Sciences Institute Clinical Translational Science Award R01DK075787 / NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) 01EO1002; 01EO1502 / German Ministry for Education and Research (CSCC) R01HD056465 / EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD) Helmholtz Alliance ICEMED-Imaging and Curing Environmental Metabolic Diseases, through the Initiative and Networking Fund of the Helmholtz Association MR/K013351/1 / Medical Research Council; UK Research & Innovation (UKRI); Medical Research Council UK (MRC); European Commission Alexander von Humboldt Foundation Klarman Family Foundation T32MH076694 / NATIONAL INSTITUTE OF MENTAL HEALTH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Mental Health (NIMH) Institute Development Award
- Language
- English
- Date published
- 02/01/2017
- Academic Unit
- Anatomy and Cell Biology; Stead Family Department of Pediatrics; Epidemiology; Pediatric Dentistry; Craniofacial Anomalies Research Center; Dental Research
- Record Identifier
- 9985035879702771
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