VOLUME ONE HUNDRED AND FOURTY PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE Genetics of Monogenic and Syndromic Obesity VOLUME ONE HUNDRED AND FOURTY PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE Genetics of Monogenic and Syndromic Obesity Edited by Ya-Xiong Tao Department of Anatomy, Physiology and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, AL, USA AMSTERDAM • BOSTON • HEIDELBERG • LONDON NEW YORK • OXFORD • PARIS • SAN DIEGO SAN FRANCISCO • SINGAPORE • SYDNEY • TOKYO Academic Press is an imprint of Elsevier Academic Press is an imprint of Elsevier 125 London Wall, London EC2Y 5AS, United Kingdom 525 B Street, Suite 1800, San Diego, CA 92101-4495, United States 50 Hampshire Street, 5th Floor, Cambridge, MA 02139, United States The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, UK First edition 2016 Copyright © 2016 Elsevier Inc All Rights Reserved No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein) Notices Knowledge and best practice in this field are constantly changing As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein ISBN: 978-0-12-804615-9 ISSN: 1877-1173 For information on all Academic Press publications visit our website at https://www.elsevier.com/ Publisher: Zoe Kruze Acquisition Editor: Mary Ann Zimmerman Editorial Project Manager: Helene Kabes Production Project Manager: Magesh Kumar Mahalingam Designer: Mark Rogers Typeset by Thomson Digital CONTRIBUTORS E Burgio European Cancer and Environment Research Institute (ECERI), Bruxelles, Belgium; ISDE International Society of Doctors for Environment (Scientific Office), Arezzo, Italy M.G Butler Departments of Psychiatry & Behavioral Sciences and Pediatrics, University of Kansas Medical Center, Kansas City, KS, United States of America D.D Duan Laboratory of Cardiovascular Phenomics, Center for Cardiovascular Research, Department of Pharmacology, and Center for Molecular Medicine, University of Nevada School of Medicine, Reno, NV, United States J.C Han Department of Pediatrics, University of Tennessee Health Science Center and Children’s Foundation Research Institute, Le Bonheur Children’s Hospital, Memphis, TN, United States of America I Lindberg Department of Anatomy and Neurobiology, University of Maryland, Baltimore, MD, United States of America A Lopomo Department of Translational Research and New Technologies in Medicine and Surgery, Medical Genetics Laboratories, University of Pisa, Pisa, Italy; Doctoral School in Genetics, Oncology, and Clinical Medicine; University of Siena; Siena, Italy M.G Martin Department of Pediatrics, Division of Gastroenterology and Nutrition, Mattel Children’s Hospital and the David Geffen School of Medicine, Los Angeles, CA, United States of America L Migliore Department of Translational Research and New Technologies in Medicine and Surgery, Medical Genetics Laboratories, University of Pisa, Pisa, Italy B Ramos-Molina Department of Human Genetics, KU Leuven, Leuven, Belgium M Stachowiak Department of Genetics, Animal Breeding, Poznań University of Life Sciences, Poznań, Poland ix x Contributors M Switonski Department of Genetics, Animal Breeding, Poznań University of Life Sciences, Poznań, Poland I Szczerbal Department of Genetics, Animal Breeding, Poznań University of Life Sciences, Poznań, Poland Y.-X Tao Department of Anatomy, Physiology and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, AL, United States of America W Wang Department of Anatomy, Physiology, and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, AL, United States of America Z Yang Department of Anatomy, Physiology and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, AL, United States of America Y.-P Zhang Pediatric Heart Center, Beijing Anzhen Hospital, Capital Medical University, Beijing, China Y.-Y Zhang Department of Cardiology, Changzhou Second People’s Hospital, Changzhou, Jiangsu, China PREFACE Obesity is an epidemic in developed countries and becoming ever more prevalent in developing countries Obesity is strongly associated with several metabolic diseases, including type diabetes mellitus, non-alcoholic fatty liver disease, hypertension, arteriosclerosis, and cardiovascular disease It is also associated with sleep apenea, and some types of cancers such as breast cancer in women and prostate cancer in men It also has significant psychological effects on the obese Therefore obesity has become a major public health problem worldwide, with tremendous health, economic and social costs Childhood obesity presents an even bigger challenge, due to the increased chance of developing metabolic syndrome early in adulthood Obesity significantly decreases the potential of life expectancy increase that could be achieved with reduced smoking and improved health care Obesity is caused by multiple factors, including genetic, environment, and social elements Genetic contribution to obesity was clearly demonstrated with elegant studies in naturally occurring rodent obesity models (such as ob/ob and db/db mice and Zucker Fatty rat) as well as twin studies in humans Indeed, mutations in several genes, such as leptin, leptin receptor, proopiomelanocortin, prohormone convertase 1/3, melanocortin-4 receptor, brain-derived neurotrophic factor, and Sim1, causing monogenic obesity have been identified Some of these genes were discussed in previous chapters in this Series This volume reviews several aspects of the genetics of monogenic and syndromic obesity Starting with Butler’s introduction to several examples of monogenic and syndromic obesity, Ramos-Molina, Martin, and Lindberg discussed mutations in prohormone convertase 1/3 and human obesity Han summarized the studies on brain-derived neurotrophic factor variants and human obesity My students and I reviewed variants in melanocortin-3 receptor and ghrelin receptor and obesity Epigenetic aspect of obesity was reviewed by Migliore and her colleagues Duan and his colleagues provided a guided tour for us “From genome-wide association study to phenome-wide association study” as applied to obesity studies Last but not least, Switonski and his colleagues demonstrated that genetics is also relevant in our best friend (dogs) and an important source of our meat (pigs) They also argued xi xii Preface that these species could serve as large animal models for human obesity studies, complementing rodent studies I am immensely grateful to all the authors for their wonderful contributions to this volume I also greatly appreciate the expert guidance and enormous patience of the colleagues at Elsevier, Mary Ann Zimmerman and Helene Kabes It has been a great pleasure to work with you on this and other volumes Finally, without the unwavering support of the Series Editor, Professor P Michael Conn, this volume would not possible I thank you all for the support Finally, as always, I thank my family for continuous support and unconditional love YA-XIONG TAO Auburn, Alabama CHAPTER ONE Single Gene and Syndromic Causes of Obesity: Illustrative Examples M.G Butler1 Departments of Psychiatry & Behavioral Sciences and Pediatrics, University of Kansas Medical Center, Kansas City, KS, United States of America Corresponding author: e-mail address: mbutler4@kumc.edu Contents Introduction and Background Genetic Variant and Genome-Wide Association Studies in Obesity Recognized Single Gene Causes of Obesity Obesity Genes and Their Encoded Proteins Syndromic Causes of Obesity Prader–Willi Syndrome 6.1 Genomic Imprinting Defects in Prader–Willi Syndrome 6.2 Genetic and Clinical Aspects of Prader–Willi Syndrome 6.3 Molecular Genetics and Prader–Willi Syndrome 6.4 Clinical Features in Prader–Willi Syndrome 6.5 Clinical Findings Associated with Typical 15q11-q13 Deletions (Type I and Type II) in Prader–Willi Syndrome Fragile X Syndrome and the Prader–Willi Phenotype Alström Syndrome: A Rare Obesity-Related Single Gene Disorder Albright Hereditary Osteodystrophy References 11 13 19 19 21 27 29 32 33 35 37 40 Abstract Obesity is a significant health problem in westernized societies, particularly in the United States where it has reached epidemic proportions in both adults and children The prevalence of childhood obesity has doubled in the past 30 years The causation is complex with multiple sources, including an obesity promoting environment with plentiful highly dense food sources and overall decreased physical activity noted for much of the general population, but genetic factors clearly play a role Advances in genetic technology using candidate gene approaches, genome-wide association studies, structural and expression microarrays, and next generation sequencing have Progress in Molecular BiologyandTranslational Science, Volume 140 ISSN 1877-1173 http://dx.doi.org/10.1016/bs.pmbts.2015.12.003 © 2016 Elsevier Inc All rights reserved M.G Butler led to the discovery of hundreds of genes recognized as contributing to obesity Polygenic and monogenic causes of obesity are now recognized including dozens of examples of syndromic obesity with Prader–Willi syndrome, as a classical example and recognized as the most common known cause of life-threatening obesity Genetic factors playing a role in the causation of obesity will be discussed along with the growing evidence of single genes and the continuum between monogenic and polygenic obesity The clinical and genetic aspects of four classical but rare obesityrelated syndromes (ie, Prader–Willi, Alström, fragile X, and Albright hereditary osteodystrophy) will be described and illustrated in this review of single gene and syndromic causes of obesity INTRODUCTION AND BACKGROUND Obesity is an increasing serious health problem recognized worldwide and reaching epidemic status particularly in westernized societies A role for genetic factors is now recognized as contributing to obesity and will be summarized in this review on single gene and syndromic causes of obesity The United States currently leads as the most obese nation The causation of obesity is clearly complex The rising obesity prevalence is partially due to an obesity-promoting environment with highly dense, inexpensive, and plentiful food sources with a relatively sedentary lifestyle due to advances in modern technology leading to decreased energy expenditure for employees in the work place.1–3 A survival advantage over time has led to a thrifty phenotype due to a more efficient use of calories with fat deposition thereby contributing to the obesity epidemic in the presence of increased caloric intake Major health concerns related to long term obesity status include insulin resistance, type diabetes, fatty liver, sleep apnea, cancer, hypertension, cardiovascular disease, stroke, and physical limitations with disabilities Obesity, as a global public health problem, is on the rise as evidenced in 1997 at 19.4%; 24.5% in 2004, 33.8% in 2008, and 35.7% of adults in 2010.3 Childhood obesity is also present at 17% in the United States with 70% of obese adolescents becoming obese adults The prevalence of childhood obesity has doubled in the past 30 years.4 The medical costs for treating complications from an overweight and obesity status are inordinate with estimates for treating people for overweight and obesity estimated at $72 billion and $198 billion, respectively impacted by the current obesogenic environment.3,5–10 Body mass index (BMI) is a commonly used measure of obesity in adults and children and defined as weight measured in kilograms divided by the Single Gene and Syndromic Causes of Obesity: Illustrative Examples square of height in meters (kg/m2), but this measure is not as accurate for determination of obesity in the pediatric age group A BMI between 25 and 30 is considered overweight while BMIs greater than or equal to 30 are considered obese in adulthood Since the 1980s, the mean BMI has increased by 0.4–0.5 kg/m2 per decade in adults In childhood a BMI from the 85th to 95th percentile may be considered overweight and equal to or greater than the 95th percentile for obesity.3,11–13 Twin and family studies strongly implicate genetic factors as playing an important role in the development of obesity Genetic predisposition for obesity can also be influenced by ethnicity Monozygotic twin studies show concordance for obesity at a range from 70 to 90%, while in dizygotic twins range from 35 to 45% Heritability estimates derived from twin studies report a representative number of 77% for BMI.14,15 Increased physical activity and exercise can lower the effects of genes impacting BMI and therefore obesity status Hence, genes play an important central role in the determination of BMI and pathogenesis of obesity In addition, strong genetic factors influence percentage body fat, waist circumference, energy expenditure, eating behavior, and level of physical activity Specific gene mutations are found in 5–10% of obesity in childhood supported by a recent review of 370 recognized genes identified in the literature playing a role in obesity.16 Several genes have been studied in relationship to obesity, particularly in mongenic causation; for example, MC4R, which is the single most commonly recognized gene causing childhood obesity and found in about 4% of cases.6,7 Structural chromosomal anomalies involving genomic regions containing causative genes for obesity have been reported such as 3p25 duplications and 16p11.2 deletions.17 With continually improved and varied complex genetic techniques requiring smaller quantities of DNA (and RNA) such as next generation sequencing further supported by prometaphase chromosome analysis, fluorescence in situ hybridization, linkage and genome-wide association studies (GWAS), copy number variant (CNV), and single nucleotide polymorphism (SNP) probes utilized in high resolution microarrays have been instrumental in identifying structural, chromosomal, and DNA abnormalities in genomic regions and candidate genes causing both rare and common forms of obesity Specifically, chromosome abnormalities (deletions, duplications) have been recorded in humans with dysmorphic and syndromic obesity including chromosome 1p36 deletion; chromosome 2q37.3 deletion; chromosome 3p23 duplication; 3p25.3 duplication (contains the GHRL gene); chromosome 4q32.1 duplication; 4q35.1 duplication; chromosome 5p13.1 Index overexpressing gene vector, 78 protein-coding exon, 79 protein translation, 77 signaling, 89 SNP rs12291063, 89 Breast milk, 165 Breeding strategies, 234 Burnside Butler syndrome, 25 C Caloric restriction, 165 cAMP See Cyclic AMP (cAMP) Candidate gene, 3, 137, 192, 244, 246, 253, 254, 259 methylation, 156 number of, 239 in obesity, 158 sets, 261 studies, 140 Canine obesity genetic studies of, 258 Cannabinoid receptor (CNR1), Carboxyl terminal domain autocatalytic cleavage of, 51 Carboxypeptidase E (CPE gene), 64 Carboxy-terminal domain, 49 Cardiomyopathy, 36 Cardiovascular disease (CVD), 187 CART See Cocaine- and amphetamineregulated transcript (CART) Catalyzed n-octanoyl, 132 CCAAT-enhancer-binding protein β (C/EBPβ), 161 CC-specific therapies, 90 CDGP See Constitutional delay of growth and puberty (CDGP) CDW See Clinical data warehouse (CDW) Cell signaling, 36 Cell surface expression, 110 114, 115 Central nervous system, 102 Cerebral gigantism, 34 CHF See Congestive heart failure (CHF) Childhood obesity, 3, 197 Seealso Obesity DNA markers in, 273 Chromosome abnormalities, locations, microarray, 23 studies, Circadian clock system, 156 Clinical data warehouse (CDW), 207 Clock genes abnormal rhythmic expression of, 103 CNR1 See Cannabinoid receptor (CNR1) CNV See Copy number variations (CNV) Cocaine- and amphetamine-regulated transcript (CART), 54, 84 Cohen syndromes, 194 Comethylated genes, 240 Common DNA markers discovery of, 243 Complex genetic techniques, Complex genomic imprinting disorder, 29 Computerized axial tomography, 190 Congestive heart failure (CHF), 36 Constitutional delay of growth and puberty (CDGP), 139 Constitutive signaling activity, 142 Copy number variations (CNV), 3, 246 regions (CNVR), 260 Corticotropin-releasing hormone (CRH), 55 Cosegregation analysis, 139 CPE gene See Carboxypeptidase E (CPE gene) CpG dinucleotides, 21, 201 hypermethylation of, 158 islands, hypermethylation of, 156 methylation, 164 rich differentially methylated region (DMR), 19 CRH See Corticotropin-releasing hormone (CRH) Cryptorchidism, 31 CUTL1 See Cut-like homeobox (CUTL1) protein Cut-like homeobox (CUTL1) protein, 208 CVD See Cardiovascular disease (CVD) Cyclic AMP (cAMP), 39 274 Cytochrome c oxidase subunit mRNA levels of, 175 Cytogenetic region, 21 Cytoplasmic FMR1 interacting protein (CYFIP1), 34 D DDE See Dichloro diphenyl ethylene (DDE) DDT See Dichloro diphenyl trichloroethane (DDT) Deciphering genome organization, 244 DEHP See Diethyl-hexyl-phthalate (DEHP) Developmental origins of health and disease (DOHaD) theory, 154, 168 DEXA See Dual-energy X-ray absorptiometry (DEXA) DHA See Docosahexaenoic acid (DHA) Diabetes Prevention Program (DPP), 87 Dichloro diphenyl ethylene (DDE), 170 Dichloro diphenyl trichloroethane (DDT), 170 Dietary supplementation, 174 Diethyl-hexyl-phthalate (DEHP), 170 Diet induced obese (DIO) mice, 172 Diet-induced obesity, 235 paternal obesity, 168 rodent model of, 175 Differentially methylated regions (DMRs), 240 Differentially methylated (DM) sites, 239 DIO See Diet induced obese (DIO) mice Disease causing mutations, 36 Disease-gene associations, 207 Disease-SNP associations, 208 Disease-specific molecular signature patterns, 36 DMH See Dorsomedial hypothalamus (DMH) DMRs See Differentially methylated regions (DMRs) DNA, abnormalities in genomic regions, base pairs, 21 biobanks, 203 code, 11 Index hypomethylation, 156, 165 methylation, 21, 27, 156, 239–166, 168, 173, 200, 201, 239, 241 candidate genes, 202 changes in, 239 errors, 26 functions of, 21 imprinted IGF2 gene, 163 map, 240 patterns, 159, 168 profiles, 158, 173 reaction, 198 testing, 25 molecule, CpG dinucleotides of, 19 nucleotide coding structure, 20 replication, 21 sequences, 21 synthesis, 156 DNA methyltransferases (DNMTs), 156, 172, 198, 201 DNA-protein interactions, 199 DNMTs See DNA methyltransferases (DNMTs) Docosahexaenoic acid (DHA), 172 Dog adiposity phenotypic evaluation of, 262 Dog genome marker map, 243 DogMap, 243 DOHaD See Developmental origins of health and disease (DOHaD) theory Domestic animals long-lasting breeding of, 234 Dopamine receptor (DRD2), Dorsomedial hypothalamus (DMH), 77 DPP See Diabetes Prevention Program (DPP) DRD2 See Dopamine receptor (DRD2) Drug-genotype interactions, 199–200 Dual-energy X-ray absorptiometry (DEXA), 190, 237 Duplicons, 21 E Early stimulation programs, 30 EHRs See Electronic health records (EHRs) 275 Index Electronic health records (EHRs), 206, 207 Electronic medical records (EMRs), 207 Electronic Medical Records and Genomics (eMERGE) Network, 206 eMERGE See Electronic Medical Records and Genomics (eMERGE) Network EMRs See Electronic medical records (EMRs) Endocrine hormone system, 170 Endogenous ligands, 101 ghrelin, 145 Endoplasmic reticulum (ER), 49 associated degradation, 63 retained mutant proteins, 63 stress, 57 End-organ resistance, 37 Endoscopic biopsies, 61 Endothelial nitricoxide synthase (eNOS), 165 End-stage liver disease, 36 Energy homeostasis regulation of, 102 eNOS See Endothelial nitricoxide synthase (eNOS) Enteroendocrine cell dysfunction, 65 Epigenetic biomarkers, 160, 201 Epigenetic drugs, 175 Epigenetics alterations, identification of, 175 changes in response to dietary intervention, 173–174 changes related to obesity, 155–156 effects of maternal and paternal diet on fetus development, 163–168 histone modifications, 161–162 mechanisms, 155, 156 implication of, 202 microRNAs (miRNAs), 162–163 of obesity, 152–155 obesogens, 170–173 silencing, 165 studies in human and animals, 156–161 DNA methylation, 156–161 traits, 168 transgenerational effects, 168–170 Epigenome-wide association studies (EWAS), 202, 239 ER See Endoplasmic reticulum (ER) European Pig Gene Mapping Project (PiGMaP), 243 EWAS See Epigenome-wide association studies (EWAS) Extracellular signal-regulated kinase and (ERK1/2), 115 F Familial intellectual disability cause of, 24 Fat mass and obesity-associated gene (FTO), 5, 195, 196, 246 expression, 11 mRNA levels for, 11 polymorphism, 246 transcript, 246 variants, 208 Fat tissue accumulation traits functional candidates for, 252 deposition, variability of, 236 Fatty acid oxidation, 103 Fe´de´ration Cynologique Internationale (FCI), 234 Feeding-related signals, 103 Fetal programming hypothesis, 154, 163 F3 generation sperm epigenome, 172 Flavonoid genistein, 156 FMR1 See Fragile X mental retardation (FMR1) FMRP See Fragile X mental retardation protein (FMRP) Foetal sirtuin (SIRT1), 166 Fragile X mental retardation (FMR1), 24 gene, 33, 34 Fragile X mental retardation protein (FMRP), 33 Fragile X syndrome (FXS), 33 cause of intellectual disability, 14 diagnosis of, 34 knockout mouse model, 33 FTO See Fat mass and obesity-associated gene (FTO) Functional receptor, 134 FXS See Fragile X syndrome (FXS) 276 G GABA See Gamma aminobutyric acid (GABA) receptor subunits G allele, 87 Gamma aminobutyric acid (GABA) receptor subunits, 28 Gcg gene, 55 Gene alleles loss/deletion of, 19 Gene-diet interactions, 197 Gene-environment interaction, 12 Gene expression epigenetic regulation of, 200 heritable changes in, 200 profiling, comprehensive genome-wide comparison of, 240 Gene loci/markers identification of, Gene mutation, Gene pool, 235 Genes encoding proteins, Genetic and epigenetic mechanisms, 238 Genetic factors, Genetic Investigation of Anthropometric Traits (GIANT), 196 consortium, metaanalysis, 8, 197 Genetic microarray methods, 36 Genetic mutations, 40 Genetic obesity disorder, 15, 30, 36 See also Bardet-Biedl syndrome Genetic sequence variations, 188 Genetic variants identification of, 246 Genome scanning, 244 Genome selection, 234 Genome sequencing projects, 244 Genome-wide association study (GWAS), 3, 48, 188, 202, 209, 244 advent of, 199 approaches, 4, discoveries, 196 finding, replication of, 191 methodology, 245 obesity, 192–197 current clinical classification of, 189–192 Index BMI, 189–190 body fat percentage, 190–191 obesity in childhood, adolescence, and adulthood, 191 obesity-related conditions, 191–192 waist circumference and waist-hip ratio, 190 drug-genotype interactions, 199–200 epigenetics and epigenome of, 200–202 genome-wide association study of, 196–197 lifestyle and environmental impacts and epigenetics of, 197–202 lifestyle and environment on, 197–199 microRNAs (miRNA), 195 monogenic obesity, 193–194 polygenic obesity, 194–195 phenome-wide association study (See Phenome-wide association study) technology, use of, 246 Genome-wide DNA methylation 156, 173, 239 Genome-wide methods, 239 Genome-wide methylation analysis, 201 Genomic imprinting, 13, 19 Genotype-phenotype associations, 208 Genotype-specific approaches, 90 Gestational diabetes, 168 GG genotype, 87 GH See Growth hormone (GH) GHD See Growth hormone deficiency (GHD) Ghrelin, 55 expressing endocrine cells, 51 gene, 132 i.c.v injection of, 136 stimulation, 142 system, 136 versatility of, 137 versatile physiological roles of, 136 Ghrelin O-acyltransferase (GOAT), 132 Ghrelin receptor mutations, human obesity and ghrelin system, 132–135 277 Index and energy homeostasis, 136–137 ghrelin peptide hormones, 133 ghrelin receptor, 134–135 natural occurring GHSR mutations, 137–145 functional characterizations of, 141–143 identification of, 137–140 potential strategies to correct, 143–145 prevalence of, 140–141 Ghrelin-stimulated signaling, 142 GHRH See Growth hormone-releasing hormone (GHRH) GHSR See Growth hormone secretagogue receptor (GHSR) GIANT See Genetic Investigation of Anthropometric Traits (GIANT) GIP See Glucose-dependent insulinotropic polypeptide (GIP) Glomerular disease degrees of, 36 Glucocorticoid receptor (GR) hypomethylation of, 165 Glucosamine-6-phosphate deaminase (GNPDA2), Glucose-dependent insulinotropic polypeptide (GIP), 55 Glucose-dependent insulin secretion, 55 Glut4 genes, 167 GNAS See G subunit-regulatory signaling protein (GNAS) GNPDA2 See Glucosamine-6-phosphate deaminase (GNPDA2) GOAT See Ghrelin O-acyltransferase (GOAT) GPCRs See G protein-coupled receptors (GPCRs) G protein-coupled receptors (GPCRs), 110, 132 active mutations of, 116 expression, 116 GPCR120, 258 mutations, 118 structure-function relationship of, 116 transmembrane receptor, 251 G protein Gs-alpha subunit, 39 Gs-cAMP pathway, 115 GR See Glucocorticoid receptor (GR) Growth hormone (GH), 133 deficiency, 10, 62, 139 releasing peptide, 133 secreting cells, 135 Growth hormone-releasing hormone (GHRH), 56, 134 Growth hormone-releasing peptide-6 (GHRP-6), 134 Growth hormone secretagogue receptor (GHSR), 132 gene expression, 137 GHSR1a tissue distribution of, 134 mutations, 139, 140 pathogenic role of, 141 Growth retardation, 19 Gs protein, 110 G subunit-regulatory signaling protein (GNAS), 38 gene, 38 transcripts of, 39 Guanine nucleotide-binding protein (G-protein), 38 GWAS See Genome-wide association study (GWAS) H Haploinsufficiency brain-derived neurotrophic factor (BDNF), 78–83 11p14 deletion, 82 11p inversion, 82–83 Wilms tumor, aniridia, genitourinary abnormalities, and mental retardation (WAGR) syndrome, 78–82 HDACs See Histone deacetylases (HDACs) HDL See High density lipoprotein (HDL) HERC2 gene, 21 Heritability, Heterozygotes, 57 HIF signaling perturbation of, 157 High-calorie food, 153 278 High density lipoprotein (HDL), 235 High resolution chromosomal microarray analysis, 23 High resolution CNV/SNP microarray studies, 25 High resolution expression microarray approach, 36 High resolution microarrays, analysis, 25 Histone deacetylases (HDACs), 172 expression of, 161 Histones methylation, 161 N-terminal amino acids of, 161 proteins, 161 Homeostatic systems, 168 Hormone imbalances, 12 role in glucose and fatty acid regulation and production, Human adipose-derived mesenchymal stem cells (hMSCs-Ad) differentiation of, 162 Human adiposity, 188, 202 pathogenesis, 118 Human body-weight regulation evolution of, 209 Human chromosome (HSA2), 245 Human disease phenome definition and diagnosis of, 205 Human genes GHSR gene, 134 MC4R gene, 251 types of, 20 Human obesity brain-derived neurotrophic factor (BDNF) in, 76–78 crucial models for, 235 related genes, 240 Human obesity, PCSK1 variants and energy homeostasis and food behavior, PC1/3 substrates involved in regulation of, 51–52 introduction, 48–49 neuropeptides in hypothalamus, PC1/3 activation of, 51–56 PC1/3 activity in gastrointestinal system, 55–56 Index PC1/3-generated peptide hormones involved in feeding behaviors, 54–54 PC1/3 processing of proinsulin to insulin in pancreatic β-cells, 54 role in melanocortin pathway, 52–54 PC1/3 deficiency and disease, 56–65 common and rare human haploinsufficient PCSK1 polymorphisms, 57–59 PC1/3 knockout mouse and PC1/3deficient N222D mouse, 56–57 ProSAAS and obesity, 64–65 rare human biallelic PCSK1 mutations cause enteric and systemic endocrinopathies and obesity, 59–64 prohormone convertase 1/3, general properties, 49–51 Human PCSK1 polymorphisms rare and common, 59 Hyperghrelinemia, 84 Hyperglycemia, 54 Hyperphagia, 36, 85 Hypogonadism, 36, 37 Hypogonadotropic hypogonadism, 64 Hypopigmentation, 30 Hypothalamic α-MSH levels, 57 Hypothalamic dysfunction, 30 Hypothalamic hypogonadism, 31 Hypothalamic leptin-melanocortin system, Hypothalamic melanocortin system, 101 Hypothalamic peptide hormones, 51 Hypothalamic-pituitary-thyroid axis, 103 Hypothalamus, 52 Hypothesis-driven candidate gene, 188 Hypothyroidism, 37 I IGFBP3 gene, 167 IL6 gene promoter aberrant DNA methylation of, 160 IMF See Intramuscular fat content (IMF) Immune-related cytokines, 240 Imprinted genes, 19, 20 expression of, 19 279 Index genome-wide search for, 20 the monoallelic expression of, 19 Infertility, 14 I183N mutant receptor, 114 Innate immune system physiological regulation of, 159 Inositol phospholipid-Ca2+ pathway, 115 INSIG2 See Insulin induced gene (INSIG2) In situ hybridization, 133 Insulin induced gene (INSIG2), Insulin-like growth factors, 15 factor (IGF1), 56 factor (IGF-2), 158 methylation percentage, 158 Insulin receptor substrate1 (IRS-1), 159 substrate (ISR-2), 162 Insulin resistance, index, 105 Interstitial Leydig cells, 133 Intracellular trafficking, 88 Intracellular signaling pathways, 168 Intramuscular fat content (IMF), 237 Intramuscular vascular stem cells (IVSC), 241 In-trans enzymatic activity, 63 Intrauterine growth restricted (IUGR), 165 In vitro adipogenesis, 241 Iodotyrosine deiodinase (IYD) gene, 242 IVSC See Intramuscular vascular stem cells (IVSC) IYD See Iodotyrosine deiodinase (IYD) gene J Jansen’s metaphyseal chondrodysplasia, 135 Janus kinase/signal transducers and activators of transcription (JAK/STAT), 102 signaling pathway, 167 Jet fuel (JP-8), 172 L Laparoscopic-adjustable gastric banding, 100 LDL See Low-density lipoproteins (LDL) LEP See Leptin (LEP) Leptin (LEP), 8, 84, 102, 156, 158 administration, appetite-suppressing effect of, 84 gene, 11 methylation of, 158 pathway, simplified overview of, 79 promoter methylation, 158 role of, 11 sensitivity, signaling pathway, 78 Leptin-melanocortin signaling pathway, 53, 61, 101, 193 Leptin receptor (LEPR), 8, 162 gene, 252 mutations, 195 Leptin-regulated melanocortin circuit, 100–102 leptin-melanocortin pathway, 101–102 melanocortin system, 100–101 Lifestyle interventions, 99 Life threatening obesity genetic causes of, 14 Ligand binding assays, 110, 141 Lipid-related metabolic processes, 245 Lipophilic hormones, 170 lncRNA See Long-noncoding RNAs (lncRNA) LOF See Loss of function (LOF) Long-noncoding RNAs (lncRNA), 241 modulation of, 241 Loss of function (LOF), 114 GHSR mutations, 143 mutations, 143 Loss of heterozygosity (LOH), 19 Low-density lipoprotein receptor adaptor protein (LDLRAP1), 163 Low-density lipoproteins (LDL), 235 Luciferase reporter gene assays, 142 M Macroorchidism, 34 MAGE See Melanoma-associated protein (MAGE) family MAGEL2 gene, 27 Magnetic resonance imaging (MRI), 190 Major inhibitory neurotransmitter, 28 280 Makorin (MKRN) RING finger protein gene family, 27 Malabsorption, 62 MAPKs See Mitogen-activated protein kinases (MAPKs) Maternal chromosome, 19 Maternal diet effects of, 243 Maternal disomy 15, 26 Maternal gestational diabetes correlations between, 168 Maternal heterodisomy, 25 Maternal low-protein diet impact of, 243 Maternally expressed genes, 22 gene3 (MEG3), 159 Maternally imprinted gene, 20 Maternal obesity, 168 foetal muscle, 167 Maternal prepregnancy obesity, 164 MBD2 See Methyl-CpG-binding domain protein (MBD2) Mc3r -/- animal models, 104 MCRs See Melanocortin receptors (MCRs) Melanocortin-1 receptor (MC1R), 101 Melanocortin-3 receptor (MC3R) gene mutations and energy homeostasis, 102–104 leptin-regulated melanocortin circuit, 100–102 leptin-melanocortin pathway, 101–102 melanocortin system, 100–101 naturally occurring mutationsin and human obesity, 104–117 mutants, functional characterizations of, 109–116 mutation carriers, clinical phenotypes of, 108–109 mutations, prevalence of, 105–108 structure and function of, 116–117 variants and mutations, identification of, 104–105 naturally occurring variants and mutations in, 106 Index obesity and current treatment, 98–100 current treatments for, 99–100 prevalence of, 98–99 potential therapeutic strategies, 117–118 mutations, 107 prevalence of mutations, 108 Melanocortin receptor (MC4R), 8, 52, 135, 155 agonist tetrapeptide, 104 gene, polymorphism, role of, 251 Melanocortin-3 receptor (MC3R) gene mutations naturally occurring mutations in and human obesity mutants, functional characterizations of functions, other perspectives of, 116 MAPK signaling properties of, 115–116 molecular classification of, 109–115 Melanocortin receptors (MCRs), 101 signaling, 85 Melanocortin system, 100, 101 Melanoma-associated protein (MAGE) family, 27 Membrane proteins, 143 Membrane receptor, 39 Mesoderm-specific transcript gene (MEST), 159 MEST See Mesoderm-specific transcript gene (MEST) Metabolic disease, 152, 163 Metabolic disorder, 100 Metabolic-related genes, 166 Metabolic syndrome, 236 Methionine cycle, 242 Methylated CpG loci, 201 Methylated genes, 240 Methylating micronutrients, 242 Methylation, 201 Methyl-CpG-binding domain protein (MBD2), 172 Microarray studies, 195 Index MicroRNAs (miRNAs), 162, 195, 241 expression profile of, 195 noncoding, 200 role of, 241 Mild mental deficiency, 31 miRNA See MicroRNAs (miRNA) Missense mutations, 142 Mitochondrial carrier (MTCH2), Mitogen-activated protein kinases (MAPKs), 115 Modulate molecular mechanisms, 198 Molecular mechanisms, 154 Monogenic obesity, 193–194 genes, 153 variants, 192 Mouse Phenome Database (MPD), 206 gene expression sector, 206 MPD See Mouse Phenome Database (MPD) MRI See Magnetic resonance imaging (MRI) mRNAs binding and transportation of, 34 transcripts, 79 MSTN transcript, 243 Multiple genome-wide association studies of obesity, 86 Multiple nonsense and missense mutations, 11 Multiple transcript variants, 76 Mutant receptor, 114 Mutation maternal inheritance of, 39 N National Health and Nutrition Examination Survey, 98, 190 Naturally occurring mutations, 109 GHSR mutations, 143 schematic representation, 138 Naturally occurring mutations, human obesity and, 104–117 mutants, functional characterizations of, 109–116 functions, other perspectives of, 116 MAPK signaling properties of, 115–116 281 molecular classification of, 109–115 mutation carriers, clinical phenotypes of, 108–109 mutations, prevalence of, 105–108 structure and function of, 116–117 variants and mutations, identification of, 104–105 Natural selection, 153 NCDs See Noncommunicable diseases (NCDs) ncRNA See Noncoding RNA (ncRNA) N222D PC1/3 mutant protein dominant-negative deleterious effect of, 57 N221D polymorphism, 58 Necdin (NDN), 27 Neel’s theory, 154 Nervous system, 76 Neuroendocrine cells, 48 Neuroendocrine peptides, 29 NEUROG3 deficiency, 61 loss-of-function mutations of, 61 Neuronal growth regulator (NGR 1), Neuronatin gene (NNAT), 159 Neuropeptides, 48 in hypothalamus, PC1/3 activation of, 51–56 PC1/3 activity in gastrointestinal system, 55–56 PC1/3-generated peptide hormones involved in feeding behaviors, 54–54 PC1/3 processing of proinsulin to insulin in pancreatic β-cells, 54 role in melanocortin pathway, 52–54 Neuropeptide Y (NPY), 52, 84, 101, 159 expression, 135 Npy gene, 159 Neurotrophic tyrosine kinase receptor type gene (NTRK2), mutation, 83 heterozygous missense mutation of, 83 Next generation DNA sequencing, 12 Next-generation sequencing (NGS) technology, 195, 245 282 NGR See Neuronal growth regulator (NGR 1) NGS See Next-generation sequencing (NGS) technology NNAT See Neuronatin gene (NNAT) Noncoding RNA (ncRNA), 155, 241 categories of, 241 role of, 239 Noncommunicable diseases (NCDs), 202 Nongenetic factors importance of, 254 Nonsense mutation, 137 Nonsynonymous SNPs, 245 Normal weight obesity (NWO), 190 N-3 polyunsaturated fatty acids (n-3 PUFAs), 172 NPY See Neuropeptide Y (NPY) NTRK2 See Neurotrophic tyrosine kinase receptor type gene (NTRK2) Nuclear hormone receptor-mediated gene, 161 Nuclear receptors, 170 Nuclear ribonucleoprotein D0B, 89 Nucleus architecture, 241–242 Nutrient-related disease, 198 Nutrigenomics convergence of, 198 and epigenetic modifications, 242–243 NWO See Normal weight obesity (NWO) O Obesity, 237 Albright hereditary osteodystrophy (AHO), 3740 Alstroăm syndrome, rare obesity-related single gene disorder, 35–37 associated health problems, 191 biomarker of, 162 biomarkers for, 195 brain-derived neurotrophic factor (BDNF), 83–86 NTRK2 (TrkB) mutation, 83 Prader-Willi syndrome (PWS), 83–85 RAI1 haploinsufficiency in SmithMagenis and ROHHAD syndromes, 85–86 Index cause of T2D, 191 characterizations of, 188 in childhood, adolescence, and adulthood, 191 childhood obesity, in children and adolescents, 99 classification of, 187 current epidemic of, 152 and current treatment, 98–100 current treatments for, 99–100 prevalence of, 98–99 current treatments for, 99 definition of, 189 development of, DNA factors, 12 epigenetics of, 170 epigentic regulation in, 160 etiology-based classification of, 189 Fragile X syndrome and Prader-Willi phenotype, 33–35 genes, 5, 201 and encoded proteins, 11–13 ideogram, genetic disorders, 13 genetics, 192 forms of, variant and genome-wide association studies in, 4–8 global prevalence of, 152 in humans, syndromic causes of, 14 induced inflammation, 103 mediated inflammation, 174 Mendelian inheritance of, 193 monogenic nonsyndromic, 192 monogenic syndromic, 192 personalized therapy for, 202 polygenic obesity, 192 Prader-Willi syndrome, 19–33 clinical features in, 29–32 clinical findings associated with typical 15q11-q13 deletions, 32–33 genetic and clinical aspects of, 21–27 genomic imprinting defects in, 19–21 molecular genetics and, 27–29 recognized single gene causes of, 8–11 related comorbidities, 100 related conditions, 191–192 Index related disorder, 35 related genetic disorder, 18 related GWAS, 88 related infertility, 10 related proteins, 11 related syndromic genetic disorders, related traits, 200 risk, biomarkers of, 201 single gene and syndromic causes of, 1–40, 2, 2–4 Society, 99 susceptibility, 192, 197 syndrome, 35 syndromic causes of, 13–18 Obesogens, 170 Obsessive-compulsive disorder, 28 Obstructive pulmonary disease, 15 Oculocutaneous albinism II, 28 Orexigenic factor, 134 Orexigenic peptide hormones, 51 NPY, 54 Orexigenic peptides, 136 Overweight See also Obesity classification of, 187 global prevalence of, 152 P Paired box (PAX6) genes, 194 Pair-feeding experiments, 77 Pancreatic duodenal homeobox factor-1 (Pdx1), 165 Paraventricular hypothalamus (PVH), 77 Parental gametes epigenetic programming of, 155, 174 Parent-reported hyperphagia questionnaire, 78 Paternal alleles heterozygous deletions of, 83 Paternally expressed gene imprinted genes, 19 PEG3, 159 Paternal obesity, 168 Pathogenic GHSR mutations, 142 PCs See Prohormone convertases (PCs) 11p14 deletion, 82 PDK4 See Pyruvate dehydrogenase kinase, isozyme4 (PDK4) 283 Pediatric obesity in United States, 12 Pedigree selection, 234 Peptide, 133 hormone processing, 66 hormone-producing cells, 65 precursor processing, 59 Performance traits, 237 Peripheral insulin role of, 54 Peroxisome proliferator-activated receptor α (PPAR-α), 162 coactivator1 (PGC1), 158 hypomethylation of, 165 promoter, 169 Peroxisome proliferator-activated receptor gamma (PPARγ), Persistent organic pollutants (POPs), 170 Pharmacological chaperones, 143 Pharmacoperones, 143 Pharmacotherapy, 100, 199 Phenome-genome approach, 204 Phenome-wide association study (PheWAS), 188 development of, 203 of obesity, 202–211 obesity research, challenges and paradigm shift in, 209–211 phenome and phenomics of, 204–207 PheWAS of, 207–209 Phenomics, 204 PheWAS See Phenome-wide association study (PheWAS) Phosphoenol pyruvate carboxykinase (Pepck), 167 Phosphoinositide 3-kinase (PI3K) pathways, 102 Photoreceptor dystrophy, 35 Pig genome sequence, 259 PiGMaP See European Pig Gene Mapping Project (PiGMaP) PigQTL database, 244 PI3K See Phosphoinositide 3-kinase (PI3K) pathways 11p inversion, 82–83 Pituitary hormone abnormalities, 85 284 PLAGL1 See Pleiomorphic adenoma gene-like 1(PLAGL1) Plasma ghrelin levels, 29 Pleiomorphic adenoma gene-like (PLAGL1), 159 Pleiotropy, 202 analysis, 208 Point mutations of RAI1, 85 Polycystic ovarian disease, 172 Polygenic obesity, 194–195 Polygenic trait, 117 See also Obesity Polymorphisms, 253, 255 associated with fat tissue accumulation, 246–261 CNVs in dogs, 260–261 CNVs in pigs, 259–260 SNPs and indels in pigs, 246–254 SNPs in dogs, 254–259 on PC1/3 activity, 58 relevance of, 253 Polynesians populations, 153 POMC See Preprohormone proopiomelanocortin (POMC) POPs See Persistent organic pollutants (POPs) Population surveys, 24 Porcine adipogenesis positive and negative regulators of, 239 Porcine fatness traits genetic markers for, 253 Porcine maps, 243 Potassium channel tetramerization domain containing 15 (KCTD15), PPAR-α See Peroxisome proliferatoractivated receptor α (PPAR-α) PPARγ See Peroxisome proliferatoractivated receptor gamma (PPARγ) PPARG genes, 258 Prader-Willi/Angelman syndrome gene, 24 Prader-Willi phenotype (PWP), 13, 14, 33 Prader-Willi syndrome (PWS), 83–19–20, 33, 85, 156, 194 adolescents, 31 cardinal feature of, 33 Index children with, 30 clinical features in, 29–32 clinical findings associated with typical 15q11-q13 deletions, 32–33 disordered satiety, cause of, 84 feature of, 32 features of, 28, 84 genetic and clinical aspects of, 21–27 genetic cause of, 25 genetic subtypes in, 26 genomic imprinting defects in, 19–21 growth charts, 32 molecular genetics and, 27–29 stages infantile hypotonia, 29 temperature instability, 29 type I deletion, 32 type II deletion, 32 Preadipocyte factor-1 (Pref-1), 161 Predisposing DNA variants, 236 Preeclampsia, 10 Pregnancy antibiotic use, 163 related weight gain, 10 Prenatal exposure to polycyclic aromatic hydrocarbon (PAH), 171 Preprohormone proopiomelanocortin (POMC), 101 pre-proPC1 cellular maturation of, 50 Pro-brain-derived neurotrophic factor (BDNF) in human obesity, rare syndromes and common variants of, 76 intracellular trafficking of, 86 N-terminal prodomain of, 86 Procholecystokinin (proCCK), 55 Progeny testing, 234 Proglucagon, 55 processing, 55 Prohormone convertase 1, deficiency, 59, 61 exon sequencing, 59 gene, 48, 56 products, 56 inactivating mutations, 64 loss-of-function mutations in, 61 285 Index mutations, 65 polymorphisms, 59, 66 Prohormone convertase 1/3 (PC1/3), 48 binding protein, 64 carboxy-terminal processing, 58 deficiency, 55 and disease, 56–65 common and rare human haploinsufficient PCSK1 polymorphisms, 57–59 PC1/3 knockout mouse and PC1/3-deficient N222D mouse, 56–57 ProSAAS and obesity, 64–65 rare human biallelic PCSK1 mutations cause enteric and systemic endocrinopathies and obesity, 59–64 mouse models of, 56 expression, 51 N222D missense mutation, 57 processed neuropeptides, 64 processing, 62 proteins, 58 synthesized gut hormone, 62 synthesized peptides, 51 Prohormone convertases (PCs) 11, 48, 101 Prohormones, 48 processes, 61 Prometaphase chromosome analysis, Proopiomelanocortin (POMC), 84, 156 cleavages of, 50 gene, 174 expression level, 11 Pomc/leptin ratio, 159 processing, 53 promoter, 166 CpG methylation of, 159 hypomethylation of, 159 signaling, disruption of, 85 system, 64 Proopiomelanocortin (POMC)-expressing neurons, 52 Propeptide domain, 49 Proprotein convertase family, 48 PC1/3, 49 ProPC1/3 processing dominant-negative effect on, 63 proSAAS polymorphism, 65 proSAAS transgenic mice, 64 Prostate diseases, 172 Protein coding gene, 18, 28 coding sequences, 79 LY86 encodes for, 159 Psychotropic drugs, 31 Public health burden, 99 PVH See Paraventricular hypothalamus (PVH) PWP See Prader-Willi phenotype (PWP) PWS See Prader-Willi syndrome (PWS) Pyruvate dehydrogenase kinase, isozyme4 (PDK4), 173 Q Q665E/S690T paired polymorphisms, 66 Q665E/S690T variation, 57 QTLs See Quantitative trait loci (QTLs) Quantitative trait loci (QTLs), 137, 193, 236, 243 studies, 245 R RAI1 haploinsufficiency in Smith-Magenis and ROHHAD syndromes 85–86 Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysfunction (ROHHAD) syndrome, 85 RA1 protein, 85 Rare mutations, 59, 90 heterozygous mutations, 59 missense human mutations, 63 Rare PCSK1 mutations, 58 Regulated secretory pathway, 48 PC1/3 trafficking in, 50 Renal disease, 36 Reporter gene expression, 141 Reproductive dysfunction, 37 Restricted feeding protocol, 103 286 Retinoid X receptor-α (RXR-A) methylation of, 165 Reversible gastrointestinal lipase inhibitor, 100 RNA expression patterns, folding, in silico analysis of, 252 Rouxen-Y gastric bypass (RYGB), 173 RXR-A See Retinoid X receptor-α (RXR-A) RYGB See Rouxen-Y gastric bypass (RYGB) S S-adenosylmethionine (SAM), 156 SAM See S-adenosylmethionine (SAM) Second protein coding sequence (SNURF), 27 SNURF-SNRPN complex gene locus, 28 SNURF-SNRPN gene complex, 27 Secretory pathway trafficking, 63 Selective MC3R agonist central administration of, 104 Selective noradrenaline/serotonin reuptake inhibitor, 100 Sensitive time windows, 165 Serotonin receptor 2C (HTR2C), Serotonin receptors, 29 SH2B adaptor protein (SH2B1), SH3 domain-containing protein, 201 Short simple repeats (SS), 243 Short tandem repeats (STR), 243 Signaling-impaired mutants, 110 Signal peptide-bearing inactive precursor, 49 Silencing tumor-suppressing genes, 21 Silver-Russell syndrome, 19 Single gene obesity-related disorders, 40 Single-minded homolog (SIM1), SIM1 gene, 11 Single nucleotide polymorphisms (SNPs), 86, 105, 137, 195, 244 comprehensive analysis of, 139 genotyping array, 259 microarrays, 234 probes, query, 206 use of, Index Small nuclear ribonucleoprotein N (SNRPN), 27 Small nucleolar RNAs (snoRNAs), 9, 36 Small RNAs, 195 Smith-Magenis syndrome, 85 snoRNAs See Small nucleolar RNAs (snoRNAs) SNPs See Single nucleotide polymorphisms (SNPs) SNRPN See Small nuclear ribonucleoprotein N (SNRPN) SNURF See Second protein coding sequence (SNURF) Spliceosomal protein (SmN), 27 STR See Short tandem repeats (STR) Subcutaneous mineralization, 37 Subcutaneous vascular stem cells (SVSC), 241 Subscapular skinfold thickness (SUB), 245 Susceptibility variants, 153 Syndromic obesity, 3, 12, 13, 193 Synthetic peptides, 134 T TGN See Trans-Golgi network (TGN) Thrifty phenotype hypothesis, 154 Tissue gene expression epigenetic regulation of, 155 TMDs See Transmembrane domains (TMDs) Transcription regulation of, 241 Transgenerational epigenetic effect, 242 Transgenerational epigenetic transmission, 168 Transgenerational phenomenon, 168 Trans-Golgi network (TGN), 50 Transmembrane (TM) domain, 102 Transmembrane domains (TMDs), 134 Transmembrane protein 18 (TMEM18), Trimeric regulatory protein, 39 Tripartite motif-containing (TRIM3) gene, 201 Trisomy 15, 26 TrkB See Tropomyosin-related kinase B receptor (TrkB) 287 Index Tropomyosin-related kinase B receptor (TrkB), 76 Truncal obesity, 35 Trypsin-like proteases, 49 Tubulin gamma complex associated protein gene, 24 Tumor necrosis factor α (Tnfa), 161 Type diabetes (T2D), 152, 187 U United States Department of Agriculture (USDA), 243 USDA See United States Department of Agriculture (USDA) V Vagal sensory innervation, 77 Vascular endothelial growth factor receptor, 253 VAT See Visceral adipose tissue (VAT) Ventromedial hypothalamus (VMH), 77 Ventromedial nucleus, 103 Visceral adipose tissue (VAT), 190 VMH See Ventromedial hypothalamus (VMH) W Waist circumferences (WCs), 189 Waist-hip ratio (WHR), 189, 190 Weight control, 32 Weight loss, 10 WHO See World Health Organization (WHO) Whole-cell enzyme-linked immunosorbent assay, 142 Whole genome methylation, 173 WHR See Waist-hip ratio (WHR) Wild-type enzyme function, 66 Wild-type PC1/3 protein, 65 Wilm’s tumor1 (WT1), 194 Wilms tumor, aniridia, genitourinary abnormalities, and mental retardation (WAGR) syndrome, 78–82, 194 children and adults with, 82 critical region, 78, 80 region critical genes, 82 World Health Assembly, 152 World Health Organization (WHO), 98, 152 WT1 See Wilm’s tumor1 (WT1) X X chromosomes, 26 process of, 26 Xenobiotics, 170 X-linked genes, 26 X-linked inheritance pattern, 34 Z ZPLD1gene, 260 ... experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein In using such information or methods they should be mindful of their own safety and. .. association studies, structural and expression microarrays, and next generation sequencing have Progress in Molecular BiologyandTranslational Science, Volume 140 ISSN 1877-1173 http://dx.doi.org/10.1016/bs.pmbts.2015.12.003... important in regulating androgen activity and sensitivity to sex hormones in both males and females involved in weight and body composition This X-linked gene contains a polymorphic CAG trinucleotide