Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution

TLDR: A meta-analysis of genome-wide association studies for WHR adjusted for body mass index provides evidence for multiple loci that modulate body fat distribution independent of overall adiposity and reveal strong gene-by-sex interactions.

Abstract: Waist-hip ratio (WHR) is a measure of body fat distribution and a predictor of metabolic consequences independent of overall adiposity. WHR is heritable, but few genetic variants influencing this trait have been identified. We conducted a meta-analysis of 32 genome-wide association studies for WHR adjusted for body mass index (comprising up to 77,167 participants), following up 16 loci in an additional 29 studies (comprising up to 113,636 subjects). We identified 13 new loci in or near RSPO3, VEGFA, TBX15-WARS2, NFE2L3, GRB14, DNM3-PIGC, ITPR2-SSPN, LY86, HOXC13, ADAMTS9, ZNRF3-KREMEN1, NISCH-STAB1 and CPEB4 (P = 1.9 × 10⁻⁹ to P = 1.8 × 10⁻⁴⁰) and the known signal at LYPLAL1. Seven of these loci exhibited marked sexual dimorphism, all with a stronger effect on WHR in women than men (P for sex difference = 1.9 × 10⁻³ to P = 1.2 × 10⁻¹³). These findings provide evidence for multiple loci that modulate body fat distribution independent of overall adiposity and reveal strong gene-by-sex interactions.

Full text

Meta-analysis identifies 13 new loci associated with waist-hip
ratio and reveals sexual dimorphism in the genetic basis of fat
distribution
Iris M Heid
1,2,214
, Anne U Jackson
3,214
, Joshua C Randall
4,214
, Thomas W Winkler
1,214
, Lu
Qi
5,6,214
, Valgerdur Steinthorsdottir
7,214
, Gudmar Thorleifsson
7,214
, M Carola Zillikens
8,9
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Elizabeth K Speliotes
10,11
, Reedik Mägi
4
, Tsegaselassie Workalemahu
5
, Charles C White
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,
Nabila Bouatia-Naji
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, Tamara B Harris
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, Sonja I Berndt
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, Erik Ingelsson
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, Cristen J
Willer
3
, Michael N Weedon
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, Jian’An Luan
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, Sailaja Vedantam
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, Tõnu Esko
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, Zoltán Kutalik
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, Lee M Kaplan
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Europe PMC Funders Group
Author Manuscript
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Published in final edited form as:
Nat Genet
. 2010 November ; 42(11): 949–960. doi:10.1038/ng.685.
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1
Regensburg University Medical Center, Department of Epidemiology and Preventive Medicine,
Regensburg, Germany.
2
Institute of Epidemiology, Helmholtz Zentrum München-German
Research Center for Environmental Health, Neuherberg, Germany.
3
Department of Biostatistics,
Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan, USA.
4
Wellcome
Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
5
Department of Nutrition,
Harvard School of Public Health, Boston, Massachusetts, USA.
6
Channing Laboratory,
Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston,
Massachusetts, USA.
7
deCODE Genetics, Reykjavik, Iceland.
8
Department of Internal Medicine,
Erasmus Medical Center (MC), Rotterdam, The Netherlands.
9
Netherlands Genomics Initiative
(NGI)-sponsored Netherlands Consortium for Healthy Aging (NCHA), Rotterdam, The
Netherlands.
10
Metabolism Initiative and Program in Medical and Population Genetics, Broad
Institute, Cambridge, Massachusetts, USA.
11
Division of Gastroenterology, Massachusetts
General Hospital, Boston, Massachusetts, USA.
12
Department of Biostatistics, Boston University
School of Public Health, Boston, Massachusetts, USA.
13
Centre National de la Recherche
Scientifique (CNRS), UMR8199-IBL-Institut Pasteur de Lille, Lille, France.
14
University Lille Nord
de France, Lille, France.
15
Laboratory of Epidemiology, Demography, Biometry, National Institute
on Aging, National Institutes of Health, Bethesda, Maryland, USA.
16
Division of Cancer
Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department
of Health and Human Services, Bethesda, Maryland, USA.
17
Department of Medical
Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
18
Genetics of Complex
Traits, Peninsula College of Medicine and Dentistry, University of Exeter, Exeter, UK.
19
Medical
Research Council (MRC) Epidemiology Unit, Institute of Metabolic Science, Addenbrooke’s
Hospital, Cambridge, UK.
20
Divisions of Genetics and Endocrinology and Program in Genomics,
Heid et al.
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Children’s Hospital, Boston, Massachusetts, USA.
21
Estonian Genome Center, University of
Tartu, Tartu, Estonia.
22
Estonian Biocenter, Tartu, Estonia.
23
Institute of Molecular and Cell
Biology, University of Tartu, Tartu, Estonia.
24
Department of Medical Genetics, University of
Lausanne, Lausanne, Switzerland.
25
Swiss Institute of Bioinformatics, Lausanne, Switzerland.
26
Department of Epidemiology, School of Public Health, University of North Carolina at Chapel
Hill, Chapel Hill, North Carolina, USA.
27
Department of Pharmacy and Pharmacology, University
of Bath, Bath, UK.
28
MRC Harwell, Harwell Science and Innovation Campus, Oxfordshire, UK.
29
Department of Statistics, University of Oxford, Oxford, UK.
30
Harvard Medical School, Boston,
Massachusetts, USA.
31
Massachusetts General Hospital (MGH) Weight Center, Massachusetts
General Hospital, Boston, Massachusetts, USA.
32
Department of Epidemiology, Harvard School
of Public Health, Boston, Massachusetts, USA.
33
Department of Biostatistics, Harvard School of
Public Health, Boston, Massachusetts, USA.
34
Human Genetics, Leiden University Medical
Center, Leiden, The Netherlands.
35
National Heart and Lung Institute, Imperial College London,
London, UK.
36
Merck Research Laboratories, Merck & Co., Inc., Boston, Massachusetts, USA.
37
Pacific Biosciences, Menlo Park, California, USA.
38
Sage Bionetworks, Seattle, Washington,
USA.
39
Genetic and Genomic Epidemiology Unit, Wellcome Trust Centre for Human Genetics,
Oxford, UK.
40
Department of Genetics, Washington University School of Medicine, St. Louis,
Missouri, USA.
41
Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
42
On behalf of the
MAGIC (Meta-Analyses of Glucose and Insulin-related traits Consortium) investigators.
43
Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands.
44
University of
Melbourne, Parkville, Australia.
45
Department of Primary Industries, Melbourne, Victoria,
Australia.
46
Montreal Heart Institute, Montreal, Quebec, Canada.
47
Department of Medicine,
Université de Montréal, Montreal, Quebec, Canada.
48
Department of Twin Research and Genetic
Epidemiology, King’s College London, London, UK.
49
Neurogenetics Laboratory, Queensland
Institute of Medical Research, Queensland, Australia.
50
Center for Human Genetic Research,
Massachusetts General Hospital, Boston, Massachusetts, USA.
51
The Broad Institute of Harvard
and Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts, USA.
52
Department of Psychiatry, Harvard Medical School, Boston, Massachusetts, USA.
53
Icelandic
Heart Association, Kopavogur, Iceland.
54
University of Iceland, Reykjavik, Iceland.
55
Queensland
Statistical Genetics Laboratory, Queensland Institute of Medical Research, Queensland,
Australia.
56
Program in Medical and Population Genetics, Broad Institute of Harvard and MIT,
Cambridge, Massachusetts, USA.
57
Department of Molecular Biology, Massachusetts General
Hospital, Boston, Massachusetts, USA.
58
Hudson Alpha Institute for Biotechnology, Huntsville,
Alabama, USA.
59
Department of Epidemiology and Biostatistics, School of Public Health, Faculty
of Medicine, Imperial College London, London, UK.
60
Department of Medicine, University of
Washington, Seattle, Washington, USA.
61
Cardiovascular Health Research Unit, University of
Washington, Seattle, Washington, USA.
62
MRC Human Genetics Unit, Institute for Genetics and
Molecular Medicine, Western General Hospital, Edinburgh, Scotland, UK.
63
Department of
Neurology, Boston University School of Medicine, Boston, Massachusetts, USA.
64
Department of
Biological Psychology, Vrije Universiteit (VU) University Amsterdam, Amsterdam, The
Netherlands.
65
Department of Genetics and Pathology, Rudbeck Laboratory, University of
Uppsala, Uppsala, Sweden.
66
Department of Cancer Research and Molecular Medicine, Faculty
of Medicine, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.
67
Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of
Medicine and Dentistry, Queen Mary, University of London, London, UK.
68
Clinical Pharmacology
and Barts and The London Genome Centre, William Harvey Research Institute, Barts and The
London School of Medicine and Dentistry, Queen Mary University of London, London UK.
69
Institute of Health Sciences, University of Oulu, Oulu, Finland.
70
Biocenter Oulu, University of
Oulu, Oulu, Finland.
71
Department of Medicine, Stanford University School of Medicine, Stanford,
California, USA.
72
Division of Genetic Epidemiology, Department of Medical Genetics, Molecular
and Clinical Pharmacology, Innsbruck Medical University, Innsbruck, Austria.
73
Department of
Heid et al.
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Biostatistics, University of Washington, Seattle, Washington, USA.
74
Andrija Stampar School of
Public Health, Medical School, University of Zagreb, Zagreb, Croatia.
75
Gen-Info Ltd, Zagreb,
Croatia.
76
Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford,
Oxford, UK.
77
Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki,
Finland.
78
National Institute for Health and Welfare, Department of Chronic Disease Prevention,
Unit of Public Health Genomics, Helsinki, Finland.
79
Istituto di Neurogenetica e
Neurofarmacologia del CNR, Monserrato, Cagliari, Italy.
80
Interfaculty Institute for Genetics and
Functional Genomics, Ernst-Moritz-Arndt-University Greifswald, Greifswald, Germany.
81
National
Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
82
Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke,
Nuthetal, Germany.
83
Department of Genetics, University of North Carolina, Chapel Hill, North
Carolina, USA.
84
Hagedorn Research Institute, Gentofte, Denmark.
85
Regensburg University
Medical Center, Clinic and Policlinic for Internal Medicine II, Regensburg, Germany.
86
MRC
Centre for Causal Analyses in Translational Epidemiology, Department of Social Medicine,
Oakfield House, Bristol, UK.
87
Department of Physiology and Biophysics, Keck School of
Medicine, University of Southern California, Los Angeles, California, USA.
88
Department of
Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles,
California, USA.
89
Division of Preventive Medicine, Brigham and Women’s Hospital, Boston,
Massachusetts, USA.
90
Centre for Genetic Epidemiology and Biostatistics, University of Western
Australia, Crawley, Western Australia, Australia.
91
Department of Physiology, Institute of
Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg,
Sweden.
92
Department of Internal Medicine, Institute of Medicine, Sahlgrenska Academy,
University of Gothenburg, Gothenburg, Sweden.
93
Lund University Diabetes Centre, Department
of Clinical Sciences, Lund University, Malmö, Sweden.
94
Zentrum für Zahn-, Mund- und
Kieferheilkunde, Greifswald, Germany.
95
Department of Medicine III, University of Dresden,
Dresden, Germany.
96
Division of Endocrinology, Keck School of Medicine, University of Southern
California, Los Angeles, California, USA.
97
Centre for Population Health Sciences, University of
Edinburgh, Teviot Place, Edinburgh, Scotland, UK.
98
Department of Internal Medicine B, Ernst-
Moritz-Arndt University, Greifswald, Germany.
99
MRC-Health Protection Agency (HPA) Centre for
Environment and Health, London, UK.
100
Department of General Practice and Primary Health
Care, University of Helsinki, Helsinki, Finland.
101
National Institute for Health and Welfare,
Helsinki, Finland.
102
Helsinki University Central Hospital, Unit of General Practice, Helsinki,
Finland.
103
Folkhalsan Research Centre, Helsinki, Finland.
104
Vasa Central Hospital, Vasa,
Finland.
105
Center for Neurobehavioral Genetics, University of California, Los Angeles, California,
USA.
106
Department of Medicine, University of Maryland School of Medicine, Baltimore,
Maryland, USA.
107
Department of Medicine III, Pathobiochemistry, University of Dresden,
Dresden, Germany.
108
Department of Clinical Sciences/Obstetrics and Gynecology, University of
Oulu, Oulu, Finland.
109
National Institute for Health and Welfare, Department of Chronic Disease
Prevention, Chronic Disease Epidemiology and Prevention Unit, Helsinki, Finland.
110
Institute of
Biomedicine, Department of Physiology, University of Oulu, Oulu, Finland.
111
Department of
Psychiatry, Kuopio University Hospital and University of Kuopio, Kuopio, Finland.
112
Institute of
Genetic Medicine, European Academy Bozen-Bolzano (EURAC), Bolzano-Bozen, Italy (affiliated
Institute of the University of Lübeck, Lübeck, Germany).
113
PathWest Laboratory of Western
Australia, Department of Molecular Genetics, J Block, QEII Medical Centre, Nedlands, Western
Australia, Australia.
114
Busselton Population Medical Research Foundation Inc., Sir Charles
Gairdner Hospital, Nedlands, Western Australia, Australia.
115
National Institute for Health and
Welfare, Department of Chronic Disease Prevention, Population Studies Unit, Turku, Finland.
116
Hospital for Children and Adolescents, Helsinki University Central Hospital and University of
Helsinki, Helsinki, Finland.
117
National Institute for Health and Welfare, Diabetes Prevention Unit,
Helsinki, Finland.
118
Interdisciplinary Centre for Clinical Research, University of Leipzig, Leipzig,
Germany.
119
Institut für Pharmakologie, Universität Greifswald, Greifswald, Germany.
120
Croatian
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Centre for Global Health, School of Medicine, University of Split, Split, Croatia.
121
Department of
Medicine, University of Kuopio and Kuopio University Hospital, Kuopio, Finland.
122
Nord-
Trøndelag Health Study (HUNT) Research Centre, Department of Public Health and General
Practice, Norwegian University of Science and Technology, Levanger, Norway.
123
Finnish
Institute of Occupational Health, Oulu, Finland.
124
Institut inter-regional pour la sante (IRSA), La
Riche, France.
125
Centre National de Genotypage, Evry, Paris, France.
126
Transplantation
Laboratory, Haartman Institute, University of Helsinki, Helsinki, Finland.
127
Department of Public
Health and Primary Care, Institute of Public Health, University of Cambridge, Cambridge, UK.
128
Avon Longitudinal Study of Parents and Children (ALSPAC) Laboratory, Department of Social
Medicine, University of Bristol, Bristol, UK.
129
Division of Health, Research Board, An Bord
Taighde Sláinte, Dublin, Ireland.
130
Department of Pathology and Molecular Medicine, McMaster
University, Hamilton, Ontario, Canada.
131
Amgen, Cambridge, Massachusetts, USA.
132
Department of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital,
Headington, Oxford, UK.
133
Finnish Twin Cohort Study, Department of Public Health, University of
Helsinki, Helsinki, Finland.
134
Obesity Research Unit, Department of Psychiatry, Helsinki
University Central Hospital, Helsinki, Finland.
135
Department of Medicine, Levanger Hospital, The
Nord-Trøndelag Health Trust, Levanger, Norway.
136
National Institute for Health and Welfare,
Oulu, Finland.
137
Department of Clinical Sciences, Lund University, Malmö, Sweden.
138
Department of Cardiovascular Sciences, University of Leicester, Glenfield Hospital, Leicester,
UK.
139
Leicester National Institute for Health Research (NIHR) Biomedical Research Unit in
Cardiovascular Disease, Glenfield Hospital, Leicester, UK.
140
South Karelia Central Hospital,
Lappeenranta, Finland.
141
Division of Cardiology, Cardiovascular Laboratory, Helsinki University
Central Hospital, Helsinki, Finland.
142
Department of Psychiatry/Instituut voor Extramuraal
Geneeskundig Onderzoek (EMGO) Institute, VU University Medical Center, Amsterdam, The
Netherlands.
143
Atherosclerosis Research Unit, Department of Medicine, Solna, Karolinska
Institutet, Karolinska University Hospital, Stockholm, Sweden.
144
Department of Human Genetics,
Leiden University Medical Center, Leiden, The Netherlands.
145
Center of Medical Systems
Biology, Leiden University Medical Center, Leiden, The Netherlands.
146
Institut für Klinische
Chemie und Laboratoriumsmedizin, Universität Greifswald, Greifswald, Germany.
147
Steno
Diabetes Center, Gentofte, Denmark.
148
Department of Physiatrics, Lapland Central Hospital,
Rovaniemi, Finland.
149
School of Pathology and Laboratory Medicine, University of Western
Australia, Nedlands, Western Australia, Australia.
150
School of Medicine and Pharmacology,
University of Western Australia, Perth, Western Australia, Australia.
151
Department of Clinical
Physiology, University of Tampere and Tampere University Hospital, Tampere, Finland.
152
Department of Clinical Chemistry, University of Tampere and Tampere University Hospital,
Tampere, Finland.
153
Research Centre of Applied and Preventive Cardiovascular Medicine,
University of Turku, Turku, Finland.
154
The Department of Clinical Physiology, Turku University
Hospital, Turku, Finland.
155
Department of Medicine, University of Leipzig, Leipzig, Germany.
156
Leipziger Interdisziplinärer Forschungskomplex zu molekularen Ursachen umwelt- und
lebensstilassoziierter Erkrankungen (LIFE) Study Centre, University of Leipzig, Leipzig, Germany.
157
Coordination Centre for Clinical Trials, University of Leipzig, Leipzig, Germany.
158
Department
of Medicine, University of Turku and Turku University Hospital, Turku, Finland.
159
INSERM Centre
de Recherche en Epidémiologie et Santé des Populations (CESP) U1018, Villejuif, France.
160
University Paris Sud 11, Unité Mixte de Recherche en Santé (UMRS) 1018, Villejuif, France.
161
Department of Social Medicine, University of Bristol, Bristol, UK.
162
The London School of
Hygiene and Tropical Medicine, London, UK.
163
South Asia Network for Chronic Disease, New
Delhi, India.
164
Department of Genomics of Common Disease, School of Public Health, Imperial
College London, London, UK.
165
Faculty of Health Science, University of Southern Denmark,
Odense, Denmark.
166
Klinik und Poliklinik für Innere Medizin II, Universität Regensburg,
Regensburg, Germany.
167
Regensburg University Medical Center, Innere Medizin II, Regensburg,
Germany.
168
Department of Social Services and Health Care, Jakobstad, Finland.
169
Research
Heid et al.
Page 5
Nat Genet
. Author manuscript; available in PMC 2011 May 01.
Europe PMC Funders Author Manuscripts Europe PMC Funders Author Manuscripts

Frequently asked questions

Q1. What contributions have the authors mentioned in the paper "Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution" ?

The authors conducted a meta-analysis of 32 genome-wide association studies for WHR adjusted for body mass index ( comprising up to 77,167 participants ), following up 16 loci in an additional 29 studies ( comprising up to 113,636 subjects ). Within the Genetic Investigation of Anthropometric Traits ( GIANT ) consortium, the authors performed a large-scale meta-analysis of genome-wide association studies ( GWAS ) informative for WHR using adjustment for BMI to focus discovery toward genetic loci associated with body fat distribution rather than overall adiposity14-16. 

Q2. What future works have the authors mentioned in the paper "Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution" ?

By providing new insights into the regulation of body fat distribution, the present study raises a number of issues for future investigation. Efforts to tackle overall obesity through therapeutic or lifestyle-based modulation of overall energy balance have proved extremely challenging to implement, and the manipulation of processes associated with more beneficial patterns of fat distribution offers an alternative perspective for future drug discovery. From the genetic perspective, resequencing, dense-array genotyping and fine-mapping approaches will be required to characterize causal variants at the loci the authors have identified and to support further discoveries that may account for the substantial proportion of genetic variance unexplained by their findings. 

Q3. How many SNPs were examined in the discovery stage?

In the discovery stage, up to 2,850,269 imputed and genotyped SNPs were examined in 32 GWAS comprising up to 77,167 participants informative for anthropometric measures of body fat distribution. 

Q4. What is the role of the waist circumference in obesity?

WHR is of particular interest as a measure of body fat distribution because it integrates the adverse metabolic risk associated with increasing waist circumference with the more protective role of gluteal fat deposition with respect to diabetes, hypertension and dyslipidemia5,6. 

Q5. How many women were included in the discovery and follow-up studies?

These analyses included up to 108,979 women (42,735 in the discovery stage and 66,244 in the follow up) and 82,483 men (34,601 in the discovery and 47,882 in the follow up). 

Q6. What was the effect size of the LY86 locus on the WHR?

After adding an interaction term of SNP with BMI into the model, the authors observed that BMI modified the WHR association at the LY86 locus (P for interaction = 9.5 × 10−5), with a larger WHR effect among obese individuals compared to non-obese individuals(Supplementary Note). 

Q7. What was the effect size of the ten loci in the discovery analysis?

Of the ten loci shown to be associated with BMI in previous GWAS14,15,18, only two showed nominally significant (P < 0.05) associations for BMI-adjusted WHR in the discovery analysis (FTO, rs8050136, P = 0.03, n = 77,074; TMEM18, rs6548238, P = 3.0 × 10−3, n = 77,016). 

Q8. What is the significance of the WHR association in fat depots?

To determine whether genes within the WHR-associated loci showed evidence of differential transcription in distinct fat depots, the authors compared expression levels in gluteal or abdominal SAT in 49 individuals. 

Q9. How much of the variance in WHR was explained by the 14 loci?

These 14 loci explain 1.34% of the variance in WHR (after adjustment for BMI and age) in women but only 0.46% of the variance in WHR in men. 

Q10. What is the primary objective of genetic discovery efforts?

The primary objective of genetic discovery efforts is to characterize the specific mechanisms involved in regulating the trait of interest. 

Q11. How many SNPs were evaluated in the discovery phase?

The authors selected SNPs representing the top 16 independent (defined as being located >1 Mb apart) regions of association (discovery P < 1.4 × 10−6; Table 1) and evaluated them in 29 additional, independent studies (comprising up to 113,636 individuals) using a mixture of in silico data and de novo genotyping. 

Q12. What is the relationship between the WHR-associated loci and metabolic traits?

To identify potential functional connections and pathway relationships between genes mapping at the WHR-associated loci, the authors focused on the 95 genes located in a 2-Mb interval centered around each of the 48 independent SNPs that attained P < 1.0 × 10−5 in the WHR discovery studies.