1. ^*King's College London, Guy's, King's & St. Thomas' School of Medicine, London, United Kingdom
2. ^†King's College London, Social, Genetic and Developmental Psychiatry Research Centre, Institute of Psychiatry, London, United Kingdom
3. ^‡Division of Genetics and Molecular Medicine, King's College London School of Medicine at Guy's, King's College & St. Thomas' Hospitals, London, United Kingdom
4. ^§King's College London, Division of Psychological Medicine, Institute of Psychiatry, London, United Kingdom
5. Department of Cardiovascular Research, "Mario Negri" Institute, Milan, Italy
6. ^¶Myriad Genetics, Inc., Salt Lake City, Utah
7. ^#National Human Genome Center, Howard University, Genetic Epidemiology Unit, Washington, DC
8. ^**Division of Biostatistics, Mayo Clinic, Rochester, Minnesota
9. ^††Department of Medicine/Epidemiology, University of Texas Health Science Center, San Antonio, Texas
10. ^‡‡Tulane Center for Cardiovascular Health and Department of Epidemiology, Tulane School of Public Health & Tropical Medicine, New Orleans, Louisiana
11. ^§§Department of Genetics, Southwest Foundation for Biomedical Research, San Antonio, Texas
12. Division of Statistical Genomics, Centre for Genome Sciences, Washington University School of Medicine, St. Louis, Missouri
13. ^¶¶Genomic Laboratory, Laval University Research Center Robert-Giffard, Beauport, Québec, Canada
14. ^##Osteoporosis Research Center, Creighton University Medical Center, Omaha, Nebraska; Key Laboratory of Biomedical Information Engineering of Ministry of Education and Institute of Molecular Genetics, School of Life Science and Technology Xi'an Jiaotong University, Xi'an, P. R. China; and Laboratory of Molecular and Statistical Genetics, College of Life Sciences, Hunan Normal University, Changsha, Hunan, P. R. China
15. ^***Genomic Medicine, Imperial College London, Hammersmith Hospital, London, United Kingdom
16. ^†††DECR/NIDDK/NIH, Phoenix, Arizona
17. ^‡‡‡Clinical Research Group, Department of Child and Adolescent Psychiatry, Rheinische Kliniken Essen, University of Duisburg-Essen, Essen, Germany
18. ^§§§Medical College of Wisconsin, TOPS Center for Obesity and Metabolic Research, Milwaukee, Wisconsin
19. Center for Neurobiology and Behavior, University of Pennsylvania, Philadelphia, Pennsylvania
20. ^¶¶¶Department of Preventive Medicine & Epidemiology, Loyola University Medical Center, Maywood, Illinois
21. ^###Department of Pediatrics, Cincinnati Children's Hospital Medical Center and the University of Cincinnati School of Medicine, Cincinnati, Ohio
22. ^****Department of Medical Genetics, University of Helsinki and Department of Molecular Medicine, National Public Health Institute Biomedicum, Helsinki, Finland
23. ^††††Western Australia Institute for Medical Research and UWA Centre for Medical Research, University of Western Australia, Perth Australia
24. ^‡‡‡‡Broad Institute of Massachusetts Institute of Technology and Harvard, Carmbridge, Massachusetts
25. ^§§§§Department of Pediatrics, Rainbow Babies and Children's Hospital, University Hospitals of Cleveland, Case Western Reserve University, Cleveland, Ohio
26. Department of Biostatistics, University of Michigan, Ann Arbor, Michigan
27. ^¶¶¶¶Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota
28. ^####Genetics Department, University Medical Center Groningen, Groningen, The Netherlands
29. ^*****Department of Internal Medicine, Cardiology, University of Michigan, Ann Arbor, Michigan

Correspondence: David A. Collier Social, Genetic and Developmental Psychiatry Centre (P82), King's College London, The Institute of Psychiatry, De Crespigny Park, Denmark Hill, London SE5 8AF, United Kingdom. E-mail: d.collier@iop.kcl.ac.uk

³⁰Drs. Saunders and Chiodini contributed equally to this study.

^*The costs of publication of this article were defrayed, in part, by the payment of page charges. This article must, therefore, be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 14 June 2006; Revised  0000; Accepted 13 February 2007.

Abstract

Objective: The objective was to provide an overall assessment of genetic linkage data of BMI and BMI-defined obesity using a nonparametric genome scan meta-analysis.

Research Methods and Procedures: We identified 37 published studies containing data on over 31,000 individuals from more than >10,000 families and obtained genome-wide logarithm of the odds (LOD) scores, non-parametric linkage (NPL) scores, or maximum likelihood scores (MLS). BMI was analyzed in a pooled set of all studies, as a subgroup of 10 studies that used BMI-defined obesity, and for subgroups ascertained through type 2 diabetes, hypertension, or subjects of European ancestry.

Results: Bins at chromosome 13q13.2- q33.1, 12q23-q24.3 achieved suggestive evidence of linkage to BMI in the pooled analysis and samples ascertained for hypertension. Nominal evidence of linkage to these regions and suggestive evidence for 11q13.3-22.3 were also observed for BMI-defined obesity. The FTO obesity gene locus at 16q12.2 also showed nominal evidence for linkage. However, overall distribution of summed rank p values <0.05 is not different from that expected by chance. The strongest evidence was obtained in the families ascertained for hypertension at 9q31.1-qter and 12p11.21-q23 (p < 0.01).

Conclusion: Despite having substantial statistical power, we did not unequivocally implicate specific loci for BMI or obesity. This may be because genes influencing adiposity are of very small effect, with substantial genetic heterogeneity and variable dependence on environmental factors. However, the observation that the FTO gene maps to one of the highest ranking bins for obesity is interesting and, while not a validation of this approach, indicates that other potential loci identified in this study should be investigated further.