Genetics, Vol. 159, 1163-1178, November 2001, Copyright © 2001

Pooling Analysis of Genetic Data: The Association of Leptin Receptor (LEPR) Polymorphisms With Variables Related to Human Adiposity

M. Heoa, R. L. Leibelb, B. B. Boyerc, W. K. Chungb, M. Koulud, M. K. Karvonend, U. Pesonend, A. Rissanene, M. Laaksof, M. I. J. Uusitupaf, Y. Chagnong, C. Bouchardh, P. A. Donohouei, T. L. Burnsj, A. R. Shuldinerk, K. Silverk, R. E. Andersenl, O. Pedersenl, S. Echwaldm, T. I. A. Sørensenn, P. Behno, M. A. Permuttp, K. B. Jacobsq, R. C. Elstonq, D. J. Hoffmana, and D. B. Allisonr
a New York Obesity Research Center, Columbia University College of Physicians and Surgeons, New York, New York 10025,
b Department of Pediatrics, Columbia University College of Physicians and Surgeons, New York, New York 10032,
c Department of Molecular Biology, University of Alaska, Fairbanks, Alaska 99775,
d Department of Pharmacology and Clinical Pharmacology, University of Turku, 20520 Turku, Finland,
e Eating Disorder Unit, University of Helsinki, 00014 Helsinki, Finland,
f Department of Medicine, University of Kuopio, 70210 Kuopio, Finland,
g Kinesiologie, Physical Activity Sciences Lab, Laval University, Ste-Foy, Quebec G1K7P4, Canada,
h Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, Louisiana 70808,
i Department of Pediatrics, University of Iowa College of Medicine, Iowa City, Iowa 52242,
j Department of Preventive Medicine, University of Iowa College of Public Health, Iowa City, Iowa 52242,
k Division of Endocrinology, University of Maryland, Baltimore, Maryland 21224,
l Department of Geriatrics, Johns Hopkins University, Baltimore, Maryland 21224,
m Steno Diabetes Center, Hagedorn Research Institute, DK-2820 Gentofte, Denmark,
n Danish Epidemiology Science Center, Institute of Preventive Medicine, Copenhagen 1399, Denmark,
o Internal Medicine Associates, Bloomington, Indiana 47403,
p Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri 63110,
q Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio 44109
r Department of Biostatistics, University of Alabama, Birmingham, Alabama 35294-0022

Corresponding author: D. B. Allison, Department of Biostatistics, School of Public Health, University of Alabama, RPHB 327M, 1530 Third Ave. S., Birmingham, AL 35294-0022., dallison{at}ms.soph.uab.edu (E-mail)

Communicating editor: C. HALEY

Analysis of raw pooled data from distinct studies of a single question generates a single statistical conclusion with greater power and precision than conventional metaanalysis based on within-study estimates. However, conducting analyses with pooled genetic data, in particular, is a daunting task that raises important statistical issues. In the process of analyzing data pooled from nine studies on the human leptin receptor (LEPR) gene for the association of three alleles (K109R, Q223R, and K656N) of LEPR with body mass index (BMI; kilograms divided by the square of the height in meters) and waist circumference (WC), we encountered the following methodological challenges: data on relatives, missing data, multivariate analysis, multiallele analysis at multiple loci, heterogeneity, and epistasis. We propose herein statistical methods and procedures to deal with such issues. With a total of 3263 related and unrelated subjects from diverse ethnic backgrounds such as African-American, Caucasian, Danish, Finnish, French-Canadian, and Nigerian, we tested effects of individual alleles; joint effects of alleles at multiple loci; epistatic effects among alleles at different loci; effect modification by age, sex, diabetes, and ethnicity; and pleiotropic genotype effects on BMI and WC. The statistical methodologies were applied, before and after multiple imputation of missing observations, to pooled data as well as to individual data sets for estimates from each study, the latter leading to a metaanalysis. The results from the metaanalysis and the pooling analysis showed that none of the effects were significant at the 0.05 level of significance. Heterogeneity tests showed that the variations of the nonsignificant effects are within the range of sampling variation. Although certain genotypic effects could be population specific, there was no statistically compelling evidence that any of the three LEPR alleles is associated with BMI or waist circumference in the general population.




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