To identify genetic loci influencing central obesity and fat distribution, we performed a meta-analysis of 16 genome-wide association studies (GWAS, N = 38,580) informative for adult waist circumference (WC) and waist–hip ratio (WHR). We selected 26 SNPs for follow-up, for which the evidence of association with measures of central adiposity (WC and/or WHR) was strong and disproportionate to that for overall adiposity or height. Follow-up studies in a maximum of 70,689 individuals identified two loci strongly associated with measures of central adiposity; these map near TFAP2B (WC, P = 1.9×10−11) and MSRA (WC, P = 8.9×10−9). A third locus, near LYPLAL1, was associated with WHR in women only (P = 2.6×10−8). The variants near TFAP2B appear to influence central adiposity through an effect on overall obesity/fat-mass, whereas LYPLAL1 displays a strong female-only association with fat distribution. By focusing on anthropometric measures of central obesity and fat distribution, we have identified three loci implicated in the regulation of human adiposity.

Serum uric acid concentrations are correlated with gout and clinical entities such as cardiovascular disease and diabetes. In the genome-wide association study KORA (Kooperative Gesundheitsforschung in der Region Augsburg) F3 500K (n = 1,644), the most significant SNPs associated with uric acid concentrations mapped within introns 4 and 6 of SLC2A9, a gene encoding a putative hexose transporter (effects: -0.23 to -0.36 mg/dl per copy of the minor allele). We replicated these findings in three independent samples from Germany (KORA S4 and SHIP (Study of Health in Pomerania)) and Austria (SAPHIR; Salzburg Atherosclerosis Prevention Program in Subjects at High Individual Risk), with P values ranging from 1.2 x 10(-8) to 1.0 x 10(-32). Analysis of whole blood RNA expression profiles from a KORA F3 500K subgroup (n = 117) showed a significant association between the SLC2A9 isoform 2 and urate concentrations. The SLC2A9 genotypes also showed significant association with self-reported gout. The proportion of the variance of serum uric acid concentrations explained by genotypes was about 1.2% in men and 6% in women, and the percentage accounted for by expression levels was 3.5% in men and 15% in women.

Many "complex" human diseases, which involve multiple genetic and environmental determinants, have increased in incidence during the past 2 decades. During the same time period, considerable effort and expense have been expended in whole-genome screens aimed at detection of genetic loci contributing to the susceptibility to complex human diseases. However, the success of positional cloning attempts based on whole-genome screens has been limited, and many of the fundamental questions relating to the genetic epidemiology of complex human disease remain unanswered. Both to review the success of the positional cloning paradigm as applied to complex human disease and to investigate the characteristics of the whole-genome scans undertaken to date, we created a database of 101 studies of complex human disease, which were found by a systematic Medline search (current as of December 2000). We compared these studies, concerning 31 different human complex diseases, with regard to design, methods, and results. The "significance" categorizations proposed by Lander and Kruglyak were used as criteria for the "success" of a study. Most (66.3% [n=67]) of the studies did not show "significant" linkage when the criteria of Lander and Kruglyak (1995) were used, and the results of studies of the same disease were often inconsistent. Our analyses suggest that no single study design consistently produces more-significant results. Multivariate analysis suggests that the only factors independently associated with increased study success are (a) an increase in the number of individuals studied and (b) study of a sample drawn from only one ethnic group. Positional cloning based on whole-genome screens in complex human disease has proved more difficult than originally had been envisioned; detection of linkage and positional cloning of specific disease-susceptibility loci remains elusive.

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Results confirm previous observations of a significant association between the CMA1 promoter polymorphism rs1800875 and atopic eczema, but not with serum IgE levels, and support the hypothesis that CMA1 serves as candidate gene for atopic eczema.

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Previously, estimation of genotype misclassification of single nucleotide polymorphisms (SNPs) as encountered in epidemiologic practice and involving thousands of subjects was lacking. The authors collected representative data on approximately 14,000 subjects from 8 studies and 646,558 genotypes assessed in 2005 by means of matrix-assisted laser desorption ionization time-of-flight mass spectrometry. Overall discordance among 57,805 double genotypes from routine quality control was 0.36%. Fitting different misclassification models by maximum likelihood assuming identical misclassification for all SNPs, the estimated misclassification probabilities ranged from 0.0000 to 0.0035. When applying the misclassification simulation and extrapolation (MC-SIMEX) method for the first time to genetic data to account for the misclassification in a reanalysis of adiponectin-encoding (APM1) gene SNP associations with plasma adiponectin in 1,770 subjects, the authors found no impact of this small error on association estimates but increased estimates for a more substantial error. This study is the first to provide large-scale epidemiologic data on SNP genotype misclassification. The estimated misclassification in this example was small and negligible for association estimates, which is reassuring and essential for detecting SNP associations. In situations with more substantial error, the presented approach using duplicate genotyping and the MC-SIMEX method is practical and helpful for quantifying the genotyping error and its impact.