Association of FTO variants with BMI and fat mass in the self-contained population of Sorbs in Germany

Tönjes, Anke; Zeggini, Eleftheria; Kovacs, Peter; Böttcher, Yvonne; Schleinitz, Dorit; Dietrich, Katharina; Morris, Andrew P.; Enigk, Beate; Rayner, Nigel W.; Koriath, Moritz; Eszlinger, Markus; Kemppinen, Anu; Prokopenko, Inga; Hoffmann, Katrin; Teupser, Daniel; Thiery, Joachim; Krohn, Knut; McCarthy, Mark I.; Stümvoll, Michael

doi:10.1038/ejhg.2009.107

Cited by 76 publications

(84 citation statements)

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“…Recently, the Sorbs have been successfully utilized in candidate gene and genome-wide association studies of height and metabolic syndrome traits. [13][14][15][16][17] Although these studies are suggestive of the power of using the Sorbs for mapping, they do not make clear the extent to which Sorbs are a genetic isolate.…”

Section: Introductionmentioning

confidence: 95%

Genetic variation in the Sorbs of eastern Germany in the context of broader European genetic diversity

et al. 2011

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Population isolates have long been of interest to genetic epidemiologists because of their potential to increase power to detect disease-causing genetic variants. The Sorbs of Germany are considered as cultural and linguistic isolates and have recently been the focus of disease association mapping efforts. They are thought to have settled in their present location in eastern Germany after a westward migration from a largely Slavic-speaking territory during the Middle Ages. To examine Sorbian genetic diversity within the context of other European populations, we analyzed genotype data for over 30 000 autosomal single-nucleotide polymorphisms from over 200 Sorbs individuals. We compare the Sorbs with other European individuals, including samples from population isolates. Despite their geographical proximity to German speakers, the Sorbs showed greatest genetic similarity to Polish and Czech individuals, consistent with the linguistic proximity of Sorbian to other West Slavic languages. The Sorbs also showed evidence of subtle levels of genetic isolation in comparison with samples from non-isolated European populations. The level of genetic isolation was less than that observed for the Sardinians and French Basque, who were clear outliers on multiple measures of isolation. The finding of the Sorbs as only a minor genetic isolate demonstrates the need to genetically characterize putative population isolates, as they possess a wide range of levels of isolation because of their different demographic histories.

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Section: Introductionmentioning

confidence: 95%

Genetic variation in the Sorbs of eastern Germany in the context of broader European genetic diversity

et al. 2011

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“…13,14 The Sorbs are of Slavonic origin, and during the past 1100 years, they lived as a well-defined ethnic minority among the Germanic majority. At present, 1052 Sorbs are enrolled in the study.…”

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confidence: 99%

“…The SNP genotypes were filtered from the previously generated 500K Affymetrix GeneChip and the Affymetrix Genome-Wide Human SNP Array 6.0 (Affymetrix Inc.) data set in the Sorbs. 13,14 Statistical analysis PASW software version 18.0.1 (SPSS, Chicago, IL, USA) was used in all statistical analyses. Before statistical analysis, nonnormally distributed parameters were logarithmically transformed to approximate a normal distribution.…”

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confidence: 99%

Metabolic and genetic predictors of circulating adipocyte fatty acid-binding protein

et al. 2011

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Background: Adipocyte fatty acid-binding protein (AFABP) was recently introduced as a novel adipokine playing an important role in glucose homeostasis. In this study, we investigated the relationship between serum AFABP levels and metabolic, as well as cardiovascular parameters, in the self-contained population of Sorbs. Furthermore, we conducted a genome-wide association study on serum AFABP concentrations in the Sorbs and we separately analyzed the effects of two common variants in the FABP4 gene on AFABP serum concentration. Methods: Serum AFABP concentrations were quantified by enzyme-linked immunosorbent assay and correlated with metabolic and cardiovascular parameters, as well as inflammatory markers and renal function, in 868 well-characterized non-diabetic Sorbs from Germany. Results: Median AFABP serum concentrations were 1.5-fold higher in female subjects (23.03 mg l À1 ) as compared to male subjects (15.86 mg l À1 ). Waist-to-height ratio and glomerular filtration rate were independently associated with AFABP concentrations in multiple regression analysis in both female and male subjects. The genome-wide scan for association of single-nucleotide polymorphisms with serum AFABP levels in the Sorbs revealed 39 loci reaching P-values o10 À4 . Two single-nucleotide polymorphisms, rs16909187 and rs10808846, representing common genetic variation in FABP4 did not show any effect on serum AFABP concentrations in our study cohort. Conclusion: AFABP serum concentrations are determined by parameters of fat distribution, renal function and gender.

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“…2 To test the SNP in a population closely related to the Sorbs, the authors genotyped this polymorphism in a Czech-Slavonic population. They failed to replicate the initial association and postulated that gene-gene and/or gene-environmental interactions might explain variability in the exact role of this variant in the pathogenesis of obesity in different populations.…”

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“…These analyses show signatures of recent selection at the FTO locus in human populations, 7 and the strongest signal is observed in the third intron, the region in which the strong association with BMI in the Sorbs was recently described. 2 Resequencing studies will be required to further elucidate the functional variants behind the association signals.…”

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Reply to Dlouha et al

Tönjes

Kovacs²,

Elliott

et al. 2010

Eur J Hum Genet

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We appreciate the opportunity to reply to the letter by Dlouha et al, 1 who have attempted to replicate the association of the FTO variant rs17818902 with obesity that we have recently identified in a selfcontained population of Sorbs from Germany. 2 To test the SNP in a population closely related to the Sorbs, the authors genotyped this polymorphism in a Czech-Slavonic population. They failed to replicate the initial association and postulated that gene-gene and/or gene-environmental interactions might explain variability in the exact role of this variant in the pathogenesis of obesity in different populations.We agree that a different definition of the investigated phenotype (BMI) is unlikely to explain the observed discrepancy between Czechs and Sorbs. Even though no major differences in genetic background between two neighbouring middle-European Slavonic populations can be assumed, 3 recent studies provide strong evidence that population structure represents a well-recognized challenge for disease-association studies, and that spurious associations can arise if genetic structure is not adequately accounted for. 4 So far, there is no straightforward explanation for different effect sizes, or even effect directions, of recently identified susceptibility loci in diverse populations (also if ethnic background is comparable). Even if the combined effect in a meta-analysis strongly supports a genetic association the variant does not show replicable effects in all investigated samples. This cannot be explained exclusively by sample size, allele frequencies or phenotypic distribution.As geographic origin of a sample has to be considered when evaluating genome-wide association studies among Europeans, 4 the same may be true when attempting to replicate initial association findings. Using principal component analysis we are currently evaluating the genetic variation between Slavonic populations (Sorbs, Czechs, and Poles) and Germans. Our preliminary data indicate that the Sorbs were most closely related to the Poles, but measures such as Fst are summaries and do not necessarily capture all kinds of changes in a certain genetic region.When we investigated the proportion of individuals with at least one other individual IBS at all SNPs across random genomic regions (methods based on Kong et al 5 ), we found that IBS sharing in the Sorbs was much greater compared with that in outbred populations, such as the controls from the WTCCC. 6 The proportions of subjects who have at least one other individual with IBSX1 at all SNPs across the chromosome 15-long and MHC region were 29.3 and 40.7%, respectively, in the Sorbs compared with 0.8 and 10.2%, respectively, in the WTCCC sample set.We would not necessarily expect to see association at exactly the same SNP because of possible allelic heterogeneity. Moreover, linkage disequilibrium patterns are also likely to be different and, although we cannot provide a definitive explanation for the discrepancies observed, we believe that a unique population history of the Sorbs may contr...

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Association of FTO variants with BMI and fat mass in the self-contained population of Sorbs in Germany

Cited by 76 publications

References 38 publications

Genetic variation in the Sorbs of eastern Germany in the context of broader European genetic diversity

Genetic variation in the Sorbs of eastern Germany in the context of broader European genetic diversity

Metabolic and genetic predictors of circulating adipocyte fatty acid-binding protein

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