Further Evidence for a QTL Influencing Body Mass Index on Chromosome 7p from a Genome-wide Scan in Dutch Families

SummaryThrombosis and obesity are complex epidemiologically associated diseases. The mechanism of this association is not yet understood. It was the objective of this study to identify genetic components of body mass index (BMI) and their possible role in the risk of thromboembolic disease. With the self-reported BMI of 397 individuals from 21 extended families enrolled in the GAIT (Genetic Analysis of Idiopathic Thrombophilia) Project, we estimated the heritability of BMI and the genetic correlation with the risk of thrombosis. Subjects were genotyped for an autosomal genome-wide scan with 363 highly-informative DNA markers. Univariate and bivariate multipoint linkage analyses were performed. The heritability for BMI was 0.31 (p= 2.9×10–5). Thromboembolic disease (including venous and arterial) and BMI had a significant genetic correlation (ρG= 0.54, p= 0.005). Two linkage signals for BMI were obtained, one at 13q34 (LOD= 3.36, p= 0.0004) and other at 2q34, highly suggestive of linkage (LOD= 1.95). Bivariate linkage analysis with BMI and thrombosis risk also showed a significant signal at 13q34 (LOD= 3), indicating that this locus influences at the same time normal variation in the BMI phenotype as well as susceptibility to thrombosis. In conclusion, BMI and thrombosis are genetically correlated. The locus 13q34, which showed pleiotropy with both phenotypes, contains two candidate genes, which may explain our linkage pleiotropic signal and deserve further investigation as possible risk factors for obesity and thrombosis.

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Genome-Wide Scan of Obesity in Finnish Sibpairs Reveals Linkage to Chromosome Xq24*

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jcem.85.9.6797 ◽

2000 ◽

Vol 85 (9) ◽

pp. 3183-3190 ◽

Cited By ~ 1

Author(s):

Miina Öhman ◽

Laura Oksanen ◽

Jaakko Kaprio ◽

Markku Koskenvuo ◽

Pertti Mustajoki ◽

...

Keyword(s):

Body Mass Index ◽

Body Mass ◽

Chromosomal Region ◽

Adult Population ◽

Average Density ◽

Model Free ◽

Melanocortin 4 Receptor ◽

Genome Wide ◽

Sample Set ◽

Genome Wide Scan

Abstract Obesity is a multifactorial trait with evidence of a genetic component. Obesity is very common in all westernized countries, including Finland, where 10% of the adult population has a body mass index of 32 kg/m2 or more. Here we report results from a three-stage genome-wide scan of obesity in 188 affected subjects (body mass index,≥ 32 kg/m2) from 87 Finnish families. Initially, 374 markers with an average density of 10 centimorgans were genotyped. The strongest evidence for linkage to obesity was detected on chromosome Xq24, with the marker DXS6804 providing a maximum likelihood score (MLS) 3.14 in a model-free 2-point sibpair analysis. Fine-mapping in an extended sample set of 367 affected subjects from 166 families yielded a multipoint MLS of 3.48 over this X-chromosomal region. The Xq24 region contains a plausible candidate gene, serotonin 2C receptor, variants of which have been shown to predispose to obesity and type II diabetes in mice. Another chromosomal region also provided suggestive evidence of linkage, an area on 18q21, flanking the melanocortin-4 receptor, where a 2-point MLS of 2.42 with marker D18S1155 was obtained with a set of 367 affected subjects. In conclusion, our results in this Finnish study sample suggest that a locus on chromosome Xq24 influences the risk of obesity.

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A genome-wide association study of body mass index across early life and childhood

International Journal of Epidemiology ◽

10.1093/ije/dyv077 ◽

2015 ◽

Vol 44 (2) ◽

pp. 700-712 ◽

Cited By ~ 70

Author(s):

N. M. Warrington ◽

L. D. Howe ◽

L. Paternoster ◽

M. Kaakinen ◽

S. Herrala ◽

...

Keyword(s):

Body Mass Index ◽

Association Study ◽

Body Mass ◽

Early Life ◽

Genome Wide Association Study ◽

Genome Wide Association ◽

Genome Wide ◽

A Genome

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TCF7L2 lncRNA: a link between bipolar disorder and body mass index through glucocorticoid signaling

Molecular Psychiatry ◽

10.1038/s41380-021-01274-z ◽

2021 ◽

Author(s):

Duan Liu ◽

Thanh Thanh Le Nguyen ◽

Huanyao Gao ◽

Huaizhi Huang ◽

Daniel C. Kim ◽

...

Keyword(s):

Body Mass Index ◽

Bipolar Disorder ◽

Body Mass ◽

Genome Wide Association Study ◽

Induced Pluripotent Stem Cell ◽

Sequencing Data ◽

Peripheral Tissues ◽

Genome Wide ◽

A Genome ◽

Trait Locus

AbstractBipolar disorder (BD) and obesity are highly comorbid. We previously performed a genome-wide association study (GWAS) for BD risk accounting for the effect of body mass index (BMI), which identified a genome-wide significant single-nucleotide polymorphism (SNP) in the gene encoding the transcription factor 7 like 2 (TCF7L2). However, the molecular function of TCF7L2 in the central nervous system (CNS) and its possible role in the BD and BMI interaction remained unclear. In the present study, we demonstrated by studying human induced pluripotent stem cell (hiPSC)-derived astrocytes, cells that highly express TCF7L2 in the CNS, that the BD-BMI GWAS risk SNP is associated with glucocorticoid-dependent repression of the expression of a previously uncharacterized TCF7L2 transcript variant. That transcript is a long non-coding RNA (lncRNA-TCF7L2) that is highly expressed in the CNS but not in peripheral tissues such as the liver and pancreas that are involved in metabolism. In astrocytes, knockdown of the lncRNA-TCF7L2 resulted in decreased expression of the parent gene, TCF7L2, as well as alterations in the expression of a series of genes involved in insulin signaling and diabetes. We also studied the function of TCF7L2 in hiPSC-derived astrocytes by integrating RNA sequencing data after TCF7L2 knockdown with TCF7L2 chromatin-immunoprecipitation sequencing (ChIP-seq) data. Those studies showed that TCF7L2 directly regulated a series of BD risk genes. In summary, these results support the existence of a CNS-based mechanism underlying BD-BMI genetic risk, a mechanism based on a glucocorticoid-dependent expression quantitative trait locus that regulates the expression of a novel TCF7L2 non-coding transcript.

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rs11670527 Upstream of ZNF264 Associated with Body Mass Index in the Coriell Personalized Medicine Collaborative

Military Medicine ◽

10.1093/milmed/usz216 ◽

2019 ◽

Vol 185 (Supplement_1) ◽

pp. 649-655

Author(s):

Dara M Kusic ◽

Wendy N Roberts ◽

Joseph P Jarvis ◽

Pan Zhang ◽

Laura B Scheinfeldt ◽

...

Keyword(s):

Body Mass Index ◽

Personalized Medicine ◽

Body Mass ◽

P Value ◽

Healthy Weight ◽

Military Health ◽

Complex Genetics ◽

Genome Wide ◽

A Genome ◽

The Military

Abstract Introduction: the effects of obesity on health are a concern for the military as they affect the fitness to serve of active service members, increase costs to the Military Health System, and reduce quality of life for veterans and beneficiaries. Although obesity can be influenced by behavioral and environmental factors, it has also been shown to be associated with genetic risk factors that are not fully understood. Materials and Methods: we performed a genome-wide association study of 5,251 participants in the Coriell Personalized Medicine Collaborative, which includes 2,111 Air Force participants. We applied a generalized linear model, using principal component analysis to account for population structure, and analyzed single-variant associations with body mass index (BMI) as a continuous variable, using a Bonferroni-corrected P-value threshold to account for multiplicity. Results: we identified one genome-wide significant locus, rs11670527, upstream of the ZNF264 gene on chromosome 19, associated with BMI. Conclusions: the finding of an association between rs11670527 and BMI adds to the growing body of literature characterizing the complex genetics of obesity. These efforts may eventually inform personalized interventions aimed at achieving and maintaining healthy weight.

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