An affected pedigree member analysis of linkage between the dopamine D2 receptor gene TaqI polymorphism and obesity and hypertension

Yu, Fang; Thomas, G. Neil; Xu, Zongli; Fang, Jian; Critchley, J. A. J. H.; Tomlinson, Brian

doi:10.1016/j.ijcard.2004.05.010

Cited by 33 publications

(23 citation statements)

References 28 publications

(38 reference statements)

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“…This is consistent with genetic studies, which have specifically implicated the D2 receptor gene (TAQ-IA polymorphism), as one that is involved in vulnerability to obesity (Fang et al, 2005;Pohjalainen et al, 1998;Bowirrat and Oscar-Berman, 2005). Moreover, the TAQ-IA polymorphism, which appears to result in lower D2 receptor levels in brain (striatum) (Ritchie and Noble, 2003;Pohjalainen et al, 1998; Jonsson et al, 1999) was recently found to be associated with decreased ability to inhibit behaviors that result in negative consequences and with impaired activation of prefrontal regions (Klein et al, 2007).…”

Section: Association Between D2 Receptors and Prefrontal Metabolismsupporting

confidence: 90%

Low dopamine striatal D2 receptors are associated with prefrontal metabolism in obese subjects: Possible contributing factors

et al. 2008

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Dopamine's role in inhibitory control is well recognized and its disruption may contribute to behavioral disorders of discontrol such as obesity. However, the mechanism by which impaired dopamine neurotransmission interferes with inhibitory control is poorly understood. We had previously documented a reduction in dopamine D2 receptors in morbidly obese subjects. To assess if the reductions in dopamine D2 receptors were associated with activity in prefrontal brain regions implicated in inhibitory control we assessed the relationship between dopamine D2 receptor availability in striatum with brain glucose metabolism (marker of brain function) in ten morbidly obese subjects (BMI>40 kg/m 2 ) and compared it to that in twelve non-obese controls. PET was used with [ 11 C]raclopride to assess D2 receptors and with [ 18 F] FDG to assess regional brain glucose metabolism. In obese subjects striatal D2 receptor availability was lower than controls and was positively correlated with metabolism in dorsolateral prefrontal, medial orbitofrontal, anterior cingulate gyrus and somatosensory cortices. In controls correlations with prefrontal metabolism were not significant but comparisons with those in obese subjects were not significant, which does not permit to ascribe the associations as unique to obesity. The associations between striatal D2 receptors and prefrontal metabolism in obese subjects suggest that decreases in striatal D2 receptors could contribute to overeating via their modulation of striatal prefrontal pathways, which participate in inhibitory control and salience attribution. The association between striatal D2 receptors and metabolism in somatosensory cortices (regions that process palatability) could underlie one of the mechanisms through which dopamine regulates the reinforcing properties of food. KeywordsOrbitofrontal cortex; Cingulate gyrus; Dorsolateral prefrontal; Dopamine transporters; Raclopride, PET The increase in obesity and associated metabolic diseases seen over the past decade has raised concern that if not controlled this may become the number one preventable public health threat for the 21st century (Sturm, 2002 (Berthoud, 2007). The extent to which individuals differ in their ability to inhibit these responses and control how much they eat is likely to modulate their risk for overeating in our current food rich environments (Berthoud, 2007).We had shown that in healthy individuals D2 receptor availability in the striatum modulated eating behavioral patterns (Volkow et al., 2003). Specifically the tendency to eat when exposed to negative emotions was negatively correlated with D2 receptor availability (the lower the D2 receptors the higher the likelihood that an individual would eat if emotionally stressed). In addition, in a different study, we showed that morbidly obese subjects (BMI>40) had lower than normal D2 receptor availability and these reductions were proportional to their BMI (Wang et al., 2001). These findings led us to postulate that low D2 receptor availability could put an...

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Section: Association Between D2 Receptors and Prefrontal Metabolismsupporting

confidence: 90%

Low dopamine striatal D2 receptors are associated with prefrontal metabolism in obese subjects: Possible contributing factors

et al. 2008

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“…This implies that the ancestral forms of the two sites (A1 and B2) are present at high frequencies in African populations, whereas in rest of the world, as supported by the presently studied populations, the ancestral A1 allele is present at low frequency, pushing the A2 allele to a higher frequency that is similar to that of the B2 allele. A1 has a selective disadvantage because of its clinical association with addictive disorders like alcoholism and hypertension (Blum et al, 1991;Noble, 2003;Fang et al, 2005) and, as such, its frequency has been reduced in many populations of world, including India. As the TaqIA site is in linkage disequilibrium with the TaqIB site in most populations studied, the variation in B2 frequencies is related to the A2 allele.…”

Section: Discussionmentioning

confidence: 99%

Brief communication: Allelic and haplotypic structure at the DRD2 locus among five North Indian caste populations

Saraswathy

Meitei

Gupta³

et al. 2010

American J Phys Anthropol

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The dopamine D2 receptor (DRD2) gene, with its known human-specific derived alleles that can facilitate haplotype reconstruction, presents an important locus for anthropological studies. The three sites (TaqIA, TaqIB, and TaqID) of the DRD2 gene are widely studied in various world populations. However, no work has been previously published on DRD2 gene polymorphisms among North Indian populations. Thus, the present study attempts to understand the genetic structure of North Indian upper caste populations using the allele and haplotype frequencies and distribution patterns of the three TaqI sites of the DRD2 gene. Two hundred forty-six blood samples were collected from five upper caste populations of Himachal Pradesh (Brahmin, Rajput and Jat) and Delhi (Aggarwal and Sindhi), and analysis was performed using standard protocols. All three sites were found to be polymorphic in all five of the studied populations. Uniform allele frequency distribution patterns, low heterozygosity values, the sharing of five common haplotypes, and the absence of two of the eight possible haplotypes observed in this study suggest a genetic proximity among the selected populations. The results also indicate a major genetic contribution from Eurasia to North Indian upper castes, apart from the common genetic unity of Indian populations. The study also demonstrates a greater genetic inflow among North Indian caste populations than is observed among South Indian caste and tribal populations.

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“…Several of the GPCRs in the cluster are related to obesity traits in mice when mutated or overexpressed [33–36], and others have been proposed as candidate genes for human obesity [37–39] (Figure S3A). An additional subset of the GPCR cluster represents GABA receptor subunits (Figure S3B).…”

Section: Discussionmentioning

confidence: 99%

Combined Expression Trait Correlations and Expression Quantitative Trait Locus Mapping

et al. 2006

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Coordinated regulation of gene expression levels across a series of experimental conditions provides valuable information about the functions of correlated transcripts. The consideration of gene expression correlation over a time or tissue dimension has proved valuable in predicting gene function. Here, we consider correlations over a genetic dimension. In addition to identifying coregulated genes, the genetic dimension also supplies us with information about the genomic locations of putative regulatory loci. We calculated correlations among approximately 45,000 expression traits derived from 60 individuals in an F2 sample segregating for obesity and diabetes. By combining the correlation results with linkage mapping information, we were able to identify regulatory networks, make functional predictions for uncharacterized genes, and characterize novel members of known pathways. We found evidence of coordinate regulation of 174 G protein–coupled receptor protein signaling pathway expression traits. Of the 174 traits, 50 had their major LOD peak within 10 cM of a locus on Chromosome 2, and 81 others had a secondary peak in this region. We also characterized a Riken cDNA clone that showed strong correlation with stearoyl-CoA desaturase 1 expression. Experimental validation confirmed that this clone is involved in the regulation of lipid metabolism. We conclude that trait correlation combined with linkage mapping can reveal regulatory networks that would otherwise be missed if we studied only mRNA traits with statistically significant linkages in this small cross. The combined analysis is more sensitive compared with linkage mapping alone.

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An affected pedigree member analysis of linkage between the dopamine D2 receptor gene TaqI polymorphism and obesity and hypertension

Abstract: Our data in normoglycaemic Hong Kong Chinese supports that the DD2R gene TaqI polymorphism is a marker associated with the pathogenesis of obesity and hypertension.

Cited by 33 publications

References 28 publications

Low dopamine striatal D2 receptors are associated with prefrontal metabolism in obese subjects: Possible contributing factors

Low dopamine striatal D2 receptors are associated with prefrontal metabolism in obese subjects: Possible contributing factors

Brief communication: Allelic and haplotypic structure at the DRD2 locus among five North Indian caste populations

Combined Expression Trait Correlations and Expression Quantitative Trait Locus Mapping

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