Human Genetics

, Volume 117, Issue 6, pp 545–557 | Cite as

Complex HTR2C linkage disequilibrium and promoter associations with body mass index and serum leptin

  • Shane McCarthy
  • Salim Mottagui-Tabar
  • Yumi Mizuno
  • Bengt Sennblad
  • Johan Hoffstedt
  • Peter Arner
  • Claes Wahlestedt
  • Björn Andersson
Original Investigation

Abstract

The occurrence of obesity, eating disorders, and related diseases has increased in many parts of the world. Given that few strong genetic factors have been found, it is clear that these are complex multi-factorial diseases. The serotonin receptor 2C, a member of the 5-HTergic system, has been implicated in the control of phagia and obesity. We report a detailed investigation of linkage disequilibrium (LD) within and between the HTR2C promoter and the flanking sequences around a commonly utilized marker in the second coding exon of HTR2C. We suggest that inconsistent associations between HTR2C and several phenotypes, including obesity, may be due to the LD pattern across the gene in which recombination and gene conversion have been influential. The nucleotide and haplotype distribution is consistent with that of the neutral mutation model. The number of haplotypes suggests demographic influences or over dominant selection that may have a function in HTR2C expression. Using the fine LD pattern, we describe a possible association with promoter haplotypes and diplotypes, including a GT microsatellite, and body mass index (BMI) ≥30 kgm−2 (P<0.0001). SNP −995G>A heterozygotes, as well as promoter diplotypes, were found to marginally influence higher serum leptin corrected for percentage body fat (P=0.01), which might suggest that these subjects are leptin resistant. Our results complement previous studies of HTR2C in both mice and humans, and suggest the importance of genetic variation and elucidating the fine LD structure in uncovering the genetic factors of obesity.

Supplementary material

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Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • Shane McCarthy
    • 1
  • Salim Mottagui-Tabar
    • 1
  • Yumi Mizuno
    • 1
  • Bengt Sennblad
    • 1
    • 3
  • Johan Hoffstedt
    • 2
  • Peter Arner
    • 2
  • Claes Wahlestedt
    • 1
  • Björn Andersson
    • 1
  1. 1.Center for Genomics and BioinformaticsKarolinska InstitutetStockholmSweden
  2. 2.Department of MedicineKarolinska Instututet, Karolinska University Hospital at HuddingeStockholmSweden
  3. 3.Stockholm Bioinformatics CenterAlbaNova Stockholm UniversityStockholmSweden

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