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Sequence Variation in TMEM18 in Association with Body Mass Index: Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study

Citation

Liu, Ching-Ti; Young, Kristin L.; Brody, Jennifer A.; Olden, Matthias; Wojczynski, Mary K.; Heard-Costa, Nancy L.; Li, Guo; Morrison, Alanna C.; Muzny, Donna; & Gibbs, Richard A., et al. (2014). Sequence Variation in TMEM18 in Association with Body Mass Index: Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study. Circulation: Cardiovascular Genetics, 7(3), 344-349. PMCID: PMC4135723

Abstract

BACKGROUND: Genome-wide association studies for body mass index (BMI) previously identified a locus near TMEM18. We conducted targeted sequencing of this region to investigate the role of common, low-frequency, and rare variants influencing BMI.
METHODS AND RESULTS: We sequenced TMEM18 and regions downstream of TMEM18 on chromosome 2 in 3976 individuals of European ancestry from 3 community-based cohorts (Atherosclerosis Risk in Communities, Cardiovascular Health Study, and Framingham Heart Study), including 200 adults selected for high BMI. We examined the association between BMI and variants identified in the region from nucleotide position 586 432 to 677 539 (hg18). Rare variants (minor allele frequency, <1%) were analyzed using a burden test and the sequence kernel association test. Results from the 3 cohort studies were meta-analyzed. We estimate that mean BMI is 0.43 kg/m(2) higher for each copy of the G allele of single-nucleotide polymorphism rs7596758 (minor allele frequency, 29%; P=3.46x10(-4)) using a Bonferroni threshold of P<4.6x10(-4). Analyses conditional on previous genome-wide association study single-nucleotide polymorphisms associated with BMI in the region led to attenuation of this signal and uncovered another independent (r(2)<0.2), statistically significant association, rs186019316 (P=2.11x10(-4)). Both rs186019316 and rs7596758 or proxies are located in transcription factor binding regions. No significant association with rare variants was found in either the exons of TMEM18 or the 3' genome-wide association study region.
CONCLUSIONS: Targeted sequencing around TMEM18 identified 2 novel BMI variants with possible regulatory function.

URL

http://dx.doi.org/10.1161/CIRCGENETICS.13.000067

Reference Type

Journal Article

Year Published

2014

Journal Title

Circulation: Cardiovascular Genetics

Author(s)

Liu, Ching-Ti
Young, Kristin L.
Brody, Jennifer A.
Olden, Matthias
Wojczynski, Mary K.
Heard-Costa, Nancy L.
Li, Guo
Morrison, Alanna C.
Muzny, Donna
Gibbs, Richard A.
Reid, Jeffrey G.
Shao, Yaming
Zhou, Yanhua
Boerwinkle, Eric A.
Heiss, Gerardo M.
Wagenknecht, Lynne E.
McKnight, Barbara
Borecki, Ingrid B.
Fox, Caroline S.
North, Kari E.
Cupples, L. Adrienne

PMCID

PMC4135723