title: Sequence variation in TMEM18 in association with body mass index: Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study.
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.
  
  
  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=3.46×10(-4)) using a Bonferroni threshold of P<4.6×10(-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=2.11×10(-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.
authors.forename: Ching-Ti
authors.initials: CT
authors.lastname: Liu
authors.forename: Kristin L
authors.initials: KL
authors.lastname: Young
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Brody
authors.forename: Matthias
authors.initials: M
authors.lastname: Olden
authors.forename: Mary K
authors.initials: MK
authors.lastname: Wojczynski
authors.forename: Nancy
authors.initials: N
authors.lastname: Heard-Costa
authors.forename: Guo
authors.initials: G
authors.lastname: Li
authors.forename: Alanna C
authors.initials: AC
authors.lastname: Morrison
authors.forename: Donna
authors.initials: D
authors.lastname: Muzny
authors.forename: Richard A
authors.initials: RA
authors.lastname: Gibbs
authors.forename: Jeffrey G
authors.initials: JG
authors.lastname: Reid
authors.forename: Yaming
authors.initials: Y
authors.lastname: Shao
authors.forename: Yanhua
authors.initials: Y
authors.lastname: Zhou
authors.forename: Eric
authors.initials: E
authors.lastname: Boerwinkle
authors.forename: Gerardo
authors.initials: G
authors.lastname: Heiss
authors.forename: Lynne
authors.initials: L
authors.lastname: Wagenknecht
authors.forename: Barbara
authors.initials: B
authors.lastname: McKnight
authors.forename: Ingrid B
authors.initials: IB
authors.lastname: Borecki
authors.forename: Caroline S
authors.initials: CS
authors.lastname: Fox
authors.forename: Kari E
authors.initials: KE
authors.lastname: North
authors.forename: L Adrienne
authors.initials: LA
authors.lastname: Cupples
mesh_terms: D000328:Adult; D000368:Aged; D000375:Aging / Q000235:genetics*; D015992:Body Mass Index; D015331:Cohort Studies; D005260:Female; D056726:Genetic Association Studies; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D023281:Genomics; D006331:Heart Diseases / Q000453:epidemiology / Q000235:genetics*; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA; D055815:Young Adult
chemical_list: D008565:Membrane Proteins; C530715:TMEM18 protein, human
keywords: body mass index; genetic association studies