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.

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=3.46×10(-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.

Keywords: body mass index; genetic association studies.

Figure 1

Description of Variants Found in TMEM18 Region. There are 2180 variants (288 common variants) in total found in chr2:586432-677539 region. The classification of these variants includes 1891 variants annotated as intergenic, 164 intronic, 33 upstream, 25 downstream, 46 UTR3, 5 UTR5, 9 exonic nonsynonymous, 6 exonic synonymous, and 1 splicing. The figure shows the percent of variants within each category stratified by the allele frequency (rare/common variant). In addition, among 2180 variants, 405 (35 common) are in the transcriptional region.

Figure 2

Regional Association Plot for the Single Variant Analysis. The most significant variant rs7596758 among a cluster of variants which are more significant than the GIANT Hit (rs6548238 and rs2867125 with nominally significant p<0.05) is significant after adjusting for multiple testing. SNP rs186019316 is not significant with p = 4.94E-4 in the single variant analysis but is significant in the analysis conditioning on rs6548238 and rs2867125, respectively.