Genome-wide association study of abdominal MRI-measured visceral fat: The multiethnic cohort adiposity phenotype study

Abstract

Few studies have explored the genetic underpinnings of intra-abdominal visceral fat deposition, which varies substantially by sex and race/ethnicity. Among 1,787 participants in the Multiethnic Cohort (MEC)-Adiposity Phenotype Study (MEC-APS), we conducted a genome-wide association study (GWAS) of the percent visceral adiposity tissue (VAT) area out of the overall abdominal area, averaged across L1-L5 (%VAT), measured by abdominal magnetic resonance imaging (MRI). A genome-wide significant signal was found on chromosome 2q14.3 in the sex-combined GWAS (lead variant rs79837492: Beta per effect allele = -4.76; P = 2.62 × 10-8) and in the male-only GWAS (lead variant rs2968545: (Beta = -6.50; P = 1.09 × 10-9), and one suggestive variant was found at 13q12.11 in the female-only GWAS (rs79926925: Beta = 6.95; P = 8.15 × 10-8). The negatively associated variants were most common in European Americans (T allele of rs79837492; 5%) and African Americans (C allele of rs2968545; 5%) and not observed in Japanese Americans, whereas the positively associated variant was most common in Japanese Americans (C allele of rs79926925, 5%), which was all consistent with the racial/ethnic %VAT differences. In a validation step among UK Biobank participants (N = 23,699 of mainly British and Irish ancestry) with MRI-based VAT volume, both rs79837492 (Beta = -0.026, P = 0.019) and rs2968545 (Beta = -0.028, P = 0.010) were significantly associated in men only (n = 11,524). In the MEC-APS, the association between rs79926925 and plasma sex hormone binding globulin levels reached statistical significance in females, but not in males, with adjustment for total adiposity (Beta = -0.24; P = 0.028), on the log scale. Rs79837492 and rs2968545 are located in intron 5 of CNTNAP5, and rs79926925, in an intergenic region between GJB6 and CRYL1. These novel findings differing by sex and racial/ethnic group warrant replication in additional diverse studies with direct visceral fat measurements.

Fig 1. Manhattan plots of SNP P-values from the visceral fat to abdominal area ratio genome-wide association study in the Multiethnic Cohort-Adiposity Phenotype Study (MEC-APS).

The Y-axis shows the negative base ten logarithm of the P-values and the X-axis shows the chromosomes. The genome-wide significance threshold, P<5x10^-8, is shown in red: a) Overall (N = 17,87), b) Males (n = 878), c) Females (n = 909).

Fig 2. Regional plots of SNP P-values in a +/-200 kb window around rs79837429, rs2968545, and rs79926925.

The X-axis shows the chromosome and physical location (Mb), the left Y-axis shows the negative base ten logarithm of the P-values, and the right Y-axis shows recombination activity (cM/Mb) as a blue line. Positions, recombination rates, and gene annotations are according to NCBI’s build 37 (hg 19) and the 1000 Genomes Project Phase 3 multiethnic data set: a) Regional plot of rs79837429, b) Regional plot of rs2968545, c) Regional plot of rs79926925.