Weight loss after gastric bypass is associated with a variant at 15q26.1

Abstract

The amount of weight loss attained after Roux-en-Y gastric bypass (RYGB) surgery follows a wide and normal distribution, and recent evidence indicates that this weight loss is due to physiological, rather than mechanical, mechanisms. To identify potential genetic factors associated with weight loss after RYGB, we performed a genome-wide association study (GWAS) of 693 individuals undergoing RYGB and then replicated this analysis in an independent population of 327 individuals undergoing RYGB. We found that a 15q26.1 locus near ST8SIA2 and SLCO3A1 was significantly associated with weight loss after RYGB. Expression of ST8SIA2 in omental fat of these individuals at baseline was significantly associated with weight loss after RYGB. Gene expression analysis in RYGB and weight-matched, sham-operated (WMS) mice revealed that expression of St8sia2 and Slco3a1 was significantly altered in metabolically active tissues in RYGB-treated compared to WMS mice. These findings provide strong evidence for specific genetic influences on weight loss after RYGB and underscore the biological nature of the response to RYGB.

Figure 1

Manhattan Plot of the Results of a GWAS of 1,943,373 SNPs and Percent Weight Loss after RYGB in 693 Individuals of European Descent Each SNP is plotted relative to its chromosomal location (x axis) and –log₁₀ p value (left y axis). The horizontal blue line represents p < 5 × 10⁻⁵.

Figure 2

Weight Loss after RYGB by rs17702901 Genotype Status (A) Percent weight loss in individuals after Roux-en-Y gastric bypass by rs17702901 genotype. Error bars denote the minimum and maximum value by group. (B) Distribution of percent weight loss in individuals after Roux-en-Y gastric bypass by rs17702901 status. Grey bars indicate individuals with no rs17702901 minor alleles; purple bars indicate individuals with one copy of the minor allele; and the red bar indicates the single individual with two copies of the minor allele.

Figure 3

Comparative Expression of St8sia2 and Slco3a1 in RYGB-Treated and Sham-Operated, Weight-Matched Mice Grey bars denote the sham-operated, weight-matched (WMS) group, and blue bars indicate the RYGB group. Error bars denote the standard error of the mean. ^*p < 0.05, ^**p < 0.01, and ^***p < 0.001.

Figure 4

Analysis of the AQP11 Region (A) Regional association plot of the AQP11 locus. Each SNP is plotted as a diamond on the basis of its chromosomal location (x axis) and −log₁₀ p value (left y axis). Recombination rates are plotted in blue (right y axis). The large red diamond represents the region's top SNP (rs7129556) from the GWAS, and the large blue diamond represents the p value for that SNP in the replication cohort. White diamonds are not in significant linkage disequilibrium (LD) with rs7129556, whereas red, orange, and yellow diamonds are in strong (r² ≥ 0.8), moderate (0.5 ≤ r² < 0.8), and weak (0.2 ≤ r² < 0.5) LD, respectively. Expression of Aqp11 (B) and Clns1a (C) is shown. Grey bars denote the WMS group, and blue bars denote the RYGB group. Error bars denote the standard error of the mean. ^*p < 0.05, ^**p < 0.01, and ^***p < 0.001.