A survey of the genetics of stomach, liver, and adipose gene expression from a morbidly obese cohort

Abstract

To map the genetics of gene expression in metabolically relevant tissues and investigate the diversity of expression SNPs (eSNPs) in multiple tissues from the same individual, we collected four tissues from approximately 1000 patients undergoing Roux-en-Y gastric bypass (RYGB) and clinical traits associated with their weight loss and co-morbidities. We then performed high-throughput genotyping and gene expression profiling and carried out a genome-wide association analyses for more than 100,000 gene expression traits representing four metabolically relevant tissues: liver, omental adipose, subcutaneous adipose, and stomach. We successfully identified 24,531 eSNPs corresponding to about 10,000 distinct genes. This represents the greatest number of eSNPs identified to our knowledge by any study to date and the first study to identify eSNPs from stomach tissue. We then demonstrate how these eSNPs provide a high-quality disease map for each tissue in morbidly obese patients to not only inform genetic associations identified in this cohort, but in previously published genome-wide association studies as well. These data can aid in elucidating the key networks associated with morbid obesity, response to RYGB, and disease as a whole.

Figure 1.

Effect of RYGB on BMI and Leptin. (A) Change in BMI (kg/m²) from pre-surgery to post-surgery of the RYGB cohort. (B) Change in leptin (ng/mL) levels from pre-surgery to post-surgery of the RYGB cohort. Pre-op readings are taken as an average of all records per patient for a trait up to 1 yr prior to surgery. Post-op readings are an average of post-op records recorded between 6 mo and 36 mo post-surgery.

Figure 2.

Cis-eQTLs overlaps. (A) Venn diagram for the cis eSNPs detected in three tissues using a subpopulation of 107 individuals. (B) Overlaps of the cis eSNPs identified in three tissues at maximum sample size in the RYGB cohort. Regardless of sample size, the OA and SA tissues share many more cis eQTLs in comparison to liver versus adipose. (C) Plot of mean distance of the eSNP to the gene. Symbols marked in the legend with “Only” represent the subset of the cis eSNPs specific to a particular tissue, “All” for all cis eSNPs detected in a tissue, and “Common” for the subset of cis eSNPs common to all three tissues. Cis eSNPs common to all three tissues are significantly closer to the associated genetic signal regardless of the sample size or tissue in which they were detected compared to cis eSNPs unique to a single tissue. The mean distance for all cis eQTLs detected in each tissue show little change between the small subpopulation and the full sample.