Abstract
Obesity represents a major global public health problem that increases the risk for cardiovascular or metabolic disease. The pigs represent an exceptional biomedical model related to energy metabolism and obesity in humans. To pinpoint causal genetic factors for a common form of obesity, we conducted local genomic de novo sequencing, 18.2 Mb, of a porcine QTL region affecting fatness traits, and carried out SNP association studies for backfat thickness and intramuscular fat content in pigs. In order to relate the association studies in pigs to human obesity, we performed a targeted genome wide association study for subcutaneous fat thickness in a cohort population of 8,842 Korean individuals. These combined association studies in human and pig revealed a significant SNP located in a gene family with sequence similarity 73, member A (FAM73A) associated with subscapular skin-fold thickness in humans (rs4121165, GC-corrected p-value = 0.0000175) and with backfat thickness in pigs (ASGA0029495, p-value = 0.000031). Our combined association studies also suggest that eight neuronal genes are responsible for subcutaneous fat thickness: NEGR1, SLC44A5, PDE4B, LPHN2, ELTD1, ST6GALNAC3, ST6GALNAC5, and TTLL7. These results provide strong support for a major involvement of the CNS in the genetic predisposition to a common form of obesity.
Highlights
The pig (Sus scrofa domesticus) was domesticated from Sus scrofa, the wild boar, approximately 9,000 years ago in multiple regions of the world [1,2]
Two genome-wide association (GWA) studies have expanded the number of genetic susceptibility loci for obesity by identifying SNPs associated with body mass index (BMI) and weight, contributing to obesity risk
Using a false discovery rate (FDR) q value [41],0.05, we identified one SNP located in a gene family with sequence similarity 73, member A (FAM73A) gene associated with SUB (Figure 4A and Table S5)
Summary
The pig (Sus scrofa domesticus) was domesticated from Sus scrofa, the wild boar, approximately 9,000 years ago in multiple regions of the world [1,2] It has become an important animal as one of the major animal protein sources for humans and is an exceptionally relevant biomedical model for energy metabolism and obesity in humans since it is devoid of brown fat postnatally and due to its similar metabolic features, cardiovascular systems, and proportional organ sizes [3]. The loci identified are located in or near ten genes including the neuronal growth regulator 1 (NEGR1) genes [7,8] Both of the GWA studies hypothesized a role of the central nervous system (CNS) in the predisposition to a common form of obesity as has previously been shown for rare monogenic forms of obesity. To relate and expand the QTL results observed in pigs to human common forms of obesity, we performed a targeted genome wide association study with subcutaneous fat thickness in a cohort population of 8,842 Korean individuals
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