Neuronal Genes for Subcutaneous Fat Thickness in Human and Pig Are Identified by Local Genomic Sequencing and Combined SNP Association Study

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.

Genome-wide association study for conformation traits in three Danish pig breeds

“…Another association study that combined human and pig data showed that several neuronal genes were associated with subcutaneous fat accumulation, which provides further support for a role of the nervous system on fat metabolism [47]. Another gene, SLC14A2 which is a member of the SLC super family, is mainly expressed in brain [52] and associated with fat thickness in humans and pigs [47]. Since the fat accumulation process probably affects the body structure and movement pattern of an animal, it would be interesting to investigate further how the nervous system influences conformation traits.…”

“…For example, some of the candidate genes are expressed in neuronal tissues and are related to the activity of the neuronal system, i.e. SLC14A2 , PPM1G and NGFR [47–49]. The role of neuronal genes in the regulation of the metabolism, fat accumulation and body weight gain was investigated in humans and pigs [47, 50, 51].…”

“…SLC14A2 , PPM1G and NGFR [47–49]. The role of neuronal genes in the regulation of the metabolism, fat accumulation and body weight gain was investigated in humans and pigs [47, 50, 51]. Willer et al [50] conducted a meta-analysis of 15 GWAS, which detected eight loci that are significantly associated with body mass index in humans.…”

“…Willer et al [50] conducted a meta-analysis of 15 GWAS, which detected eight loci that are significantly associated with body mass index in humans. Another association study that combined human and pig data showed that several neuronal genes were associated with subcutaneous fat accumulation, which provides further support for a role of the nervous system on fat metabolism [47]. Another gene, SLC14A2 which is a member of the SLC super family, is mainly expressed in brain [52] and associated with fat thickness in humans and pigs [47].…”

Whole Genome Association Studies of Residual Feed Intake and Related Traits in the Pig

“…The adjusted phenotypes were used in the association analyses with the PLINK basic “–assoc” command. To control for population structure and to perform multiple testing, genomic control (GC) followed by FDR was implemented on the empirical P values using the “–gc –adjust” command in PLINK software [28]. As no SNP was significantly associated with the studied traits after GC and FDR, except for LMA, associations were considered significant based on GC corrected P values at a threshold of 0.01, as earlier reported by [28].…”