Keele Gregory R, Prokop Jeremy W, He Hong, Holl Katie, Littrell John, Deal Aaron, Francic Sanja, Cui Leilei, Gatti Daniel M, Broman Karl W, Tschannen Michael, Tsaih Shirng-Wern, Zagloul Maie, Kim Yunjung, Baur Brittany, Fox Joseph, Robinson Melanie, Levy Shawn, Flister Michael J, Mott Richard, Valdar William, Solberg Woods Leah C
Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
HudsonAlpha Institute, Huntsville, Alabama, USA.
Obesity (Silver Spring). 2018 Jan;26(1):213-222. doi: 10.1002/oby.22075. Epub 2017 Nov 28.
Obesity is a major risk factor for multiple diseases and is in part heritable, yet the majority of causative genetic variants that drive excessive adiposity remain unknown. Here, outbred heterogeneous stock (HS) rats were used in controlled environmental conditions to fine-map novel genetic modifiers of adiposity.
Body weight and visceral fat pad weights were measured in male HS rats that were also genotyped genome-wide. Quantitative trait loci (QTL) were identified by genome-wide association of imputed single-nucleotide polymorphism (SNP) genotypes using a linear mixed effect model that accounts for unequal relatedness between the HS rats. Candidate genes were assessed by protein modeling and mediation analysis of expression for coding and noncoding variants, respectively.
HS rats exhibited large variation in adiposity traits, which were highly heritable and correlated with metabolic health. Fine-mapping of fat pad weight and body weight revealed three QTL and prioritized five candidate genes. Fat pad weight was associated with missense SNPs in Adcy3 and Prlhr and altered expression of Krtcap3 and Slc30a3, whereas Grid2 was identified as a candidate within the body weight locus.
These data demonstrate the power of HS rats for identification of known and novel heritable mediators of obesity traits.
肥胖是多种疾病的主要风险因素，且部分具有遗传性，但导致过度肥胖的大多数致病基因变异仍不明确。在此，将远交系异质群体（HS）大鼠置于可控环境条件下，以精细定位肥胖的新型基因修饰因子。
测量雄性HS大鼠的体重和内脏脂肪垫重量，并对其进行全基因组基因分型。通过使用线性混合效应模型对估算的单核苷酸多态性（SNP）基因型进行全基因组关联分析来识别数量性状基因座（QTL），该模型考虑了HS大鼠之间的不等亲缘关系。分别通过蛋白质建模和对编码及非编码变异的表达进行中介分析来评估候选基因。
HS大鼠在肥胖性状上表现出很大差异，这些性状具有高度遗传性且与代谢健康相关。对脂肪垫重量和体重的精细定位揭示了三个QTL，并确定了五个候选基因。脂肪垫重量与Adcy3和Prlhr中的错义SNP相关，并改变了Krtcap3和Slc30a3的表达，而Grid2被确定为体重基因座内的一个候选基因。
这些数据证明了HS大鼠在识别肥胖性状的已知和新型遗传介质方面的能力。
Zotero 插件
