Department of Psychiatry, University of California, San Diego, La Jolla, California, USA.
Human and Molecular Genetic Center, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
Obesity (Silver Spring). 2020 Oct;28(10):1964-1973. doi: 10.1002/oby.22927. Epub 2020 Aug 29.
Obesity is influenced by genetic and environmental factors. Despite the success of human genome-wide association studies, the specific genes that confer obesity remain largely unknown. The objective of this study was to use outbred rats to identify the genetic loci underlying obesity and related morphometric and metabolic traits.
This study measured obesity-relevant traits, including body weight, body length, BMI, fasting glucose, and retroperitoneal, epididymal, and parametrial fat pad weight in 3,173 male and female adult N/NIH heterogeneous stock (HS) rats across three institutions, providing data for the largest rat genome-wide association study to date. Genetic loci were identified using a linear mixed model to account for the complex family relationships of the HS and using covariates to account for differences among the three phenotyping centers.
This study identified 32 independent loci, several of which contained only a single gene (e.g., Epha5, Nrg1, Klhl14) or obvious candidate genes (e.g., Adcy3, Prlhr). There were strong phenotypic and genetic correlations among obesity-related traits, and there was extensive pleiotropy at individual loci.
This study demonstrates the utility of HS rats for investigating the genetics of obesity-related traits across institutions and identify several candidate genes for future functional testing.
肥胖受遗传和环境因素的影响。尽管人类全基因组关联研究取得了成功，但赋予肥胖的具体基因仍知之甚少。本研究的目的是使用杂种大鼠来确定肥胖及相关形态和代谢特征的遗传位点。
本研究在三个机构的 3173 只成年雄性和雌性 N/NIH 异质品系（HS）大鼠中测量了与肥胖相关的特征，包括体重、体长、BMI、空腹血糖以及腹膜后、附睾和子宫旁脂肪垫重量，这为迄今为止最大的大鼠全基因组关联研究提供了数据。使用线性混合模型来识别遗传位点，以考虑 HS 的复杂家族关系，并使用协变量来考虑三个表型中心之间的差异。
本研究确定了 32 个独立的位点，其中一些仅包含单个基因（例如 EphA5、NRG1、KLHL14）或明显的候选基因（例如 ADCY3、PRLHR）。肥胖相关特征之间存在强烈的表型和遗传相关性，并且在个体位点存在广泛的多效性。
本研究表明 HS 大鼠可用于跨机构研究肥胖相关特征的遗传学，并确定了几个候选基因，以供未来进行功能测试。
