Protein quantitative trait locus study in obesity during weight-loss identifies a leptin regulator

• Published in: Nature communications Vol. 8; no. 1; pp. 2084 - 14
• Main Authors: Carayol, Jérôme, Chabert, Christian, Di Cara, Alessandro, Armenise, Claudia, Lefebvre, Gregory, Langin, Dominique, Viguerie, Nathalie, Metairon, Sylviane, Saris, Wim H. M., Astrup, Arne, Descombes, Patrick, Valsesia, Armand, Hager, Jörg
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 12.12.2017; Nature Publishing Group; Nature Portfolio
• Subjects: 631/208/200; 631/208/480; 631/45/612/1248; 692/699/1702/393; Adolescent; Adult; Body Mass Index; Body weight loss; Female; Functional analysis; Gene expression; Gene mapping; Gene Regulatory Networks; Genetic diversity; Genetic variance; Genome-wide association studies; Genomes; Genotype & phenotype; Humanities and Social Sciences; Humans; Leptin; Leptin - genetics; Leptin - metabolism; Male; Middle Aged; Molecular modelling; multidisciplinary; Obesity; Obesity - diet therapy; Obesity - genetics; Obesity - metabolism; Proteins; Proteins - genetics; Proteins - metabolism; Proteomes; Proteomics - methods; Quantitative Trait Loci; Regulatory Elements, Transcriptional; Science; Science (multidisciplinary); Weight control; Weight loss; Weight Loss - genetics; Young Adult
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-017-02182-z

Thousands of genetic variants have been associated with complex traits through genome-wide association studies. However, the functional variants or mechanistic consequences remain elusive. Intermediate traits such as gene expression or protein levels are good proxies of the metabolic state of an organism. Proteome analysis especially can provide new insights into the molecular mechanisms of complex traits like obesity. The role of genetic variation in determining protein level variation has not been assessed in obesity. To address this, we design a large-scale protein quantitative trait locus (pQTL) analysis based on a set of 1129 proteins from 494 obese subjects before and after a weight loss intervention. This reveals 55 BMI-associated cis -pQTLs and trans -pQTLs at baseline and 3 trans -pQTLs after the intervention. We provide evidence for distinct genetic mechanisms regulating BMI-associated proteins before and after weight loss. Finally, by functional analysis, we identify and validate FAM46A as a trans regulator for leptin. Although many genetic variants are known for obesity, their function remains largely unknown. Here, in a weight-loss intervention cohort, the authors identify protein quantitative trait loci associated with BMI at baseline and after weight loss and find FAM46A to be a regulator of leptin in adipocytes.