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

TY - JOUR

T1 - Protein quantitative trait locus study in obesity during weight-loss identifies a leptin regulator

AU - Carayol, Jérôme

AU - Chabert, Christian

AU - Di Cara, Alessandro

AU - Armenise, Claudia

AU - Lefebvre, Gregory

AU - Langin, Dominique

AU - Viguerie, Nathalie

AU - Metairon, Sylviane

AU - Saris, Wim H M

AU - Astrup, Arne

AU - Descombes, Patrick

AU - Valsesia, Armand

AU - Hager, Jörg

N1 - CURIS 2017 NEXS 348

PY - 2017/12/1

Y1 - 2017/12/1

N2 - Thousands of genetic variants have been associated with complex traits through genomewide 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.

AB - Thousands of genetic variants have been associated with complex traits through genomewide 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.

KW - Faculty of Science

KW - Proteome analysis

KW - Complex traits

KW - Obesity

KW - Protein quantitative trait locus (pQTL)

KW - Weight loss

KW - BMI-associated proteins

KW - FAM46A

KW - Trans regulator for leptin

U2 - 10.1038/s41467-017-02182-z

DO - 10.1038/s41467-017-02182-z

M3 - Journal article

C2 - 29234017

SN - 2041-1723

VL - 8

JO - Nature Communications

JF - Nature Communications

M1 - 2084

ER -