A GWAS top hit for circulating leptin is associated with weight gain but not with leptin protein levels in lithium-augmented patients with major depression

Lithium-treated patients often suffer from weight gain as a common adverse event. In an ear-lier investigation, we found an impact of two single-nucleotide polymorphisms (rs10487506 and rs2278815) at the leptin gene on weight gain but not on leptin protein levels in serum under lithium augmentation. A recent genome-wide association study identified a polymorphism at the leptin gene locus (rs10487505) associated with circulating leptin protein levels. To char-acterize potential effects of this variant in acute major depressive disorder, we investigated body mass indices from 180 lithium-augmented patients and serum concentrations of leptin protein from 89 patients using linear mixed model analyses and rs6979832, a proxy SNP of rs10487505. Body mass index was measured before and after 4 weeks of lithium augmenta-tion, in a subsample also after 4 and 7 months. Leptin serum levels were measured before and during lithium augmentation. G-allele homozygotes of rs6979832 had a significantly lower body mass index increase during observation compared to A-allele hetero-and homozygotes. However, we found no influence on leptin serum levels. Joint analyses of rs6979832 with the previously investigated polymorphisms rs10487506 and rs2278815, and expressed quantitative trait data, suggest a complex interplay between SNP alleles at the leptin locus. These re-sults strongly support our earlier findings that common genetic variation at the leptin gene locus may be involved in lithium augmentation-associated weight gain in major depressive disorder. (c) 2021 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/ )

Automated summary

Patients treated with lithium often experience weight gain, and genetic variations at the leptin gene locus may be involved in lithium augmentation-associated weight gain in major depressive disorder. A recent study identified a polymorphism at the leptin gene locus associated with circulating leptin protein levels.