ESPE Yearbook of Paediatric Endocrinology

To read the full abstract: Nature Genetics 2018; 50: 26–41

These authors combined data from 125 cohorts comprising more than 700,000 individuals to discover rare and low-frequency (R/LF) coding single nucleotide variants (SNVs) associated with BMI, thereby identifying novel potential targets for the treatment of obesity. They identified 14 R/LF coding SNVs in 13 genes associated with BMI, of which 8 variants were in genes newly implicated in human obesity. The effect sizes of these R/LF coding variants were 10 times larger than those of common variants. Interestingly, associations with BMI at 10 of 13 SNVs were directionally consistent in 3 childhood cohorts with those observed in adults; three of these reached nominal significance: ZBTB7B, an early growth response gene that binds to the promoter regions of type I collagen genes; PRKAG1, encoding for a regulatory subunit of an important energy-sensing enzyme AMP-activated protein kinase (AMPK); and RAB21, encoding a protein involved in the regulation of cell adhesion and migration. Furthermore they identified 92 common coding variants, of which 41 were novel.

R/LF variants associated with BMI showed significant enrichment in neuronal pathways, confirming previous findings of common variants (1), and also a novel cluster of metabolic pathways related to insulin action and adipocyte/lipid metabolism. This latter finding is exciting since the current understanding of body weight regulation is that this takes place primarily centrally. The finding that genes involved in insulin action and lipid metabolism are relevant for body weight regulation opens doors for pharmaceutical interventions on peripheral metabolism with possibly fewer side effects than acting centrally drugs.

The strength of the present work is certainly the large sample size. Limitations are the use of exome arrays rather than sequence data, and most of the samples were from European individuals. Moreover, notice should be taken of the rather small effect size of about 7 kg for the strongest variant association in MC4R.

Reference: 1. Locke AE, Kahali B, Berndt SI, Justice AE, Pers TH, Day FR, et al. Genetic studies of body mass index yield new insights for obesity biology. Nature. 2015;518(7538):197–206.