Alexander H. Li

How genes affect human obesity: Obesity is linked to many human diseases, including diabetes, cancer, and heart disease. There is thus great interest in understanding how genes predispose individuals to, or protect individuals from, obesity. Akbari et al. sequenced more than 600,000 exomes from the United Kingdom, the United States, and Mexico and identified 16 rare coding variants (see the Perspective by Yeo and O'Rahilly). Some of the alleles associated with body mass index (BMI) were brain-expressed G protein–coupled receptors. One variant allele was found in Mexican populations at low frequency and was associated with lower BMI. Deletion of this gene in mice resulted in a resistance to weight gain, suggesting that this gene provides an avenue of study for the prevention or treatment of obesity. Science , abf8683, this issue p. eabf8683 ; see also abh3556, p. 30

The metabolome is a collection of small molecules resulting from multiple cellular and biological processes that can act as biomarkers of disease, and African-Americans exhibit high levels of genetic diversity. Exome sequencing of a sample of deeply phenotyped African-Americans allowed us to analyze the effects of annotated loss-of-function (LoF) mutations on 308 serum metabolites measured by untargeted liquid and gas chromatography coupled with mass spectrometry. In an independent sample, we identified and replicated four genes harboring six LoF mutations that significantly affected five metabolites. These sites were related to a 19 to 45% difference in geometric mean metabolite levels, with an average effect size of 25%. We show that some of the affected metabolites are risk predictors or diagnostic biomarkers of disease and, using the principle of Mendelian randomization, are in the causal pathway of disease. For example, LoF mutations in SLCO1B1 elevate the levels of hexadecanedioate, a fatty acid significantly associated with increased blood pressure levels and risk of incident heart failure in both African-Americans and an independent sample of European-Americans. We show that SLCO1B1 LoF mutations significantly increase the risk of incident heart failure, thus implicating the metabolite in the causal pathway of disease. These results reveal new avenues into gene function and the understanding of disease etiology by integrating -omic technologies into a deeply phenotyped population study.