Sequencing of 640,000 exomes identifies <em>GPR75</em> variants associated with protection from obesity

doi:10.1126/science.abf8683

GSTDTAP > 气候变化

DOI	10.1126/science.abf8683
	*Sequencing of 640,000 exomes identifies GPR75* variants associated with protection from obesity**
	Parsa Akbari; Ankit Gilani; Olukayode Sosina; Jack A. Kosmicki; Lori Khrimian; Yi-Ya Fang; Trikaldarshi Persaud; Victor Garcia; Dylan Sun; Alexander Li; Joelle Mbatchou; Adam E. Locke; Christian Benner; Niek Verweij; Nan Lin; Sakib Hossain; Kevin Agostinucci; Jonathan V. Pascale; Ercument Dirice; Michael Dunn; Regeneron Genetics Center‡; DiscovEHR Collaboration‡; William E. Kraus; Svati H. Shah; Yii-Der I. Chen; Jerome I. Rotter; Daniel J. Rader; Olle Melander; Christopher D. Still; Tooraj Mirshahi; David J. Carey; Jaime Berumen-Campos; Pablo Kuri-Morales; Jesus Alegre-Díaz; Jason M. Torres; Jonathan R. Emberson; Rory Collins; Suganthi Balasubramanian; Alicia Hawes; Marcus Jones; Brian Zambrowicz; Andrew J. Murphy; Charles Paulding; Giovanni Coppola; John D. Overton; Jeffrey G. Reid; Alan R. Shuldiner; Michael Cantor; Hyun M. Kang; Goncalo R. Abecasis; Katia Karalis; Aris N. Economides; Jonathan Marchini; George D. Yancopoulos; Mark W. Sleeman; Judith Altarejos; Giusy Della Gatta; Roberto Tapia-Conyer; Michal L. Schwartzman; Aris Baras; Manuel A. R. Ferreira; Luca A. Lotta
	2021-07-02
发表期刊	Science
出版年	2021
英文摘要	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][1]; see also abh3556, p. [30][2] ### INTRODUCTION Obesity accounts for a substantial and growing burden of disease globally. Body adiposity is highly heritable, and human genetic studies can lead to biological and therapeutic insights. ### RATIONALE Whole-exome sequencing of hundreds of thousands of individuals is complementary to approaches used to date in obesity genetics and has the potential to identify rare protein-coding variants with large phenotypic impact. We sequenced the exomes of 645,626 individuals from the UK, the US, and Mexico and estimated associations of rare coding variants with body mass index (BMI), a measure of overall adiposity used to define obesity in clinical practice. We complemented exome sequencing with fine-mapping of common alleles, polygenic score analysis, and in vitro and in vivo modeling work. ### RESULTS We identified 16 genes for which the burden of rare nonsynonymous variants was associated with BMI at exome-wide statistical significance (inverse-variance weighted meta-analysis P < 3.6 × 10−7), including associations at five brain-expressed G protein–coupled receptors ( CALCR , MC4R , GIPR , GPR151 , and GPR75 ). We observed an overrepresentation of genes highly expressed in the hypothalamus, a key center for the neuroendocrine regulation of energy balance. Protein-truncating variants in GPR75 were found in ~4/10,000 sequenced people and were associated with 1.8 kg/m2 lower BMI, 5.3 kg lower bodyweight, and 54% lower odds of obesity in heterozygous carriers. Knock out of Gpr75 in mice resulted in resistance to weight gain in a high-fat diet model, which was allele-dose dependent (25% and 44% lower weight gain, respectively, for heterozygous Gpr75 − /+ mice and knockout Gpr75 − / − mice compared with wild type) and accompanied by improved glycemic control and insulin sensitivity. Protein-truncating variants in CALCR were associated with higher BMI and obesity risk, whereas protein-truncating variants in GIPR and two missense alleles [Arg190→Gln (Arg190Gln), Glu288Gly], which we show result in loss of function in vitro, were associated with lower adiposity. Among monogenic obesity genes in the leptin-melanocortin pathway, heterozygous predicted loss-of-function variants in LEP , POMC , PCSK1 , and MC4R (but not LEPR ) were associated with higher BMI. Rare protein-truncating variants in UBR2 , ANO4 , and PCSK1 were associated with more than twofold higher odds of obesity in heterozygous carriers, similar to predicted-deleterious nonsynonymous variants in MC4R , which are considered the most common cause of monogenic obesity. Polygenic predisposition due to >2 million common genetic variants influenced the penetrance of obesity in rare variant carriers in an additive fashion. ### CONCLUSION These results suggest that inhibition of GPR75 may be a therapeutic strategy for obesity and illustrate the power of massive-scale exome sequencing for the identification of large-effect coding variant associations and drug targets for complex traits. ![Figure][3] Exome sequencing–based discovery of BMI-associated genes. (Left) Design for the discovery gene-burden analysis, with a depiction of follow-up analyses along the bottom. (Top right) Relationship between allele frequency and effect-size estimates for BMI-associated genotypes. (Bottom right) Weight gain for Gpr75+/+ (wild type, WT), Gpr75−/+ (heterozygous, HET), and Gpr75−/− (knockout, KO) mice during a high-fat diet challenge. PRS, polygenic risk score. Large-scale human exome sequencing can identify rare protein-coding variants with a large impact on complex traits such as body adiposity. We sequenced the exomes of 645,626 individuals from the United Kingdom, the United States, and Mexico and estimated associations of rare coding variants with body mass index (BMI). We identified 16 genes with an exome-wide significant association with BMI, including those encoding five brain-expressed G protein–coupled receptors ( CALCR , MC4R , GIPR , GPR151 , and GPR75 ). Protein-truncating variants in GPR75 were observed in ~4/10,000 sequenced individuals and were associated with 1.8 kilograms per square meter lower BMI and 54% lower odds of obesity in the heterozygous state. Knock out of Gpr75 in mice resulted in resistance to weight gain and improved glycemic control in a high-fat diet model. Inhibition of GPR75 may provide a therapeutic strategy for obesity. [1]: /lookup/doi/10.1126/science.abf8683 [2]: /lookup/doi/10.1126/science.abh3556 [3]: pending:yes
领域	气候变化 ; 资源环境
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文献类型	期刊论文
条目标识符	http://119.78.100.173/C666/handle/2XK7JSWQ/334180
专题	气候变化资源环境科学
推荐引用方式 GB/T 7714	Parsa Akbari,Ankit Gilani,Olukayode Sosina,et al. Sequencing of 640,000 exomes identifies GPR75 variants associated with protection from obesity[J]. Science,2021.
APA	Parsa Akbari.,Ankit Gilani.,Olukayode Sosina.,Jack A. Kosmicki.,Lori Khrimian.,...&Luca A. Lotta.(2021).Sequencing of 640,000 exomes identifies GPR75 variants associated with protection from obesity.Science.
MLA	Parsa Akbari,et al."Sequencing of 640,000 exomes identifies GPR75 variants associated with protection from obesity".Science (2021).