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. 2021 Jul 2;373(6550):eabf8683.
doi: 10.1126/science.abf8683.

Sequencing of 640,000 exomes identifies GPR75 variants associated with protection from obesity

Parsa Akbari #  1 , Ankit Gilani #  2 , Olukayode Sosina #  1 , Jack A Kosmicki  1 , Lori Khrimian  3 , Yi-Ya Fang  3 , Trikaldarshi Persaud  1 , Victor Garcia  2 , Dylan Sun  1 , Alexander Li  1 , Joelle Mbatchou  1 , Adam E Locke  1 , Christian Benner  1 , Niek Verweij  1 , Nan Lin  1 , Sakib Hossain  2 , Kevin Agostinucci  2 , Jonathan V Pascale  2 , Ercument Dirice  2 , Michael Dunn  3 ; Regeneron Genetics Center; DiscovEHR Collaboration; William E Kraus  4   5 , Svati H Shah  6   7 , Yii-Der I Chen  8 , Jerome I Rotter  8 , Daniel J Rader  9 , Olle Melander  10   11 , Christopher D Still  12 , Tooraj Mirshahi  12 , David J Carey  12 , Jaime Berumen-Campos  13 , Pablo Kuri-Morales  13 , Jesus Alegre-Díaz  13 , Jason M Torres  14 , Jonathan R Emberson  14 , Rory Collins  14 , Suganthi Balasubramanian  1 , Alicia Hawes  1 , Marcus Jones  1 , Brian Zambrowicz  3 , Andrew J Murphy  3 , Charles Paulding  1 , Giovanni Coppola  1 , John D Overton  1 , Jeffrey G Reid  1 , Alan R Shuldiner  1 , Michael Cantor  1 , Hyun M Kang  1 , Goncalo R Abecasis  1 , Katia Karalis  1 , Aris N Economides  1   3 , Jonathan Marchini  1 , George D Yancopoulos  3 , Mark W Sleeman  3 , Judith Altarejos  3 , Giusy Della Gatta  1 , Roberto Tapia-Conyer #  13 , Michal L Schwartzman #  2 , Aris Baras #  15 , Manuel A R Ferreira #  1 , Luca A Lotta #  15
Affiliations

Sequencing of 640,000 exomes identifies GPR75 variants associated with protection from obesity

Parsa Akbari et al. Science. .

Abstract

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.

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Conflict of interest statement

Competing interests:

Regeneron authors receive salary from and own options and/or stock of the company. J.R.E. reports grant funding from Boehringer Ingelheim to the University of Oxford for the EMPA-KIDNEY trial of empagliflozin in patients with chronic kidney disease (clinical trials registration number NCT03594110). R.C. has obtained grants to the University of Oxford for the independent design, conduct, analysis, and reporting of randomized trials of lipid modifying therapies from Merck & Co. and from Medco/Novartis. In addition, R.C. received a research prize from Pfizer. This work has been described in one or more pending provisional patent applications. R.C. is an inventor on a patent application, for which he has waived personal royalties in favor of the Nuffield Department of Public Health, held/submitted by University of Oxford that covers a statin-related myopathy genetic test. Emma Link, Rory Collins, Sarah Parish, and Mark Lathrop are inventors on patent application EP2857525A1 held/submitted by Oxford University Innovation Ltd. that covers the method of determining the susceptibility to statin-induced myopathy. M.A.R.F. and L.A.L. are inventors on a provisional patent application (no. 63/019,589) submitted by RGC relating to PCSK1 genetics. P.A., O.S., A.B., M.A.R.F., and L.A.L. are inventors on a provisional patent application (no. 63/042,327) submitted by RGC relating to GPR75 genetics. P.A., O.S., A.B., M.A.R.F., and L.A.L. are inventors on a provisional patent application (no. 63/066,182) submitted by RGC relating to CALCR genetics. G.D.Y. is the chief scientific officer and member of the board of directors at Regeneron Pharmaceuticals. A.J.M. is an executive officer of Regeneron Pharmaceuticals.

Figures

Fig. 1.
Fig. 1.. Protein-truncating variants in GPR75 associated with lower body mass index in humans.
(A) Linear model of the GPR75 protein and its domains (top; intra- and extracellular domains in yellow, transmembrane domains in orange), the distribution on the GPR75 protein of 46 pLOF variants found by exome sequencing (middle), and the distribution of BMI in standardized units among heterozygous carriers of each variant (bottom). In the bottom subpanel, horizontal blue bars show the mean BMI in noncarriers, while horizontal red bars show the overall covariates-adjusted mean BMI in carriers of any pLOF genetic variant in GPR75. (B) Meta-analysis of the association with BMI of pLOF variants in GPR75 in discovery and additional cohorts. Abbreviations: CI, confidence interval; RR, reference-reference genotype; RA, reference-alternative heterozygous genotype; AA, alternative-alternative homozygous genotype; DHS, Dallas Heart Study; SINAI, Mount Sinai BioMe cohort; DUKE, Duke Catheterization Genetics cohort; TAICHI, Taiwanese Chinese persons from the Taiwan Metabochip Consortium; PMBB, University of Pennsylvania Medicine BioBank; MALMO, Malmö Diet and Cancer Study; AFR, African ancestry; AMR, American ancestry; EAS, East Asian ancestry; EUR, European ancestry; SAS, South Asian ancestry. MCPS included individuals of admixed American ancestry.
Fig. 2.
Fig. 2.. Distribution in body mass index categories for carriers and noncarriers of predicted loss-of-function variants in GPR75 or MC4R.
Distribution of heterozygous carriers of pLOF genetic variants in GPR75 (top), noncarriers (middle), and heterozygous carriers of Plof genetic variants in MC4R (bottom) in body mass index categories according to the World Health Organization’s classification in the UKB, GHS, and MCPS cohorts.
Fig. 3.
Fig. 3.. In vitro expression studies of two predicted loss-of-function genetic variants in GPR75.
(A) Results of quantitative reverse transcription polymerase chain reaction experiments which measured GPR75 mRNA levels. Expression of GPR75 was calculated relative to the beta-actin gene. Values represent the mean and standard deviation of three technical replicates representative of one of three biological replicate experiments performed for each condition. (B) Western blotting analysis of GPR75 protein levels. GPR75 Ala110fs and Gln234* protein products correspond to the predicted molecular weight of 14 and 25 kDa, respectively. The results are representative of three biological replicates. (C) Immunofluorescence staining experiments describing the cellular localization of GPR75. The top images show intracellular staining achieved by membrane permeabilization, while the bottom images show plasma membrane localization (nonpermeabilized cellular membrane). (D) Flow cytometry analysis of the cell surface expression of GPR75. Identified cell populations are presented in percent (%) of live HA-TAG GPR75 positive cells. Values represent the mean of four biological replicates per condition and their standard deviation. All experiments were performed in HEK293 cells that were transfected with green fluorescent protein control plasmids (Control), GPR75 wild type (GPR75), GPR75-Ala110fs, or GPR75-Gln234* plasmids. Abbreviations: GAPDH, glyceraldehyde-3-phosphate dehydrogenase; SSC, side scatter; HA, hemagglutinin tag.
Fig. 4.
Fig. 4.. Weight gain during high-fat diet and metabolic phenotype in mice with a genetic deletion of Gpr75.
(A) Weekly body weight gain during a 14-week high-fat diet (HFD) challenge. (B) Changes in fasting blood glucose before and after the high-fat diet challenge. (C) Results of a glucose tolerance test at the end of the 14-week high-fat diet challenge. (D) Plasma insulin at the end of the 14-week high-fat diet challenge. Each panel shows results in Gpr75+/+ (WT), Gpr75+/− (HET), and Gpr75−/− (KO) mice. Number of mice included in each group and analysis is shown in parentheses. Results are presented as mean ± standard error. Abbreviations: ns, not statistically significant; **P < 0.01, ***P < 0.001, ****P < 0.0001 by two-way analysis of variance with Tukey’s multiple comparisons test.
Fig. 5.
Fig. 5.. Association of protein-truncating genetic variants in GIPR with lower body mass index.
(A) Association with BMI for pLOF genetic variants in GIPR across both discovery and additional cohorts. Abbreviations: CI, confidence interval; RR, reference-reference genotype; RA, reference-alternative heterozygous genotype; AA, alternative-alternative homozygous genotype; DHS, Dallas Heart Study; SINAI, Mount Sinai BioMe cohort; DUKE, Duke Catheterization Genetics cohort; TAICHI, Taiwanese Chinese persons from the Taiwan Metabochip Consortium; PMBB, University of Pennsylvania Medicine BioBank; MALMO, Malmö Diet and Cancer Study; AFR, African ancestry; AMR, American ancestry; EAS, East Asian ancestry; EUR, European ancestry; SAS, South Asian ancestry. (B) In vitro expression results using the CRE-reporter assay for the Arg190Gln and Glu288Gly missense variants in GIPR, which were associated with lower BMI. (C) In vitro expression results using the nuclear factor of activated T cells (NFAT)–dependent assay for the variants. Both missense variants showed lower glucose-dependent insulinotropic polypeptide (GIP)–induced Gs signaling and lower GIP-induced Gq signaling than wild type.
Fig. 6.
Fig. 6.. Interplay of a genome-wide polygenic score for higher body mass index with rare genetic mutations in GPR75 and MC4R.
This figure shows the prevalence of obesity (defined as BMI ≥ 30 kg/m2) in heterozygous carriers of pLOF variants in GPR75, noncarriers, or heterozygous carriers of pLOF variants in MC4R within quintiles of a genome-wide polygenic score for higher BMI. P values for interaction between the polygenic score and rare pLOF variants on body mass index were 0.09 and 0.85 for GPR75 and MC4R, respectively. Error bars represent 95% confidence intervals.
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