Sequencing of 640,000 exomes identifies GPR75 variants associated with protection from obesity.
Sequencing of 640,000 exomes identifies GPR75 variants associated with protection from obesity.
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DOI：
10.1126/science.abf8683
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发表时间：
2021-07-02
期刊：
影响因子：
56.9
通讯作者：
Lotta, Luca A.
中科院分区：
文献类型：
--
作者：
Akbari, Parsa;Gilani, Ankit;Sosina, Olukayode;Kosmicki, Jack A.;Khrimian, Lori;Fang, Yi-Ya;Persaud, Trikaldarshi;Garcia, Victor;Sun, Dylan;Li, Alexander;Mbatchou, Joelle;Locke, Adam E.;Benner, Christian;Verweij, Niek;Lin, Nan;Hossain, Sakib;Agostinucci, Kevin;Pascale, Jonathan, V;Dirice, Ercument;Dunn, Michael;Kraus, William E.;Shah, Svati H.;Chen, Yii-Der, I;Rotter, Jerome, I;Rader, Daniel J.;Melander, Olle;Still, Christopher D.;Mirshahi, Tooraj;Carey, David J.;Berumen-Campos, Jaime;Kuri-Morales, Pablo;Alegre-Diaz, Jesus;Torres, Jason M.;Emberson, Jonathan R.;Collins, Rory;Balasubramanian, Suganthi;Hawes, Alicia;Jones, Marcus;Zambrowicz, Brian;Murphy, Andrew J.;Paulding, Charles;Coppola, Giovanni;Overton, John D.;Reid, Jeffrey G.;Shuldiner, Alan R.;Cantor, Michael;Kang, Hyun M.;Abecasis, Goncalo R.;Karalis, Katia;Economides, Aris N.;Marchini, Jonathan;Yancopoulos, George D.;Sleeman, Mark W.;Altarejos, Judith;Della Gatta, Giusy;Tapia-Conyer, Roberto;Schwartzman, Michal L.;Baras, Aris;Ferreira, Manuel A. R.;Lotta, Luca A.
肥胖症是全球范围内一个巨大且不断增长的疾病负担。身体肥胖是高度遗传的，人类基因研究可以带来生物学和治疗方面的见解。数十万个体的全外显子组测序是迄今为止肥胖遗传学中使用的方法的补充，并且有可能识别具有大表型影响的罕见蛋白质编码变体。我们对来自英国，美国和墨西哥的645，626名个体的外显子组进行了测序，并估计了罕见编码变体与体重指数（BMI）的相关性，BMI是一种用于在临床实践中定义肥胖的总体肥胖指标。我们补充外显子组测序与常见等位基因的精细定位，多基因评分分析，并在体外和体内建模工作。我们确定了16个基因，其中罕见非同义变异的负担与BMI在外显子组范围内具有统计学显著性（逆方差加权荟萃分析P < 3.6 × 10−7），包括与五种脑表达G蛋白偶联受体（CALCR，MC 4 R，GIPR，GPR 151和GPR 75）的关联。我们观察到在下丘脑中高度表达的基因的过度表达，下丘脑是神经内分泌调节能量平衡的关键中心。GPR 75中的蛋白质截短变体在约4/10，000的测序人群中发现，并且与杂合携带者的BMI降低1.8 kg/m2，体重降低5.3 kg和肥胖几率降低54%相关。在高脂饮食模型中，敲除小鼠中的Gpr 75导致对体重增加的抵抗，这是等位基因剂量依赖性的（与野生型相比，杂合Gpr 75 −/+小鼠和敲除Gpr 75 −/−小鼠的体重增加分别降低了25%和44%），并伴随着血糖控制和胰岛素敏感性的改善。CALCR中的蛋白质截短变异与较高的BMI和肥胖风险相关，而GIPR中的蛋白质截短变异和两个错义等位基因[Arg 190 →Gln（Arg 190 Gln），Glu 288 Gly]，我们在体外显示导致功能丧失，与较低的肥胖相关。在瘦素-黑皮质素途径中的单基因肥胖基因中，LEP、POMC、PCSK 1和MC 4 R（但不是LEPR）的杂合预测功能丧失变体与较高的BMI相关。UBR 2、ANO 4和PCSK 1中罕见的蛋白质截短变异与杂合子携带者肥胖几率的两倍以上相关，类似于MC 4 R中预测有害的非同义变异，后者被认为是单基因肥胖的最常见原因。多基因易感性是由超过200万个共同遗传变异引起的，以加性方式影响罕见变异携带者的肥胖发生率。这些结果表明，抑制GPR 75可能是肥胖症的治疗策略，并说明了大规模外显子组测序用于鉴定复杂性状的大效应编码变体关联和药物靶点的能力。基于外显子组测序的BMI相关基因的发现。（左）用于发现基因负荷分析的设计，沿着底部描绘了随访分析。(Top右）BMI相关基因型的等位基因频率和效应量估计值之间的关系。（右下）Gpr 75 +/+（野生型，WT）、Gpr 75 −/+（杂合型，HET）和Gpr 75 −/−（敲除型，KO）小鼠在高脂饮食激发期间的体重增加。PRS，多基因风险评分。大规模的人类外显子组测序可以识别罕见的蛋白质编码变体，这些变体对身体肥胖等复杂性状有很大影响。我们对来自英国、美国和墨西哥的645,626名个体的外显子组进行了测序，并估计了罕见编码变异与体重指数（BMI）的关联。我们确定了16个与BMI有显著关联的外显子组基因，包括编码5种脑表达G蛋白偶联受体（CALCR，MC 4 R，GIPR，GPR 151和GPR 75）的基因。在约4/10，000测序个体中观察到GPR 75中的蛋白质截短变体，并且与杂合状态下BMI降低1.8 kg/m2和肥胖几率降低54%相关。在高脂饮食模型中，敲除小鼠中的Gpr 75导致对体重增加的抵抗和改善的血糖控制。抑制GPR 75可能为肥胖症提供一种治疗策略。
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. 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. 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 commongenetic variants influenced the penetrance of obesity in rare variant carriers in an additive fashion. 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. 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.
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影响因子：
120.1
作者：
Cook, David;Brown, Dearg;Pangalos, Menelas N.
通讯作者：
Pangalos, Menelas N.
影响因子：
64.8
作者：
Bycroft C;Freeman C;Petkova D;Band G;Elliott LT;Sharp K;Motyer A;Vukcevic D;Delaneau O;O'Connell J;Cortes A;Welsh S;Young A;Effingham M;McVean G;Leslie S;Allen N;Donnelly P;Marchini J
通讯作者：
Marchini J
影响因子：
30.8
作者：
Flannick, Jason;Thorleifsson, Gudmar;Beer, Nicola L.;Jacobs, Suzanne B. R.;Grarup, Niels;Burtt, Noel P.;Mahajan, Anubha;Fuchsberger, Christian;Atzmon, Gil;Benediktsson, Rafn;Blangero, John;Bowden, Don W.;Brandslund, Ivan;Brosnan, Julia;Burslem, Frank;Chambers, John;Cho, Yoon Shin;Christensen, Cramer;Douglas, Desiree A.;Duggirala, Ravindranath;Dymek, Zachary;Farjoun, Yossi;Fennell, Timothy;Fontanillas, Pierre;Forsen, Tom;Gabriel, Stacey;Glaser, Benjamin;Gudbjartsson, Daniel F.;Hanis, Craig;Hansen, Torben;Hreidarsson, Astradur B.;Hveem, Kristian;Ingelsson, Erik;Isomaa, Bo;Johansson, Stefan;Jorgensen, Torben;Jorgensen, Marit Eika;Kathiresan, Sekar;Kong, Augustine;Kooner, Jaspal;Kravic, Jasmina;Laakso, Markku;Lee, Jong-Young;Lind, Lars;Lindgren, Cecilia M.;Linneberg, Allan;Masson, Gisli;Meitinger, Thomas;Mohlke, Karen L.;Molven, Anders;Morris, Andrew P.;Potluri, Shobha;Rauramaa, Rainer;Ribel-Madsen, Rasmus;Richard, Ann-Marie;Rolph, Tim;Salomaa, Veikko;Segre, Ayellet V.;Skaerstrand, Hanna;Steinthorsdottir, Valgerdur;Stringham, Heather M.;Sulem, Patrick;Tai, E. Shyong;Teo, Yik Ying;Teslovich, Tanya;Thorsteinsdottir, Unnur;Trimmer, Jeff K.;Tuomi, Tiinamaija;Tuomilehto, Jaakko;Vaziri-Sani, Fariba;Voight, Benjamin F.;Wilson, James G.;Boehnke, Michael;McCarthy, Mark I.;Njolstad, Pal R.;Pedersen, Oluf;Groop, Leif;Cox, David R.;Stefansson, Kari;Altshuler, David
通讯作者：
Altshuler, David
影响因子：
4.7
作者：
Dedoni S;Campbell LA;Harvey BK;Avdoshina V;Mocchetti I
通讯作者：
Mocchetti I
影响因子：
5.1
作者：
Binder, Gerhard;Grathwol, Sabrina;Paul, Thomas
通讯作者：
Paul, Thomas