title: Rare Loss-of-Function Variants inNPC1Predispose to Human Obesity.
abstract: Some Shanghai Clinical Center f a role of Niemann-Pick type C1 (NPC1) for obesity traits. However, whether the loss-of-function mutations inNPC1cause adiposity in humans remains unknown. We recruited 25 probands with rare autosomal-recessive Niemann-Pick type C (NP-C) disease and their parents in assessment of the effect of heterozygousNPC1mutations on adiposity. We found that maleNPC1+/-carriers had a significantly higher BMI than matched control subjects or the whole population-based control subjects. Consistently, maleNPC1+/-mice had increased fat storage while eating a high-fat diet. We further conducted an in-depth assessment of rare variants in theNPC1gene in young, severely obese subjects and lean control subjects and identified 17 rare nonsynonymous/frameshift variants inNPC1(minor allele frequency <1%) that were significantly associated with an increased risk of obesity (3.40% vs. 0.73%, respectively, in obese patients and control subjects,P= 0.0008, odds ratio = 4.8, 95% CI 1.7-13.2), indicating that rareNPC1variants were enriched in young, morbidly obese Chinese subjects. Importantly, participants carrying rare variants with severely damaged cholesterol-transporting ability had more fat accumulation than those with mild/no damage rare variants. In summary, rare loss-of-functionNPC1mutations were identified as being associated with human adiposity with a high penetrance, providing potential therapeutic interventions for obesity in addition to the role ofNPC1in the familial NP-C disease.
authors.affiliation: Shanghai Clinical Center for Endocrine and Metabolic Diseases, Department of Endocrinology and Metabolism, Shanghai Institute of Endocrine and Metabolic Diseases, China National Research Center for Metabolic Diseases, National Key Laboratory for Medical Genomes, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, China.
authors.forename: Ruixin
authors.initials: R
authors.lastname: Liu
authors.affiliation: Shanghai Clinical Center for Endocrine and Metabolic Diseases, Department of Endocrinology and Metabolism, Shanghai Institute of Endocrine and Metabolic Diseases, China National Research Center for Metabolic Diseases, National Key Laboratory for Medical Genomes, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, China.|Laboratory of Endocrinology and Metabolism, Institute of Health Sciences, Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS), and Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, China.
authors.forename: Yaoyu
authors.initials: Y
authors.lastname: Zou
authors.affiliation: Shanghai Clinical Center for Endocrine and Metabolic Diseases, Department of Endocrinology and Metabolism, Shanghai Institute of Endocrine and Metabolic Diseases, China National Research Center for Metabolic Diseases, National Key Laboratory for Medical Genomes, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Hong
authors.affiliation: Shanghai Clinical Center for Endocrine and Metabolic Diseases, Department of Endocrinology and Metabolism, Shanghai Institute of Endocrine and Metabolic Diseases, China National Research Center for Metabolic Diseases, National Key Laboratory for Medical Genomes, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, China.
authors.forename: Min
authors.initials: M
authors.lastname: Cao
authors.affiliation: Shanghai Clinical Center for Endocrine and Metabolic Diseases, Department of Endocrinology and Metabolism, Shanghai Institute of Endocrine and Metabolic Diseases, China National Research Center for Metabolic Diseases, National Key Laboratory for Medical Genomes, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, China.|Laboratory of Endocrinology and Metabolism, Institute of Health Sciences, Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS), and Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Cui
authors.affiliation: Department of Pediatric Endocrinology and Genetic Metabolism, Xinhua Hospital, Shanghai Institute for Pediatric Research, Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, China.
authors.forename: Huiwen
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Shanghai Clinical Center for Endocrine and Metabolic Diseases, Department of Endocrinology and Metabolism, Shanghai Institute of Endocrine and Metabolic Diseases, China National Research Center for Metabolic Diseases, National Key Laboratory for Medical Genomes, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, China.
authors.forename: Maopei
authors.initials: M
authors.lastname: Chen
authors.affiliation: Shanghai Clinical Center for Endocrine and Metabolic Diseases, Department of Endocrinology and Metabolism, Shanghai Institute of Endocrine and Metabolic Diseases, China National Research Center for Metabolic Diseases, National Key Laboratory for Medical Genomes, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Shi
authors.affiliation: Shanghai Clinical Center for Endocrine and Metabolic Diseases, Department of Endocrinology and Metabolism, Shanghai Institute of Endocrine and Metabolic Diseases, China National Research Center for Metabolic Diseases, National Key Laboratory for Medical Genomes, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, China.|Laboratory of Endocrinology and Metabolism, Institute of Health Sciences, Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS), and Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, China.
authors.forename: Tinglu
authors.initials: T
authors.lastname: Ning
authors.affiliation: Shanghai Clinical Center for Endocrine and Metabolic Diseases, Department of Endocrinology and Metabolism, Shanghai Institute of Endocrine and Metabolic Diseases, China National Research Center for Metabolic Diseases, National Key Laboratory for Medical Genomes, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, China.
authors.forename: Shaoqian
authors.initials: S
authors.lastname: Zhao
authors.affiliation: Shanghai Clinical Center for Endocrine and Metabolic Diseases, Department of Endocrinology and Metabolism, Shanghai Institute of Endocrine and Metabolic Diseases, China National Research Center for Metabolic Diseases, National Key Laboratory for Medical Genomes, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, China.
authors.forename: Wen
authors.initials: W
authors.lastname: Liu
authors.affiliation: Department of Pediatrics, Peking University First Hospital, Beijing, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Xiong
authors.affiliation: Department of Pediatrics, Peking University First Hospital, Beijing, China.
authors.forename: Cuijie
authors.initials: C
authors.lastname: Wei
authors.affiliation: Department of Pediatrics, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Zhengqing
authors.initials: Z
authors.lastname: Qiu
authors.affiliation: Shanghai Clinical Center for Endocrine and Metabolic Diseases, Department of Endocrinology and Metabolism, Shanghai Institute of Endocrine and Metabolic Diseases, China National Research Center for Metabolic Diseases, National Key Laboratory for Medical Genomes, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, China.
authors.forename: Weiqiong
authors.initials: W
authors.lastname: Gu
authors.affiliation: Shanghai Clinical Center for Endocrine and Metabolic Diseases, Department of Endocrinology and Metabolism, Shanghai Institute of Endocrine and Metabolic Diseases, China National Research Center for Metabolic Diseases, National Key Laboratory for Medical Genomes, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, China.
authors.forename: Yifei
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Shanghai Clinical Center for Endocrine and Metabolic Diseases, Department of Endocrinology and Metabolism, Shanghai Institute of Endocrine and Metabolic Diseases, China National Research Center for Metabolic Diseases, National Key Laboratory for Medical Genomes, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, China.
authors.forename: Wanyu
authors.initials: W
authors.lastname: Li
authors.affiliation: Shanghai Clinical Center for Endocrine and Metabolic Diseases, Department of Endocrinology and Metabolism, Shanghai Institute of Endocrine and Metabolic Diseases, China National Research Center for Metabolic Diseases, National Key Laboratory for Medical Genomes, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Miao
authors.affiliation: Shanghai Clinical Center for Endocrine and Metabolic Diseases, Department of Endocrinology and Metabolism, Shanghai Institute of Endocrine and Metabolic Diseases, China National Research Center for Metabolic Diseases, National Key Laboratory for Medical Genomes, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, China.
authors.forename: Yingkai
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Shanghai Clinical Center for Endocrine and Metabolic Diseases, Department of Endocrinology and Metabolism, Shanghai Institute of Endocrine and Metabolic Diseases, China National Research Center for Metabolic Diseases, National Key Laboratory for Medical Genomes, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, China.
authors.forename: Minglan
authors.initials: M
authors.lastname: Yang
authors.affiliation: Shanghai Clinical Center for Endocrine and Metabolic Diseases, Department of Endocrinology and Metabolism, Shanghai Institute of Endocrine and Metabolic Diseases, China National Research Center for Metabolic Diseases, National Key Laboratory for Medical Genomes, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Wang
authors.affiliation: Shanghai Clinical Center for Endocrine and Metabolic Diseases, Department of Endocrinology and Metabolism, Shanghai Institute of Endocrine and Metabolic Diseases, China National Research Center for Metabolic Diseases, National Key Laboratory for Medical Genomes, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, China.
authors.forename: Qinyun
authors.initials: Q
authors.lastname: Ma
authors.affiliation: Shanghai Clinical Center for Endocrine and Metabolic Diseases, Department of Endocrinology and Metabolism, Shanghai Institute of Endocrine and Metabolic Diseases, China National Research Center for Metabolic Diseases, National Key Laboratory for Medical Genomes, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, China.
authors.forename: Min
authors.initials: M
authors.lastname: Xu
authors.affiliation: Shanghai Clinical Center for Endocrine and Metabolic Diseases, Department of Endocrinology and Metabolism, Shanghai Institute of Endocrine and Metabolic Diseases, China National Research Center for Metabolic Diseases, National Key Laboratory for Medical Genomes, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Shanghai Clinical Center for Endocrine and Metabolic Diseases, Department of Endocrinology and Metabolism, Shanghai Institute of Endocrine and Metabolic Diseases, China National Research Center for Metabolic Diseases, National Key Laboratory for Medical Genomes, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, China.
authors.forename: Tiange
authors.initials: T
authors.lastname: Wang
authors.affiliation: Department of Epidemiology and Center for Global Cardiometabolic Health, School of Public Health, and Department of Medicine (Endocrinology), The Warren Alpert Medical School, Brown University, Providence, RI.
authors.forename: Kei-Hang Katie
authors.initials: KK
authors.lastname: Chan
authors.affiliation: Institute of Dermatology and Department of Dermatology at No. 1 Hospital, Anhui Medical University, Hefei, China.
authors.forename: Xianbo
authors.initials: X
authors.lastname: Zuo
authors.affiliation: State Key Laboratory for Oncogenes and Related Genes, Division of Gastroenterology and Hepatology, Renji Hospital, Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, China.
authors.forename: Haoyan
authors.initials: H
authors.lastname: Chen
authors.affiliation: Department of Nutrition, Harvard School of Public Health, Boston, MA.
authors.forename: Lu
authors.initials: L
authors.lastname: Qi
authors.affiliation: Department of Radiology and Radiological Science, Johns Hopkins School of Medicine, Baltimore, MD.
authors.forename: Shenghan
authors.initials: S
authors.lastname: Lai
authors.affiliation: The Institute of Neuroscience, Zhejiang University, Hangzhou, China.
authors.forename: Shumin
authors.initials: S
authors.lastname: Duan
authors.affiliation: College of Life Sciences, the Institute for Advanced Studies, Wuhan University, Wuhan, China.
authors.forename: Baoliang
authors.initials: B
authors.lastname: Song
authors.affiliation: Shanghai Clinical Center for Endocrine and Metabolic Diseases, Department of Endocrinology and Metabolism, Shanghai Institute of Endocrine and Metabolic Diseases, China National Research Center for Metabolic Diseases, National Key Laboratory for Medical Genomes, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, China.
authors.forename: Yufang
authors.initials: Y
authors.lastname: Bi
authors.affiliation: Department of Epidemiology and Center for Global Cardiometabolic Health, School of Public Health, and Department of Medicine (Endocrinology), The Warren Alpert Medical School, Brown University, Providence, RI wangjq@shsmu.edu.cn gning@sibs.ac.cn wqingw@hotmail.com simin_liu@brown.edu.
authors.forename: Simin
authors.initials: S
authors.lastname: Liu
authors.affiliation: Shanghai Clinical Center for Endocrine and Metabolic Diseases, Department of Endocrinology and Metabolism, Shanghai Institute of Endocrine and Metabolic Diseases, China National Research Center for Metabolic Diseases, National Key Laboratory for Medical Genomes, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, China wangjq@shsmu.edu.cn gning@sibs.ac.cn wqingw@hotmail.com simin_liu@brown.edu.
authors.forename: Weiqing
authors.initials: W
authors.lastname: Wang
authors.affiliation: Shanghai Clinical Center for Endocrine and Metabolic Diseases, Department of Endocrinology and Metabolism, Shanghai Institute of Endocrine and Metabolic Diseases, China National Research Center for Metabolic Diseases, National Key Laboratory for Medical Genomes, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, China wangjq@shsmu.edu.cn gning@sibs.ac.cn wqingw@hotmail.com simin_liu@brown.edu.|Laboratory of Endocrinology and Metabolism, Institute of Health Sciences, Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS), and Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, China.
authors.forename: Guang
authors.initials: G
authors.lastname: Ning
authors.affiliation: Shanghai Clinical Center for Endocrine and Metabolic Diseases, Department of Endocrinology and Metabolism, Shanghai Institute of Endocrine and Metabolic Diseases, China National Research Center for Metabolic Diseases, National Key Laboratory for Medical Genomes, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, China wangjq@shsmu.edu.cn gning@sibs.ac.cn wqingw@hotmail.com simin_liu@brown.edu.
authors.forename: Jiqiu
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authors.lastname: Wang
mesh_terms: D000328:Adult; D000818:Animals; D044466:Asian People / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics*; D016022:Case-Control Studies; D002681:China; D059305:Diet, High-Fat; D005260:Female; D016368:Frameshift Mutation; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006579:Heterozygote; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics*; D051379:Mice; D008875:Middle Aged; D000077296:Niemann-Pick C1 Protein; D009765:Obesity / Q000235:genetics; D009767:Obesity, Morbid / Q000235:genetics*; D010641:Phenotype; D011506:Proteins / Q000235:genetics*; D055815:Young Adult
chemical_list: D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; C106881:NPC1 protein, human; D000077296:Niemann-Pick C1 Protein; C106831:Npc1 protein, mouse; D011506:Proteins