Diabetes Volume 66, April 2017 935

Ruixin Liu,1 Yaoyu Zou,1,2 Jie Hong,1 Min Cao,1 Bin Cui,1,2 Huiwen Zhang,3 Maopei Chen,1 Juan Shi,1 Tinglu Ning,1,2 Shaoqian Zhao,1 Wen Liu,1 Hui Xiong,4 Cuijie Wei,4 Zhengqing Qiu,5 Weiqiong Gu,1 Yifei Zhang,1 Wanyu Li,1 Lin Miao,1 Yingkai Sun,1 Minglan Yang,1 Rui Wang,1 Qinyun Ma,1 Min Xu,1 Yu Xu,1 Tiange Wang,1 Kei-hang Katie Chan,6 Xianbo Zuo,7 Haoyan Chen,8 Lu Qi,9 Shenghan Lai,10 Shumin Duan,11 Baoliang Song,12 Yufang Bi,1 Simin Liu,6 Weiqing Wang,1 Guang Ning,1,2 and Jiqiu Wang1

Rare Loss-of-Function Variants in NPC1 Predispose to Human

Diabetes 2017;66:935–947 | DOI: 10.2337/db16-0877

Some Shanghai Clinical Center f a role of Niemann-Pick (3.40% vs. 0.73%, respectively, in obese patients and type C1 (NPC1) for obesity traits. However, whether the control subjects, P = 0.0008, odds ratio = 4.8, 95% CI loss-of-function mutations in NPC1 cause adiposity in 1.7–13.2), indicating that rare NPC1 variants were humans remains unknown. We recruited 25 probands enriched in young, morbidly obese Chinese subjects. with rare autosomal-recessive Niemann-Pick type C Importantly, participants carrying rare variants with se- STUDIES OBESITY (NP-C) disease and their parents in assessment of the verely damaged -transporting ability had effect of heterozygous NPC1 mutations on adiposity. more fat accumulation than those with mild/no damage We found that male NPC1+/2 carriers had a significantly rare variants. In summary, rare loss-of-function NPC1 higher BMI than matched control subjects or the whole mutations were identified as being associated with hu- population-based control subjects. Consistently, male man adiposity with a high penetrance, providing poten- NPC1+/2 mice had increased fat storage while eating a tial therapeutic interventions for obesity in addition to high-fat diet. We further conducted an in-depth assess- the role of NPC1 in the familial NP-C disease. ment of rare variants in the NPC1 in young, se- verely obese subjects and lean control subjects and identified 17 rare nonsynonymous/frameshift variants in NPC1 (minor allele frequency <1%) that were signifi- Obesity is a chronic and complex disease reflecting the cantly associated with an increased risk of obesity interplay between both genetic and environmental

1Shanghai Clinical Center for Endocrine and Metabolic Diseases, Department of 8State Key Laboratory for Oncogenes and Related , Division of Gastroen- Endocrinology and Metabolism, Shanghai Institute of Endocrine and Metabolic terology and Hepatology, Renji Hospital, Shanghai Jiao Tong University School of Diseases, China National Research Center for Metabolic Diseases, National Key Medicine (SJTUSM), Shanghai, China Laboratory for Medical Genomes, Ruijin Hospital, Shanghai Jiao Tong University 9Department of Nutrition, Harvard School of Public Health, Boston, MA School of Medicine (SJTUSM), Shanghai, China 10Department of Radiology and Radiological Science, Johns Hopkins School of 2Laboratory of Endocrinology and Metabolism, Institute of Health Sciences, Medicine, Baltimore, MD Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences 11The Institute of Neuroscience, Zhejiang University, Hangzhou, China (CAS), and Shanghai Jiao Tong University School of Medicine (SJTUSM), Shang- 12College of Life Sciences, the Institute for Advanced Studies, Wuhan University, hai, China Wuhan, China 3 Department of Pediatric Endocrinology and Genetic Metabolism, Xinhua Hospital, Corresponding authors: Jiqiu Wang, [email protected]; Guang Ning, gning@ Shanghai Institute for Pediatric Research, Shanghai Jiao Tong University School sibs.ac.cn; Weiqing Wang, [email protected]; and Simin Liu, simin_liu@ of Medicine (SJTUSM), Shanghai, China brown.edu. 4Department of Pediatrics, Peking University First Hospital, Beijing, China Received 18 July 2016