Letter

Sparse whole-genome sequencing identifies two loci for major depressive disorder

  • Nature volume 523, pages 588591 (30 July 2015)
  • doi:10.1038/nature14659
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Abstract

Major depressive disorder (MDD), one of the most frequently encountered forms of mental illness and a leading cause of disability worldwide1, poses a major challenge to genetic analysis. To date, no robustly replicated genetic loci have been identified2, despite analysis of more than 9,000 cases3. Here, using low-coverage whole-genome sequencing of 5,303 Chinese women with recurrent MDD selected to reduce phenotypic heterogeneity, and 5,337 controls screened to exclude MDD, we identified, and subsequently replicated in an independent sample, two loci contributing to risk of MDD on chromosome 10: one near the SIRT1 gene (P = 2.53 × 10−10), the other in an intron of the LHPP gene (P = 6.45 × 10−12). Analysis of 4,509 cases with a severe subtype of MDD, melancholia, yielded an increased genetic signal at the SIRT1 locus. We attribute our success to the recruitment of relatively homogeneous cases with severe illness.

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Acknowledgements

This work was funded by the Wellcome Trust (WT090532/Z/09/Z, WT083573/Z/07/Z, WT089269/Z/09/Z), NIH grant MH-100549 and the Brain and Behavior Research Foundation. All authors are part of the CONVERGE consortium (China, Oxford and VCU Experimental Research on Genetic Epidemiology) and gratefully acknowledge the support of all partners in hospitals across China. W. Kretzschmar is funded by the Wellcome Trust (WT097307). N. Cai is supported by the Agency of Science, Technology and Research (A*STAR) Graduate Academy. J. Marchini is funded by an ERC Consolidator Grant (617306). Q. Xu is funded by the 973 Program (2013CB531301) and NSFC (31430048, 31222031).

Author information

Author notes

    • Na Cai
    • , Tim B. Bigdeli
    • , Warren Kretzschmar
    •  & Yihan Li

    These authors contributed equally to this work.

    • Qi Xu
    • , Jun Wang
    • , Kenneth S. Kendler
    •  & Jonathan Flint

    These authors jointly supervised this work.

Affiliations

  1. Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK

    • Na Cai
    • , Warren Kretzschmar
    • , Yihan Li
    • , Guangyi Fu
    • , Jonathan Marchini
    • , Richard Mott
    •  & Jonathan Flint
  2. Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, Virginia 23298, USA

    • Tim B. Bigdeli
    • , Mark Reimers
    • , Todd Webb
    • , Brien Riley
    • , Silviu Bacanu
    • , Roseann E. Peterson
    •  & Kenneth S. Kendler
  3. BGI-Shenzhen, Floor 9 Complex Building, Beishan Industrial Zone, YantianDistrict, Shenzhen, Guangdong 518083, China

    • Jieqin Liang
    • , Li Song
    • , Jingchu Hu
    • , Qibin Li
    • , Wei Jin
    • , Zhenfei Hu
    • , Guangbiao Wang
    • , Linmao Wang
    • , Puyi Qian
    • , Yuan Liu
    • , Tao Jiang
    • , Yao Lu
    • , Xiuqing Zhang
    • , Ye Yin
    • , Yingrui Li
    • , Xun Xu
    • , Huanming Yang
    • , Jian Wang
    •  & Jun Wang
  4. Zhejiang Traditional Chinese Medical Hospital, No.54 Youdian Road, Hangzhou, Zhejiang 310000, China

    • Jingfang Gao
  5. CTSU, Richard Doll Building, University of Oxford, Old Road Campus, Oxford OX3 7LF, UK

    • Yiping Chen
  6. Anhui Mental Health Center, No.316 Huangshan Road, Hefei, Anhui 230000, China

    • Hui Zhong
  7. Anshan Psychiatric Rehabilitation Hospital, No.127 Shuangshan Road, Lishan District, Anshan, Liaoning 114000, China

    • Zhengrong Liu
  8. Beijing Anding Hospital of Capital University of Medical Sciences, No.5 Ankang Hutong, Deshengmen wai, Xicheng District, Beijing, Beijing 100000, China

    • Gang Wang
  9. Brain Hospital of Nanjing Medical University, No.264 Guangzhou Road, Nanjing, Jiangsu 210000, China

    • Jing Sun
  10. Changchun Mental Hospital, No.4596 Beihuan Road, Changchun, Jilin 130000, China

    • Hong Sang
  11. Chongqing Mental Health Center, No.102 Jinzishan, Jiangbei District, Chongqing 404100, China

    • Guoqing Jiang
    •  & Xiaoyan Zhou
  12. Dalian No.7 Hospital, No.179 Lingshui Road, Ganjingzi District, Dalian, Liaoning 116000, China

    • Yi Li
  13. Wuhan Mental Health Center, No.70, Youyi Road, Wuhan, Hubei 430000, China

    • Yi Li
  14. Daqing No.3 Hospital of Heilongjiang Province, No.54 Xitai Road, Ranghulu district, Daqing, Heilongjiang 163000, China

    • Wei Zhang
  15. First Hospital of Hebei Medical University, No.89 Donggang Road, Shijiazhuang, Hebei 50000, China

    • Xueyi Wang
  16. Fuzhou Psychiatric Hospital, No.451 South Erhuan Road, Cangshan District, Fuzhou, Fujian 350000, China

    • Xiang Fang
  17. Guangxi Longquanshan Hospital, No.1 Jila Road, Yufeng District, Liuzhou, Guangxi Zhuangzu 545000, China

    • Runde Pan
  18. Guangzhou Brain Hospital, Guangzhou Psychiatric Hospital, No.36 Mingxin Road, Fangcun Avenue, Liwan District, Guangzhou, Guangdong 510000, China

    • Guodong Miao
  19. Hainan Anning Hospital, No.10 East Nanhai Avenue, Haikou, Hainan 570100, China

    • Qiwen Zhang
  20. Harbin Medical University, No.23 Youzheng street, Nangang District, Haerbin, Heilongjiang 150000, China

    • Jian Hu
  21. Harbin No.1 Special Hospital, No.217 Hongwei Road, Haerbin, Heilongjiang 150000, China

    • Fengyu Yu
  22. Hebei Mental Health Center, No.572 Dongfeng Road, Baoding, Hebei 71000, China

    • Bo Du
    • , Wenhua Sang
    •  & Keqing Li
  23. Huaian No.3 Hospital, No.272 West Huaihai Road, Huaian, Jiangsu 223001, China

    • Guibing Chen
  24. Huzhou No.3 Hospital, No.255 Gongyuan Road, Huzhou, Zhejiang 313000, China

    • Min Cai
  25. Jilin Brain Hospital, No.98 West Zhongyang Road, Siping, Jilin 136000, China

    • Lijun Yang
  26. Jining Psychiatric Hospital, North Dai Zhuang, Rencheng District, Jining, Shandong 272000, China

    • Donglin Yang
  27. Liaocheng No. 4 Hospital, No.47 North Huayuan Road, Liaocheng, Shandong 252000, China

    • Baowei Ha
  28. Mental Health Center of Shantou University, No.243 Daxue Road, Shantou, Guangdong 515000, China

    • Xiaohong Hong
  29. Mental Health Center of West China Hospital of Sichuan University, No.28 South Dianxin Street, Wuhou District, Chengdu, Sichuan 610000, China

    • Hong Deng
  30. Mental Health Institute of Jining Medical College, Dai Zhuang, Bei Jiao, Jining, Shandong 272000, China

    • Gongying Li
  31. Mental Hospital of Jiangxi Province, No.43 Shangfang Road, Nanchang, Jiangxi 330000, China

    • Kan Li
  32. Mudanjiang Psychiatric Hospital of Heilongjiang Province, Xinglong, Mudanjiang, Heilongjiang 157000, China

    • Yan Song
  33. Ningbo Kang Ning Hospital, No.1 Zhuangyu Road, Zhenhai District, Ningbo, Zhejiang 315000, China

    • Shugui Gao
  34. No. 3 Hospital of Sun Yat-sen University, No.600 Tianhe Road, Tianhe District, Guangzhou, Guangdong 510630, China

    • Jinbei Zhang
    •  & Zhaoyu Gan
  35. No.1 Hospital of Chongqing Medical University, No.1 Youyi Road, Yuanjiagang, Yuzhong District, Chongqing, Chongqing 400016, China

    • Huaqing Meng
  36. No.1 Hospital of Jinan University, No.613 West Huangpu Avenue, Guangzhou, Guangdong 510000, China

    • Jiyang Pan
  37. No.1 Hospital of Medical College of Xian Jiaotong University, No. 277 West Yan Ta Road, Xian, Shaan Xi 710061, China

    • Chengge Gao
  38. No.1 Hospital of Shanxi Medical University, No.85 South Jiefang Road, Taiyuan, Shanxi 30000, China

    • Kerang Zhang
    •  & Ning Sun
  39. No.1 Hospital of Zhengzhou University, No.1 East Jianshe Road, Zhengzhou, Henan 450000, China

    • Youhui Li
    •  & Qihui Niu
  40. No.2 Hospital of Lanzhou University, No.82, Cuiyingmen, Lanzhou, Gansu 730000, China

    • Yutang Zhang
  41. No.2 Xiangya Hospital of Zhongnan University, No.139 Middle Renmin Road, Furong District, Changsha, Hunan 410000, China

    • Tieqiao Liu
  42. No.3 Hospital of Heilongjiang Province, No.135 Jiaotong Road, Beian, Heilongjiang 164000, China

    • Chunmei Hu
  43. No.4 Hospital of Jiangsu University, No.246 Nanmen Street, Zhenjiang, Jiangsu 212000, China

    • Zhen Zhang
  44. Psychiatric Hospital of Henan Province, No.388 Middle Jianshe Road, Xinxiang, Henan 453000, China

    • Luxian Lv
  45. Qingdao Mental Health Center, No.299 Nanjing Road, Shibei District, Qingdao, Shandong 266000, China

    • Jicheng Dong
  46. Renmin Hospital of Wuhan University, No.238 Jiefang Road, Wuchang District, Wuhan, Hubei 430000, China

    • Xiaoping Wang
  47. Second Affiliated Hospital of Zhejiang Chinese Medical University, No.318 Chaowang Road, Hangzhou, Zhejiang 310000, China

    • Ming Tao
  48. ShengJing Hospital of China Medical University, No.36 Sanhao Street, Heping District, Shenyang, Liaoning 110001, China

    • Xumei Wang
    •  & Jing Xia
  49. Shenzhen Key Lab for Psychological Healthcare, Kangning Hospital, No.1080, Cuizhu Street, Luohu District, Shenzhen, Guangdong 518000, China

    • Han Rong
  50. Department of General Internal Medicine, Kanazawa Medical University, Kahoku, Ishikawa 920-0293, Japan

    • Qiang He
  51. Shenzhen Key Lab for Psychological Healthcare;Shenzhen Kangning Hospital, No.1080, Cuizhu Street, Luohu District, Shenzhen, Guangdong 518000, China

    • Tiebang Liu
  52. Sichuan Mental Health Center, No.190, East Jiannan Road, Mianyang, Sichuan 621000, China

    • Guoping Huang
  53. Suzhou Guangji Hospital, No.286, Guangji Road, Suzhou, Jiangsu 215000, China

    • Qiyi Mei
  54. Tangshan No.5 Hospital, No.57 West Nanxin Road, Lunan District, Tangshan, Hebei 63000, China

    • Zhenming Shen
  55. The First Hospital of China Medical University, No.155 North Nanjing Street, Heping District, Shenyang, Liaoning 110001, China

    • Ying Liu
  56. Tianjin Anding Hospital, No.13 Liulin Road, Hexi District, Tianjin 300000, China

    • Jianhua Shen
    •  & Tian Tian
  57. Tianjin First Center Hospital, No.55 Xuetang Street, Xinkai Road, Hedong District, Tianjin 300000, China

    • Xiaojuan Liu
  58. Tongji University Hospital, No.389 Xinchun Road, Shanghai 200000, China

    • Wenyuan Wu
  59. Weihai Mental Health Center, Qilu Avenue, ETDZ, Weihai, Shandong 264200, China

    • Danhua Gu
  60. Xian Mental Health Center, No.15 Yanyin Road, New Qujiang District, Xian, Shaanxi 710000, China

    • Jianguo Shi
  61. Xijing Hospital of No.4 Military Medical University, No.17 West Changle Road, Xian, Shaanxi 710000, China

    • Yunchun Chen
  62. Department of Comparative Developmental Genetics, Max Planck Institute for Plant Breeding Research, Carl-von-Linne-Weg 10, Cologne 50829, Germany

    • Xiangchao Gan
  63. Shandong Mental Health Center, No.49 East Wenhua Road, Jinan, Shandong 250000, China

    • Lanfen Liu
    •  & Lina Wang
  64. Shanghai Jiao Tong University School of Medicine, Shanghai Mental Health Centre, No. 600 Wan Ping Nan Road, Shanghai 200030, China

    • Fuzhong Yang
    • , Enzhao Cong
    •  & Shenxun Shi
  65. Department of Statistics, University of Oxford, Oxford OX1 3TG, UK

    • Jonathan Marchini
  66. Fudan University affiliated Huashan Hospital, No. 12 Wulumuqi Zhong Road, Shanghai 200040, China

    • Shenxun Shi
  67. National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences & Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 10005, China

    • Qi Xu
  68. Department of Biology, University of Copenhagen, Ole Maal Oes Vej 5, Copenhagen 2200, Denmark

    • Jun Wang
  69. Macau University of Science and Technology, Avenida Wai long, Taipa, Macau 999078, China, Taipa, Macau 999078, China

    • Jun Wang
  70. Princess Al Jawhara Center of Excellence in the Research of Hereditary Disorders, King Abdulaziz University, Jeddah 21589, Saudi Arabia

    • Jun Wang
  71. East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, China

    • Jonathan Flint

Consortia

  1. CONVERGE consortium

Authors

    Contributions

    Manuscript preparation: N. Cai, T. B. Bigdeli, W. Kretzschmar, M. Reimers, T. Webb, B. Riley, S. Bacanu, R. E. Peterson, K. S. Kendler and J. Flint. Replication sample: Q. Xu CONVERGE sample collection: Yih. Li, Y. Chen, H. Deng, W. Sang, Ke. Li, J. Gao, B. Ha, S. Gao, J. Hu, C. Hu, G. Huang, G. Jiang, X. Zhou, You. Li, Kan Li, Q. Niu, Yi Li, G. Li, L. Liu, Z. Liu, Yi Li, X. Fang, R. Pan, G. Miao, Q. Zhang, F. Yu, G. Chen, M. Cai, D. Yang, X. Hong, Y. Song, C. Gao, J. Pan, Y. Zhang, T. Liu, J. Dong, X. Wang, L. Wang, Q. Mei, Z. Shen, X. Liu, W. Wu, D. Gu, Y. Chen, T. Liu, H. Rong, Yi. Liu, L. Lv, H. Meng, H. Sang, J. Shen, T. Tian, J. Shi, J. Sun, M. Tao, X. Wang, J. Xia, Q. He, G. Wang, X. Wang, Lina Yang, K. Zhang, N. Sun, J. Zhang, Z. Gan, Z. Zhang, W. Zhang, H. Zhong, F. Yang, E. Cong, S. Shi, G. Fu, J. Flint and K. S. Kendler. Genome sequencing and analysis: J. Liang, J. Hu, Q. Li, W. Jin, Z. Hu, G. Wang, Linm. Wang, P. Qian, Yu. Liu, T. Jiang, Y. Lu, X. Zhang, Y. Yin, Yin. Li, H. Yang, Jia. Wang, X. Gan, Yih. Li, N. Cai, R. Mott, J. Flint, Jun Wang and X. Xu. Genotype imputation: W. Kretzschmar, J. Hu, L. Song, Q. Li, N. Cai and J. Marchini. Genetic analysis: N. Cai, T. Bigdeli, Yih. Li, R. E. Peterson, S. Bacanu, T. Webb, B. Riley, K. S. Kendler, R. Mott and J. Flint.

    Competing interests

    The author declare no competing financial interests.

    Corresponding authors

    Correspondence to Qi Xu or Jun Wang or Kenneth S. Kendler or Jonathan Flint.

    All sequence data and MDD results are freely available at http://dx.doi.org/10.5524/100155. GWAS results are also available at http://www.med.unc.edu/pgc/downloads.

    Extended data

    Supplementary information

    PDF files

    1. 1.

      Supplementary Information

      This file contains Supplemental Notes 1-2, Supplementary References and Supplementary Tables 1-3.

    Excel files

    1. 1.

      Supplementary Information

      This file contains Supplementary Table 4, a list of SNPs associated with MDD with P values < 10-5.

    2. 2.

      Supplementary Information

      This file contains Supplementary Table 5, a list of SNPs associated with Melancholia with P values < 10-5.

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