Sparse whole-genome sequencing identifies two loci for major depressive disorder (original) (raw)

Change history

Editors’ note: We would like to alert our readers to a change in the data availability for this manuscript. The genotype and whole genome sequence data used in this publication were made publicly available at the time of publication through the GigaDB database at http://gigadb.org/dataset/100155\. In March 2019, Nature was notified that the whole genome sequence data files have been removed from GigaDB. The genotype data files remain available at GigaDB. The whole genome sequence data was also made available in 2016 at NCBI with accession number PRJNA289433 (https://www.ncbi.nlm.nih.gov/bioproject/?term=PRJNA289433). In March 2019, Nature was notified that this dataset was subsequently withdrawn from NCBI by request of the submitter. We are currently investigating the data availability for the whole genome sequence data and will publish an update once our investigation is complete.

A Correction to this paper has been published: https://doi.org/10.1038/s41586-023-06276-1

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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

  1. A full list of authors and affiliations appears at the end of the paper.
  2. Na Cai, Tim B. Bigdeli, Warren Kretzschmar and Yihan Li: These authors contributed equally to this work.
  3. Qi Xu, Jun Wang, Kenneth S. Kendler and Jonathan Flint: These authors jointly supervised this work.

Authors and 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, 23298, Virginia, 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, 518083, Guangdong, 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, 310000, Zhejiang, 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, 230000, Anhui, China
    Hui Zhong
  7. Anshan Psychiatric Rehabilitation Hospital, No.127 Shuangshan Road, Lishan District, Anshan, 114000, Liaoning, China
    Zhengrong Liu
  8. Beijing Anding Hospital of Capital University of Medical Sciences, No.5 Ankang Hutong, Deshengmen wai, Xicheng District, Beijing, 100000, Beijing, China
    Gang Wang
  9. Brain Hospital of Nanjing Medical University, No.264 Guangzhou Road, Nanjing, 210000, Jiangsu, China
    Jing Sun
  10. Changchun Mental Hospital, No.4596 Beihuan Road, Changchun, 130000, Jilin, 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, 116000, Liaoning, China
    Yi Li
  13. Wuhan Mental Health Center, No.70, Youyi Road, Wuhan, 430000, Hubei, China
    Yi Li
  14. Daqing No.3 Hospital of Heilongjiang Province, No.54 Xitai Road, Ranghulu district, Daqing, 163000, Heilongjiang, China
    Wei Zhang
  15. First Hospital of Hebei Medical University, No.89 Donggang Road, Shijiazhuang, 50000, Hebei, China
    Xueyi Wang
  16. Fuzhou Psychiatric Hospital, No.451 South Erhuan Road, Cangshan District, Fuzhou, 350000, Fujian, China
    Xiang Fang
  17. Guangxi Longquanshan Hospital, No.1 Jila Road, Yufeng District, Liuzhou, 545000, Guangxi Zhuangzu, China
    Runde Pan
  18. Guangzhou Brain Hospital, Guangzhou Psychiatric Hospital, No.36 Mingxin Road, Fangcun Avenue, Liwan District, Guangzhou, 510000, Guangdong, China
    Guodong Miao
  19. Hainan Anning Hospital, No.10 East Nanhai Avenue, Haikou, 570100, Hainan, China
    Qiwen Zhang
  20. Harbin Medical University, No.23 Youzheng street, Nangang District, Haerbin, 150000, Heilongjiang, China
    Jian Hu
  21. Harbin No.1 Special Hospital, No.217 Hongwei Road, Haerbin, 150000, Heilongjiang, China
    Fengyu Yu
  22. Hebei Mental Health Center, No.572 Dongfeng Road, Baoding, 71000, Hebei, China
    Bo Du, Wenhua Sang & Keqing Li
  23. Huaian No.3 Hospital, No.272 West Huaihai Road, Huaian, 223001, Jiangsu, China
    Guibing Chen
  24. Huzhou No.3 Hospital, No.255 Gongyuan Road, Huzhou, 313000, Zhejiang, China
    Min Cai
  25. Jilin Brain Hospital, No.98 West Zhongyang Road, Siping, 136000, Jilin, China
    Lijun Yang
  26. Jining Psychiatric Hospital, North Dai Zhuang, Rencheng District, Jining, 272000, Shandong, China
    Donglin Yang
  27. Liaocheng No. 4 Hospital, No.47 North Huayuan Road, Liaocheng, 252000, Shandong, China
    Baowei Ha
  28. Mental Health Center of Shantou University, No.243 Daxue Road, Shantou, 515000, Guangdong, China
    Xiaohong Hong
  29. Mental Health Center of West China Hospital of Sichuan University, No.28 South Dianxin Street, Wuhou District, Chengdu, 610000, Sichuan, China
    Hong Deng
  30. Mental Health Institute of Jining Medical College, Dai Zhuang, Bei Jiao, Jining, 272000, Shandong, China
    Gongying Li
  31. Mental Hospital of Jiangxi Province, No.43 Shangfang Road, Nanchang, 330000, Jiangxi, China
    Kan Li
  32. Mudanjiang Psychiatric Hospital of Heilongjiang Province, Xinglong, Mudanjiang, 157000, Heilongjiang, China
    Yan Song
  33. Ningbo Kang Ning Hospital, No.1 Zhuangyu Road, Zhenhai District, Ningbo, 315000, Zhejiang, China
    Shugui Gao
  34. No. 3 Hospital of Sun Yat-sen University, No.600 Tianhe Road, Tianhe District, Guangzhou, 510630, Guangdong, China
    Jinbei Zhang & Zhaoyu Gan
  35. No.1 Hospital of Chongqing Medical University, No.1 Youyi Road, Yuanjiagang, Yuzhong District, Chongqing, 400016, Chongqing, China
    Huaqing Meng
  36. No.1 Hospital of Jinan University, No.613 West Huangpu Avenue, Guangzhou, 510000, Guangdong, China
    Jiyang Pan
  37. No.1 Hospital of Medical College of Xian Jiaotong University, No. 277 West Yan Ta Road, Xian, 710061, Shaan Xi, China
    Chengge Gao
  38. No.1 Hospital of Shanxi Medical University, No.85 South Jiefang Road, Taiyuan, 30000, Shanxi, China
    Kerang Zhang & Ning Sun
  39. No.1 Hospital of Zhengzhou University, No.1 East Jianshe Road, Zhengzhou, 450000, Henan, China
    Youhui Li & Qihui Niu
  40. No.2 Hospital of Lanzhou University, No.82, Cuiyingmen, Lanzhou, 730000, Gansu, China
    Yutang Zhang
  41. No.2 Xiangya Hospital of Zhongnan University, No.139 Middle Renmin Road, Furong District, Changsha, 410000, Hunan, China
    Tieqiao Liu
  42. No.3 Hospital of Heilongjiang Province, No.135 Jiaotong Road, Beian, 164000, Heilongjiang, China
    Chunmei Hu
  43. No.4 Hospital of Jiangsu University, No.246 Nanmen Street, Zhenjiang, 212000, Jiangsu, China
    Zhen Zhang
  44. Psychiatric Hospital of Henan Province, No.388 Middle Jianshe Road, Xinxiang, 453000, Henan, China
    Luxian Lv
  45. Qingdao Mental Health Center, No.299 Nanjing Road, Shibei District, Qingdao, 266000, Shandong, China
    Jicheng Dong
  46. Renmin Hospital of Wuhan University, No.238 Jiefang Road, Wuchang District, Wuhan, 430000, Hubei, China
    Xiaoping Wang
  47. Second Affiliated Hospital of Zhejiang Chinese Medical University, No.318 Chaowang Road, Hangzhou, 310000, Zhejiang, China
    Ming Tao
  48. ShengJing Hospital of China Medical University, No.36 Sanhao Street, Heping District, Shenyang, 110001, Liaoning, China
    Xumei Wang & Jing Xia
  49. Shenzhen Key Lab for Psychological Healthcare, Kangning Hospital, No.1080, Cuizhu Street, Luohu District, Shenzhen, 518000, Guangdong, China
    Han Rong
  50. Department of General Internal Medicine, Kanazawa Medical University, Kahoku, 920-0293, Ishikawa, Japan
    Qiang He
  51. Shenzhen Key Lab for Psychological Healthcare;Shenzhen Kangning Hospital, No.1080, Cuizhu Street, Luohu District, Shenzhen, 518000, Guangdong, China
    Tiebang Liu
  52. Sichuan Mental Health Center, No.190, East Jiannan Road, Mianyang, 621000, Sichuan, China
    Guoping Huang
  53. Suzhou Guangji Hospital, No.286, Guangji Road, Suzhou, 215000, Jiangsu, 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, 110001, Liaoning, China
    Ying Liu
  56. Tianjin Anding Hospital, No.13 Liulin Road, Hexi District, 300000, Tianjin, China
    Jianhua Shen & Tian Tian
  57. Tianjin First Center Hospital, No.55 Xuetang Street, Xinkai Road, Hedong District, 300000, Tianjin, 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, 264200, Shandong, China
    Danhua Gu
  60. Xian Mental Health Center, No.15 Yanyin Road, New Qujiang District, Xian, 710000, Shaanxi, China
    Jianguo Shi
  61. Xijing Hospital of No.4 Military Medical University, No.17 West Changle Road, Xian, 710000, Shaanxi, 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, 250000, Shandong, 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, 999078, Macau, 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

CONVERGE consortium

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.

Corresponding authors

Correspondence toQi Xu, Jun Wang, Kenneth S. Kendler or Jonathan Flint.

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Competing interests

The author declare no competing financial interests.

Additional information

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 figures and tables

Extended Data Figure 1 Quantile–quantile plots for major depressive disorder.

Quantile–quantile plot of GWAS for MDD using the mixed linear model with exclusion of the chromosome that the marker is on (MLMe) method implemented in FastLMM on 10,640 samples (5,303 cases, 5,337 controls). Genomic inflation factor λ = 1.070, rescaled for an equivalent study of 1,000 cases and 1,000 controls (λ 1000) = 1.013.

Extended Data Figure 2 Forest plots of estimated SNP effects in CONVERGE and PGC studies.

This figure presents the association odds ratios (OR) at 12 SNPs in CONVERGE and the best available proxy SNPs in PGC-MDD (pairwise r 2 > 0.6, 500 kb window; the proxy SNP is marked by an asterisk). We present the alternative allele frequency (freq), odds ratio (or) with respect to the alternative allele, standard error of odds ratio (se) and P values of association (pval) for the following analyses (study): primary association analysis with a linear-mixed model using imputed allele dosages in 10,640 samples in CONVERGE (pri); validation analysis with logistic regression model with principal components (PCs) as covariates using genotypes from Sequenom on 9,921 samples in CONVERGE (sqnm); association with MDD with a logistic regression model in a replication cohort of 6,417 samples using genotypes from Sequenom (repli); joint association analysis with MDD with a logistic regression model using imputed allele dosages in CONVERGE and genotypes from Sequenom in a replication cohort (17,057 samples in total; joint).

Extended Data Figure 3 Manhattan and quantile quantile plots for melancholia.

a, Manhattan plot of GWAS for melancholia using the MLMe method implemented in FastLMM on 9,846 samples (4,509 cases, 5,337 controls). b, Quantile–quantile plot of GWAS for melancholia; λ = 1.069, λ 1000 = 1.014. c, Regional association plot of GWAS hits on chromosome 10, focusing on top SNP rs80309727 at 5′ of SIRT1 gene, generated with LocusZoom.

Extended Data Figure 4 Empirical estimation of the odds ratio increases due to the removal of cases not falling under the diagnostic class of melancholia from an association analysis with major depression.

The figures show the empirical distributions of the odds ratios for association with each of two SNPs (rs79804696, rs35936514), after removing a random set of 796 samples, equal to the number of cases of MDD not diagnosed as being melancholic. The horizontal axis is the odds ratio for each analysis, and the vertical axis the frequency of occurrence of the odds ratio in 10,000 analyses. The vertical red line is the observed odds ratio after removing cases of MDD not diagnosed as melancholic.

Extended Data Table 1 Comparison between association results using imputed dosages and directly genotyped markers

Full size table

Extended Data Table 2 Genotype distribution and P values for violation of the Hardy–Weinberg equilibrium in CONVERGE and replication cohorts

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Extended Data Table 3 Single-marker association results of top CONVERGE hits in the PGC study of MDD

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Extended Data Table 4 Polygenic risk profiling and binomial sign tests

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Supplementary information

Supplementary Information

This file contains Supplemental Notes 1-2, Supplementary References and Supplementary Tables 1-3. (PDF 478 kb)

Supplementary Information

This file contains Supplementary Table 4, a list of SNPs associated with MDD with P values < 10-5. (XLSX 60 kb)

Supplementary Information

This file contains Supplementary Table 5, a list of SNPs associated with Melancholia with P values < 10-5. (XLSX 109 kb)

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CONVERGE consortium. Sparse whole-genome sequencing identifies two loci for major depressive disorder.Nature 523, 588–591 (2015). https://doi.org/10.1038/nature14659

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