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

Nature volume 523, pages 588–591 (2015)Cite this article

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12 April 2019 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 In March 2019, Nature was notified that this dataset was subsequently withdrawn from NCBI by request of the submitter.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.

An Author Correction to this article was published on 11 August 2023

This article has been updated

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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Figure 1: Two loci associated with MDD in the CONVERGE sample.

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Change history

  • 12 April 2019

    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.

  • 11 August 2023

    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

  • Na Cai
  • , Tim B. Bigdeli
  • , Warren Kretzschmar
  • , Yihan Li
  • , 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
  • , Jingfang Gao
  • , Mark Reimers
  • , Todd Webb
  • , Brien Riley
  • , Silviu Bacanu
  • , Roseann E. Peterson
  • , Yiping Chen
  • , Hui Zhong
  • , Zhengrong Liu
  • , Gang Wang
  • , Jing Sun
  • , Hong Sang
  • , Guoqing Jiang
  • , Xiaoyan Zhou
  • , Yi Li
  • , Yi Li
  • , Wei Zhang
  • , Xueyi Wang
  • , Xiang Fang
  • , Runde Pan
  • , Guodong Miao
  • , Qiwen Zhang
  • , Jian Hu
  • , Fengyu Yu
  • , Bo Du
  • , Wenhua Sang
  • , Keqing Li
  • , Guibing Chen
  • , Min Cai
  • , Lijun Yang
  • , Donglin Yang
  • , Baowei Ha
  • , Xiaohong Hong
  • , Hong Deng
  • , Gongying Li
  • , Kan Li
  • , Yan Song
  • , Shugui Gao
  • , Jinbei Zhang
  • , Zhaoyu Gan
  • , Huaqing Meng
  • , Jiyang Pan
  • , Chengge Gao
  • , Kerang Zhang
  • , Ning Sun
  • , Youhui Li
  • , Qihui Niu
  • , Yutang Zhang
  • , Tieqiao Liu
  • , Chunmei Hu
  • , Zhen Zhang
  • , Luxian Lv
  • , Jicheng Dong
  • , Xiaoping Wang
  • , Ming Tao
  • , Xumei Wang
  • , Jing Xia
  • , Han Rong
  • , Qiang He
  • , Tiebang Liu
  • , Guoping Huang
  • , Qiyi Mei
  • , Zhenming Shen
  • , Ying Liu
  • , Jianhua Shen
  • , Tian Tian
  • , Xiaojuan Liu
  • , Wenyuan Wu
  • , Danhua Gu
  • , Guangyi Fu
  • , Jianguo Shi
  • , Yunchun Chen
  • , Xiangchao Gan
  • , Lanfen Liu
  • , Lina Wang
  • , Fuzhong Yang
  • , Enzhao Cong
  • , Jonathan Marchini
  • , Huanming Yang
  • , Jian Wang
  • , Shenxun Shi
  • , Richard Mott
  • , Qi Xu
  • , Jun Wang
  • , Kenneth S. Kendler
  •  & Jonathan Flint

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

Ethics declarations

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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