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

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 In March 2019, Nature was notified that this dataset was subsequently withdrawn from NCBI by request of the submitter.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

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.

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.

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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).

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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 or Jun Wang or 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
Extended Data Table 2 Genotype distribution and P values for violation of the Hardy–Weinberg equilibrium in CONVERGE and replication cohorts
Extended Data Table 3 Single-marker association results of top CONVERGE hits in the PGC study of MDD
Extended Data Table 4 Polygenic risk profiling and binomial sign tests

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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Cai, N., Bigdeli, T., Kretzschmar, W. et al. 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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