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Genome-wide association analysis identifies 30 new susceptibility loci for schizophrenia

Abstract

We conducted a genome-wide association study (GWAS) with replication in 36,180 Chinese individuals and performed further transancestry meta-analyses with data from the Psychiatry Genomics Consortium (PGC2). Approximately 95% of the genome-wide significant (GWS) index alleles (or their proxies) from the PGC2 study were overrepresented in Chinese schizophrenia cases, including 50% that achieved nominal significance and 75% that continued to be GWS in the transancestry analysis. The Chinese-only analysis identified seven GWS loci; three of these also were GWS in the transancestry analyses, which identified 109 GWS loci, thus yielding a total of 113 GWS loci (30 novel) in at least one of these analyses. We observed improvements in the fine-mapping resolution at many susceptibility loci. Our results provide several lines of evidence supporting candidate genes at many loci and highlight some pathways for further research. Together, our findings provide novel insight into the genetic architecture and biological etiology of schizophrenia.

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Figure 1: Comparison of Manhattan plots for the Chinese and transancestry analyses.
Figure 2: Regional plots for novel GWS loci in Chinese people.
Figure 3: Interaction network of the schizophrenia-associated pathway 'glucagon-like peptide-1 regulates insulin secretion'.
Figure 4: Polygenic risk-score profiling analysis.

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Acknowledgements

We thank all of the participants in the study and the international Psychiatric GWAS Consortium (PGC) for the large-scale data resources that made this research possible. We also appreciate H. Huang, B. Neale and M. Daly for their valuable suggestions for data analysis and manuscript organization. This work was supported by the 973 Program (2015CB559100 to Y.S.), the National Key R&D Program of China (2016YFC0903402 to Y.S. and Z.L., and 2016YFC1201701 to X.L.), the Natural Science Foundation of China (31325014 to Y.S., 81130022 to Y.S., 81421061 to L.H. and 81701321 to Z.L.), the Program of Shanghai Subject Chief Scientist (15XD1502200 to Y.S.), the National Program for Support of Top-Notch Young Professionals to Y.S., the Shanghai Key Laboratory of Psychotic Disorders (13dz2260500 to Y.X.), the 'Shu Guang' project supported by the Shanghai Municipal Education Commission and Shanghai Education Development Foundation (12SG17 to Y.S.), the China Postdoctoral Science Foundation (2016M590615 to Z.L.), the Shandong Postdoctoral Innovation Foundation (201601015 to Z.L.), the Qingdao Postdoctoral Application Research Project (2016048 to Z.L.), the Shanghai Hospital Development Center (SHDC12016115 to Y.X.), the US NIMH and NIDA (U01 MH109528 to P.F.S. and U01 MH1095320 to P.F.S.), and the Swedish Research Council (Vetenskapsrådet, award D0886501 to P.F.S.).

Author information

Authors and Affiliations

Authors

Contributions

Y.S. conceived and designed the experiments, and supervised all aspects of the work; J.C., Y.X., L.H., D.Z., W.Y., P.W., P.Y., B. Liu, W.S., Q.X., W.J., G.F., Q.Y., C.L. and X.L. performed sample collection and phenotyping; J.C., H.Y., J.Z., B.C., Y.L., J.W., J.J., M.W., Q.W., Z.W., Wenjin Li, K.L., F.H., J.Z., G.H., Weidong Li, C.W. and B. Li performed the experiments and data management; Z.L., H.Y., Z.S., J.S., S.R., P.F.S. and M.C.O'D. performed bioinformatics and statistical analyses; Y.S. and Z.L. interpreted the main findings; Y.S. and Z.L. drafted the manuscript; Y.S., L.H., Z.L., Y.X., X.L. and P.F.S. obtained the funding support; all authors revised and approved the final manuscript.

Corresponding author

Correspondence to Yongyong Shi.

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The authors declare no competing financial interests.

Integrated supplementary information

Supplementary Figure 1 PCA of the Chinese GWAS sample with the HapMap3 sample.

a) GWAS Set 1, b) GWAS Set 2, c) GWAS Set 3. Plot of the first two principal components (C1 and C2) from principal components analysis (PCA) of Chinese GWAS sample with HapMap3 sample. The enlarged area is for the Aisan sample, including our cases and controls.

Supplementary Figure 2 Quantile–quantile (Q–Q) plot of the GWAS analysis of Chinese individuals.

The Q-Q plot representative of observed (y axis) vs. expected (x axis) SNP P values distribution. Expected P values are those expected under the null hypothesis, and the uniform null distribution is marked with a red line.

Supplementary Figure 3 Manhattan plot of the GWAS analysis of Chinese individuals.

Genome-wide P-values (–log10 P, y axis) plotted against their respective chromosomal positions (x axis). The blue line is the suggestive significance level (1 × 10−5).

Supplementary Figure 4 Quantile–quantile plot of the Chinese and PGC2 GWAS meta-analysis.

The Q-Q plot representative of observed (y axis) vs. expected (x axis) SNP P values distribution. Expected P values are those expected under the null hypothesis, and the uniform null distribution is marked with a red line.

Supplementary Figure 5 Manhattan plot of the Chinese and PGC2 GWAS meta-analysis.

Genome-wide P-values (–log10 P, y axis) plotted against their respective chromosomal positions (x axis). The blue line is the suggestive significance level (5 × 10−7).

Supplementary Figure 6 Regional plots of the GWS loci from the Chinese GWAS and replication meta-analysis.

a) rs1518395 at 2p16.1, b) rs78681500 at 2q33.1, c) rs111782145 at eMHC. −log10 P values are shown for SNPs for the region 500 kb on either side of the marker SNPs. The index SNP is shown in purple, and the r2 values of the other SNPs are indicated by color. The r2 values are established based on the 1000 Genome data. The genes within the relevant regions are annotated and shown as arrows.

Supplementary Figure 7 Fine-mapping analyses for GWS loci nos. 80 and 103 with PAINTOR.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–7 and Supplementary Tables 1 and 7 (PDF 1415 kb)

Life Sciences Reporting Summary (PDF 129 kb)

Supplementary Data 1

Regional plots of the GWS loci from the Chinese and PGC2 metaanalysis (PDF 18283 kb)

–log10 P values are shown for SNPs for the region 500 kb on either side of the marker SNPs. The index SNP is shown in purple, and the r2 values of the other SNPs are indicated by color. The r2 values are established based on the 1000 Genome data (Nov2014). The genes within the relevant regions are annotated and shown as arrows.

Supplementary Table 2

Results for the independent variants in 104 GWS regions in the PGC2 and Chinese GWAS meta-analysis (XLSX 20 kb)

Genomic position was based on the UCSC hg19/NCBI Build 37. OR=odds ratio for A1 and SE=standard error. I2 index represents the degree of heterogeneity. The previously reported schizophrenia associated variants were extracted from the NHGRI-EBI GWAS Catalog (https://www.ebi.ac.uk/gwas, as to Jan. 2017). The r2 values between the index SNPs and previously reported associated variants were calculated based on 1000 Genome Project dataset.

Supplementary Table 3

Results for the Chinese GWAS and replication (XLSX 17 kb)

The genome-wide significant SNPs in the meta-analysis were indicated as bold. Genomic position was based on the UCSC hg19/NCBI Build 37. OR=odds ratio for A1 and SE=standard error.

Supplementary Table 4

Results for meta-analysis of the Chinese and PGC2 samples (XLSX 32 kb)

The genome-wide significant SNPs in the meta-analysis were indicated as bold. Genomic position was based on the UCSC hg19/NCBI Build 37. OR=odds ratio for A1 and SE=standard error. I2 index represents the degree of heterogeneity. a The SNPs were unavailable in the Chinese Replication data set.

Supplementary Table 5

GWS schizophrenia loci in this study (XLSX 19 kb)

Genomic position was based on the UCSC hg19/NCBI Build 37. OR=odds ratio for A1 and SE=standard error. The results are based on the meta-analysis of Chinese GWAS and replication samples (CHN) or all samples (ALL), which were shown in the 'Analysis' column. a The SNPs also reached GWS in the meta-analysis of Chinese GWAS and replication samples. b The LD results were based on the 1000Genome Project (European or Chinese samples). c eMHC, the extended major histocompatibility complex region.

Supplementary Table 6

Results of the meta-analysis of the Chinese and PGC2 samples for the index SNPs or their proxies identified in the PGC2 report (XLSX 26 kb)

The ID for Loci and SNP is from the PGC2 report (Nature 511, 421–427, 2014). The SNP followed by (P) indicated a proxy of the index SNP. Genomic position was based on the UCSC hg19/NCBI Build 37. OR=odds ratio for A1 and SE=standard error. I2 index represents the degree of heterogeneity. PGC2+Chinese (Fixed) are the results under a fixed-effects model meta-analysis.

Supplementary Table 8

GWS schizophrenia loci and notable genes (XLSX 18 kb)

Genomic position was based on the UCSC hg19/NCBI Build 37. a Notable genes from gene nearest to the index SNP (N); Schizophrenia-associated variant is in strong LD (r2 ≥ 0.8) with a missense variant in the indicated gene (M); genes prioritized by DEPICT (D); genes for which the mRNA levels showed cis-genetic linkage with the index SNPs (Q); genes prioritized by SMR analysis (S).

Supplementary Table 9

The fine-mapping regions for schizophrenia GWS loci in different data sets. (XLSX 25 kb)

Supplementary Table 10

Results for fine-mapping analysis using PAINTOR (XLSX 12 kb)

Supplementary Table 11

Annotations for the 16 SNPs with a posterior probability of greater than 0.80 only in the trans-ethnic analysis (XLSX 9 kb)

Supplementary Table 12

eQTL analysis of rs3814883 (XLSX 11 kb)

Supplementary Table 13

The top 100 enriched cell-type specific epigenomic annotations for schizophrenia associations in the current and PGC2 analyses (XLSX 13 kb)

EID, the epigenome identifier in the Roadmap Epigenomics Project. Descriptions for cell and tissue types, related groups, and marks at the Roadmap Epigenomics Project website (http://www.roadmapepigenomics.org). P value, enrichment P for schizophrenia associations derived from GREGOR.

Supplementary Table 14

The top ranked SNPs with higher posterior probability in the further PAINTOR analyses with the cell-type specific epigenomic annotations (XLSX 12 kb)

a EID, the epigenome identifier in the Roadmap Epigenomics Project. Descriptions for cell and tissue types, related groups, and marks at the Roadmap Epigenomics Project website (http://www.roadmapepigenomics.org).

Supplementary Table 15

Top 30 significantly enriched pathways and gene sets in the cross-ethnic meta-analysis (XLSX 10 kb)

NGENES denotes the number of genes in pathway (number of genes successfully mapped by MAGMA).

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Li, Z., Chen, J., Yu, H. et al. Genome-wide association analysis identifies 30 new susceptibility loci for schizophrenia. Nat Genet 49, 1576–1583 (2017). https://doi.org/10.1038/ng.3973

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