Genome-wide association analysis identifies 30 new susceptibility loci for schizophrenia. Li Zhiqiang,Chen Jianhua,Yu Hao,He Lin,Xu Yifeng,Zhang Dai,Yi Qizhong,Li Changgui,Li Xingwang,Shen Jiawei,Song Zhijian,Ji Weidong,Wang Meng,Zhou Juan,Chen Boyu,Liu Yahui,Wang Jiqiang,Wang Peng,Yang Ping,Wang Qingzhong,Feng Guoyin,Liu Benxiu,Sun Wensheng,Li Baojie,He Guang,Li Weidong,Wan Chunling,Xu Qi,Li Wenjin,Wen Zujia,Liu Ke,Huang Fang,Ji Jue,Ripke Stephan,Yue Weihua,Sullivan Patrick F,O'Donovan Michael C,Shi Yongyong Nature genetics 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. 10.1038/ng.3973

Effect of Damaging Rare Mutations in Synapse-Related Gene Sets on Response to Short-term Antipsychotic Medication in Chinese Patients With Schizophrenia: A Randomized Clinical Trial. Wang Qiang,Man Wu Hei,Yue Weihua,Yan Hao,Zhang Yamin,Tan Liwen,Deng Wei,Chen Qi,Yang Guigang,Lu Tianlan,Wang Lifang,Zhang Fuquan,Yang Jianli,Li Keqing,Lv Luxian,Tan Qingrong,Zhang Hongyan,Ma Xin,Yang Fude,Li Lingjiang,Wang Chuanyue,Ma Xiaohong,Zhao Liansheng,Ren Hongyan,Yu Hao,Wang Yingcheng,Hu Xun,Zhang Dai,Sham Pak,Li Tao, JAMA psychiatry Importance:The underlying mechanism for individual differences in patient response to antipsychotic medication remains unknown. Objective:To discover genes and gene sets harboring rare variants associated with short-term antipsychotic medication efficacy. Design, Setting, and Participants:In this multicenter, open-label, randomized clinical trial conducted between July 6, 2010, and December 31, 2011, 3023 patients recruited in China of Chinese Han descent with schizophrenia with total Positive and Negative Syndrome Scale (PANSS) score ≥ 60 received a 6-week treatment of antipsychotic medications randomly chosen from 5 atypical and 2 typical antipsychotic medications. Whole-exome sequencing (WES) was performed in 316 participants (grouped into those with the best response [n=156] and those who had no response [n=160] to the antipsychotic medication prescribed), according to the total PANSS score reduction rate after 6 weeks of treatment. Validation was performed using targeted sequencing in an independent sample of 1920 patients. Data analyses was performed between March 15, 2016, and March 1, 2017. Main Outcomes and Measures:Drug efficacy at week 6 was assessed according to the change in PANSS scores from baseline. Extremely good and extremely poor responders were selected for an initial WES association study, from which a subset of genes showing putative association was selected for independent replication with a targeted sequencing approach. Results:Of the 3023 patients (1549 [51.24%] female and 1474 [48.8%] male; mean [SD] age, 31.2 [7.9] years), 2336 (77.3%) were eligible for genetic analysis. After quality-control exclusions, 316 patients (10.5%) were included for WES and 1920 (63.5%) were included for replication. In the WES discovery stage, 2 gene sets (reduced NMDA [N-methyl-D-aspartate]-mediated synaptic currents and reduced AMPA [α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid]-mediated synaptic currents) were found to be enriched with rare damaging variants in the nonresponder group, suggesting the involvement of these gene sets in antipsychotic medication efficacy. Reduced NMDA-mediated synaptic currents gene set was further replicated in an independent sample using targeting sequencing. No statistically significant differences in antipsychotic drug response were found among the patients who received different antipsychotic drugs. Conclusions and Relevance:Genetic variation in glutamatergic or NMDA neurotransmission is implicated in short-term antipsychotic medication efficacy; WES may have utility in the study of rare genetic variation in pharmacogenetics. Trial Registration:Chinese Clinical Trials Registry Identifier: ChiCTR-TRC-10000934. 10.1001/jamapsychiatry.2018.3039

Comparative genetic architectures of schizophrenia in East Asian and European populations. Nature genetics Schizophrenia is a debilitating psychiatric disorder with approximately 1% lifetime risk globally. Large-scale schizophrenia genetic studies have reported primarily on European ancestry samples, potentially missing important biological insights. Here, we report the largest study to date of East Asian participants (22,778 schizophrenia cases and 35,362 controls), identifying 21 genome-wide-significant associations in 19 genetic loci. Common genetic variants that confer risk for schizophrenia have highly similar effects between East Asian and European ancestries (genetic correlation = 0.98 ± 0.03), indicating that the genetic basis of schizophrenia and its biology are broadly shared across populations. A fixed-effect meta-analysis including individuals from East Asian and European ancestries identified 208 significant associations in 176 genetic loci (53 novel). Trans-ancestry fine-mapping reduced the sets of candidate causal variants in 44 loci. Polygenic risk scores had reduced performance when transferred across ancestries, highlighting the importance of including sufficient samples of major ancestral groups to ensure their generalizability across populations. 10.1038/s41588-019-0512-x

Identification of novel risk loci with shared effects on alcoholism, heroin, and methamphetamine dependence. Sun Yan,Chang Suhua,Liu Zhen,Zhang Libo,Wang Fan,Yue Weihua,Sun Hongqiang,Ni Zhaojun,Chang Xiangwen,Zhang Yibing,Chen Yang,Liu Jiqiang,Lu Lin,Shi Jie Molecular psychiatry Different substance dependences have common effects on reward pathway and molecular adaptations, however little is known regarding their shared genetic factors. We aimed to identify the risk genetic variants that are shared for substance dependence (SD). First, promising genome-wide significant loci were identified from 3296 patients (521 alcoholic/1026 heroin/1749 methamphetamine) vs 2859 healthy controls and independently replicated using 1954 patients vs 1904 controls. Second, the functional effects of promising variants on gene expression, addiction characteristics, brain structure (gray and white matter), and addiction behaviors in addiction animal models (chronic administration and self-administration) were assessed. In addition, we assessed the genetic correlation among the three SDs using LD score regression. We identified and replicated three novel loci that were associated with the common risk of heroin, methamphetamine addiction, and alcoholism: ANKS1B rs2133896 (P = 3.60 × 10), AGBL4 rs147247472 (P = 3.40 × 10), and CTNNA2 rs10196867 (P = 4.73 × 10). Rs2133896 in ANKS1B was associated with ANKS1B gene expression and had effects on gray matter of the left calcarine and white matter of the right superior longitudinal fasciculus in heroin dependence. Overexpression of anks1b gene in the ventral tegmental area decreased addiction vulnerability for heroin and methamphetamine in self-administration rat models. Our findings could shed light on the root cause for substance dependence and will be helpful for the development of cost-effective prevention strategies for general addiction disorders. 10.1038/s41380-019-0497-y

A neuroimaging biomarker for striatal dysfunction in schizophrenia. Li Ang,Zalesky Andrew,Yue Weihua,Howes Oliver,Yan Hao,Liu Yong,Fan Lingzhong,Whitaker Kirstie J,Xu Kaibin,Rao Guangxiang,Li Jin,Liu Shu,Wang Meng,Sun Yuqing,Song Ming,Li Peng,Chen Jun,Chen Yunchun,Wang Huaning,Liu Wenming,Li Zhigang,Yang Yongfeng,Guo Hua,Wan Ping,Lv Luxian,Lu Lin,Yan Jun,Song Yuqing,Wang Huiling,Zhang Hongxing,Wu Huawang,Ning Yuping,Du Yuhui,Cheng Yuqi,Xu Jian,Xu Xiufeng,Zhang Dai,Wang Xiaoqun,Jiang Tianzi,Liu Bing Nature medicine Mounting evidence suggests that function and connectivity of the striatum is disrupted in schizophrenia. We have developed a new hypothesis-driven neuroimaging biomarker for schizophrenia identification, prognosis and subtyping based on functional striatal abnormalities (FSA). FSA scores provide a personalized index of striatal dysfunction, ranging from normal to highly pathological. Using inter-site cross-validation on functional magnetic resonance images acquired from seven independent scanners (n = 1,100), FSA distinguished individuals with schizophrenia from healthy controls with an accuracy exceeding 80% (sensitivity, 79.3%; specificity, 81.5%). In two longitudinal cohorts, inter-individual variation in baseline FSA scores was significantly associated with antipsychotic treatment response. FSA revealed a spectrum of severity in striatal dysfunction across neuropsychiatric disorders, where dysfunction was most severe in schizophrenia, milder in bipolar disorder, and indistinguishable from healthy individuals in depression, obsessive-compulsive disorder and attention-deficit hyperactivity disorder. Loci of striatal hyperactivity recapitulated the spatial distribution of dopaminergic function and the expression profiles of polygenic risk for schizophrenia. In conclusion, we have developed a new biomarker to index striatal dysfunction and established its utility in predicting antipsychotic treatment response, clinical stratification and elucidating striatal dysfunction in neuropsychiatric disorders. 10.1038/s41591-020-0793-8