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

Li, Zhiqiang; Chen, Jianhua; Yu, Hao; He, Lin; Xu, Yifeng; Zhang, Dai; Quan, Yi; 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; Gao, Feng; 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 Conlon; Shi, Yongyong

doi:10.1038/ng.3973

Cited by 402 publications

(352 citation statements)

References 66 publications

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“…Of the previously reported SNPs at these loci, 16 met the threshold for “suggestive” evidence of association with risk taking in this study (Table S18). Where the reported data allowed comparison, results were as expected (Table S18), with alleles, which increased risk of SCZ 33,34,43,44 associated with increased risk taking; the allele for increased sleep duration 46 associated with reduced risk taking; and the allele for increased information processing speed 37 also associated with reduced risk taking. In contrast, the association between alleles for increased educational attainment 32 and increased risk taking may seem counter-intuitive but is consistent with previous findings from UK Biobank ( n ~116,000) 13 .…”

Section: Resultssupporting

confidence: 55%

“…These risk-taking loci have previously been associated with: educational attainment 32 , SCZ 33,34 and PTSD 35 (Chr1 locus); cognitive function 36,37 , educational attainment 32,38 , adiposity 39–41 and alcohol consumption 42 ( CADM2 locus); SCZ 43,44 and ADHD 45 (Chr6 locus); and sleep duration 46 ( FOXP2 locus). Of the previously reported SNPs at these loci, 16 met the threshold for “suggestive” evidence of association with risk taking in this study (Table S18).…”

Section: Resultsmentioning

confidence: 99%

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Genetics of self-reported risk-taking behaviour, trans-ethnic consistency and relevance to brain gene expression

et al. 2018

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Risk-taking behaviour is an important component of several psychiatric disorders, including attention-deficit hyperactivity disorder, schizophrenia and bipolar disorder. Previously, two genetic loci have been associated with self-reported risk taking and significant genetic overlap with psychiatric disorders was identified within a subsample of UK Biobank. Using the white British participants of the full UK Biobank cohort (n = 83,677 risk takers versus 244,662 controls) for our primary analysis, we conducted a genome-wide association study of self-reported risk-taking behaviour. In secondary analyses, we assessed sex-specific effects, trans-ethnic heterogeneity and genetic overlap with psychiatric traits. We also investigated the impact of risk-taking-associated SNPs on both gene expression and structural brain imaging. We identified 10 independent loci for risk-taking behaviour, of which eight were novel and two replicated previous findings. In addition, we found two further sex-specific risk-taking loci. There were strong positive genetic correlations between risk-taking and attention-deficit hyperactivity disorder, bipolar disorder and schizophrenia. Index genetic variants demonstrated effects generally consistent with the discovery analysis in individuals of non-British White, South Asian, African-Caribbean or mixed ethnicity. Polygenic risk scores comprising alleles associated with increased risk taking were associated with lower white matter integrity. Genotype-specific expression pattern analyses highlighted DPYSL5, CGREF1 and C15orf59 as plausible candidate genes. Overall, our findings substantially advance our understanding of the biology of risk-taking behaviour, including the possibility of sex-specific contributions, and reveal consistency across ethnicities. We further highlight several putative novel candidate genes, which may mediate these genetic effects.

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Section: Resultssupporting

confidence: 55%

Section: Resultsmentioning

confidence: 99%

Genetics of self-reported risk-taking behaviour, trans-ethnic consistency and relevance to brain gene expression

et al. 2018

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“…They reported associations for the histone methylation pathway as well as for immune and neuronal signaling and postsynaptic density [92]. Li et al[93] have recently added 30 new loci to the PGC results by adding a large Chinese sample of ∼36,000 individuals and combining them with the PGC data in meta-analysis. The PGC has also continued increasing their sample size and at the 2017 World Congress of Psychiatric Genetics, they reported the identification of 248 genome-wide significant loci, confirming the speculation that a large number of genes are likely involved in schizophrenia, and providing the basis for a tremendous amount of future work on the etiology of schizophrenia.…”

Section: Common Low-penetrance Variants and Gwasmentioning

confidence: 99%

Recent Advances in the Genetics of Schizophrenia

Avramopoulos

2018

Complex Psychiatry

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The last decade brought tremendous progress in the field of schizophrenia genetics. As a result of extensive collaborations and multiple technological advances, we now recognize many types of genetic variants that increase the risk. These include large copy number variants, rare coding inherited and de novο variants, and over 100 loci harboring common risk variants. While the type and contribution to the risk vary among genetic variants, there is concordance in the functions of genes they implicate, such as those whose RNA binds the fragile X-related protein FMRP and members of the activity-regulated cytoskeletal complex involved in learning and memory. Gene expression studies add important information on the biology of the disease and recapitulate the same functional gene groups. Studies of alternative phenotypes help us widen our understanding of the genetic architecture of mental function and dysfunction, how diseases overlap not only with each other but also with non-disease phenotypes. The challenge is to apply this new knowledge to prevention and treatment and help patients. The data generated so far and emerging technologies, including new methods in cell engineering, offer significant promise that in the next decade we will unlock the translational potential of these significant discoveries.

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“…For example, in a recent SCZ GWAS in Han Chinese population, a genetic variant (rs1518395) in the intron 1 of VRK2 showed a genome-wide significant association in a total of 12,083 cases and 24,097 controls ( p = 3.78 × 10 –13 , OR = 1.160 for G allele) [15]. This is one of the most significant SNPs for SCZ in Chinese, and this SNP was also genome-wide significantly associated with SCZ in European populations (35,476 cases and 46,839 controls, p = 3.43 × 10 –8 , OR = 1.061 for G allele, Fig.…”

Section: Identification Of Vrk2 Variants In Psychiatric Disorders Amomentioning

confidence: 99%

“…While current knowledge of this gene and its protein product is relatively rudimentary, there are many unexplored questions that arise from these exciting findings. First, the effects of variants in VRK2 on the genetic risk of psychiatric disorders are considered to be only modest (odds ratio ∼1.10) [13-15, 29], and the functions of the risk variants are still unclear. It is therefore under debate whether VRK2 could be directly used as a possible target in the future clinical management of these disorders.…”

Section: Future Perspectivesmentioning

confidence: 99%

<b><i>VRK2</i></b>, a Candidate Gene for Psychiatric and Neurological Disorders

Yue

2018

Complex Psychiatry

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Recent large-scale genetic approaches, such as genome-wide association studies, have identified multiple genetic variations that contribute to the risk of mental illnesses, among which single nucleotide polymorphisms (SNPs) within or near the vaccinia related kinase 2 (VRK2) gene have gained consistent support for their correlations with multiple psychiatric and neurological disorders including schizophrenia (SCZ), major depressive disorder (MDD), and genetic generalized epilepsy. For instance, the genetic variant rs1518395 in VRK2 showed genome-wide significant associations with SCZ (35,476 cases and 46,839 controls, p = 3.43 × 10^–8) and MDD (130,620 cases and 347,620 controls, p = 4.32 × 10^–12) in European populations. This SNP was also genome-wide significantly associated with SCZ in Han Chinese population (12,083 cases and 24,097 controls, p = 3.78 × 10^–13), and all associations were in the same direction of allelic effects. These studies highlight the potential roles of VRK2 in the central nervous system, and this gene therefore might be a good candidate to investigate the shared genetic and molecular basis between SCZ and MDD, as it is one of the few genes known to show genome-wide significant associations with both illnesses. Furthermore, the VRK2 gene was found to be involved in multiple other congenital deficits related to the malfunction of neurodevelopment, adding further support for the involvement of this gene in the pathogenesis of these neurological and psychiatric illnesses. While the precise function of VRK2 in these conditions remains unclear, preliminary evidence suggests that it may affect neuronal proliferation and migration via interacting with multiple essential signaling pathways involving other susceptibility genes/proteins for psychiatric disorders. Here, we have reviewed the recent progress of genetic and molecular studies of VRK2, with an emphasis on its role in psychiatric illnesses and neurological functions. We believe that attention to this important gene is necessary, and further investigations of VRK2 may provide hints into the underlying mechanisms of SCZ and MDD.

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

Cited by 402 publications

References 66 publications

Genetics of self-reported risk-taking behaviour, trans-ethnic consistency and relevance to brain gene expression

Genetics of self-reported risk-taking behaviour, trans-ethnic consistency and relevance to brain gene expression

Recent Advances in the Genetics of Schizophrenia

<b><i>VRK2</i></b>, a Candidate Gene for Psychiatric and Neurological Disorders

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