The genome-wide risk alleles for psychiatric disorders at 3p21.1 show convergent effects on mRNA expression, cognitive function, and mushroom dendritic spine

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	The genome-wide risk alleles for psychiatric disorders at 3p21.1 show convergent effects on mRNA expression, cognitive function, and mushroom dendritic spine
	Yang, Zhihui; Zhou, Danyang; Li, Huijuan; Cai, Xin; Liu, Weipeng; Wang, Lu; Chang, Hong; Li, Ming; Xiao, Xiao
	2020
发表期刊	MOLECULAR PSYCHIATRY
ISSN	1359-4184
卷号	25 期号:1 页码:48-66
摘要	Schizophrenia and bipolar disorder (BPD) are believed to share clinical features, etiological factors, and disease pathologies (such as impaired cognitive functions and dendritic spine pathology). Meanwhile, there is growing evidence of shared genetic risk between schizophrenia and BPD, despite that our knowledge of the functional risk variations and biological mechanisms is still limited. Here, we conduct summary data-based Mendelian randomization (SMR) analyses through combining the statistical data from genome-wide association studies (GWAS) of both schizophrenia and BPD and multiple expression quantitative trait loci (eQTL) datasets of the human brain dorsolateral prefrontal cortex (DLPFC) tissues. These integrative investigations identify a lead risk locus at the chromosome 3p21.1 region, which contains numerous single-nucleotide polymorphisms (SNPs) in varied linkage disequilibrium (LD) and encompasses more than 20 genes. Further analyses suggest that many SNPs at 3p21.1 are significantly associated with both schizophrenia and BPD, and even depression, and the psychiatric risk alleles at 3p21.1 are correlated with mRNA expression of multiple genes such as NEK4, GNL3, and PBRM1. We also identify a 335-bp functional Alu polymorphism rs71052682 in significant LD with the psychiatric GWAS risk SNP rs2251219, and confirm the regulatory effects of this Alu polymorphism on transcription activities. We then explore the involvement of the 3p21.1 locus in the common clinical features and etiology of these illnesses. We reveal that psychiatric risk alleles at 3p21.1 in low-to-high LD consistently predict worse cognitive functions in humans, and manipulating the gene expression (NEK4, GNL3, and PBRM1) linked with higher genetic risk could reduce the density of mushroom dendritic spines in rat primary cortical neurons, mirroring the spine pathology in the prefrontal cortex of psychiatric patients. Our results find that, although the risk alleles at 3p21.1 are in low-to-moderate LD spanning a large genomic area, their underlying biological mechanisms in psychiatric disorders likely converge. These results provide essential insights into the neural mechanisms underlying the chromosome 3p21.1 risk locus in the shared pathological and etiological features of both schizophrenia and BPD.
收录类别	sci
语种	英语
文献类型	期刊论文
条目标识符	http://ir.kiz.ac.cn/handle/152453/12914
专题	科研部门_转化基因组（李明）
推荐引用方式 GB/T 7714	Yang, Zhihui,Zhou, Danyang,Li, Huijuan,et al. The genome-wide risk alleles for psychiatric disorders at 3p21.1 show convergent effects on mRNA expression, cognitive function, and mushroom dendritic spine[J]. MOLECULAR PSYCHIATRY,2020,25(1):48-66.
APA	Yang, Zhihui.,Zhou, Danyang.,Li, Huijuan.,Cai, Xin.,Liu, Weipeng.,...&Xiao, Xiao.(2020).The genome-wide risk alleles for psychiatric disorders at 3p21.1 show convergent effects on mRNA expression, cognitive function, and mushroom dendritic spine.MOLECULAR PSYCHIATRY,25(1),48-66.
MLA	Yang, Zhihui,et al."The genome-wide risk alleles for psychiatric disorders at 3p21.1 show convergent effects on mRNA expression, cognitive function, and mushroom dendritic spine".MOLECULAR PSYCHIATRY 25.1(2020):48-66.

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