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PMID: 31723243 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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 ·Vol. 25 ·No. 1 ·2020-00-00 ·Pages 48-66

Yang Z, Zhou D, Li H, Cai X, Liu W, Wang L, Chang H, Li M, Xiao X

Abstract

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.

MeSH Terms
Alleles Animals Bipolar Disorder/genetics Cell Line Chromosomes, Human, Pair 3/genetics Cognition/physiology Databases, Genetic Dendritic Spines/genetics Female Gene Expression/genetics Gene Frequency/genetics Genetic Predisposition to Disease Genome-Wide Association Study/methods Humans Linkage Disequilibrium/genetics Male Mental Disorders/genetics,metabolism Polymorphism, Single Nucleotide/genetics Quantitative Trait Loci/genetics Rats Rats, Sprague-Dawley Risk Factors Schizophrenia/genetics
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Yang Zhihui
Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China. | Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan, China.
Zhou Danyang
Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China. | Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan, China.
Li Huijuan
Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China. | Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan, China.
Cai Xin
Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China. | Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan, China.
Liu Weipeng
Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China. | Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan, China.
Wang Lu
Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China.
Chang Hong
Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China.
Li Ming ORCID
Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China. [email protected]. | Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan, China. [email protected]. | CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, China. [email protected].
Xiao Xiao
Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China. [email protected].
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Article Info
Journal
Molecular psychiatry
Abbr.
Mol Psychiatry
ISSN
1476-5578
DOI
10.1038/s41380-019-0592-0
Email
[email protected]
[email protected]
Published
2020-00-00
Epub
2019-00-13
Pages
48-66
Language
English
Region
England
NLM ID
9607835
Subset
IM
External Links
PubMed source DOI: 10.1038/s41380-019-0592-0 View journal details
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