A functional missense variant in ITIH3 affects protein expression and neurodevelopment and confers schizophrenia risk in the Han Chinese population

Kaiqin Li; Yifan Li; Junyang Wang; Yongxia Huo; Di Huang; Shiwu Li; Jiewei Liu; Xiaoyan Li; Rong Liu; Xiaogang Chen; Yong-Gang Yao; Ceshi Chen; Xiao Xiao; Ming Li; Xiong-Jian Luo

doi:10.1016/j.jgg.2020.04.001

Volume 47 Issue 5

May 2020

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Article Navigation > Journal of Genetics and Genomics > 2020 > 47(5): 233-248

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A functional missense variant in ITIH3 affects protein expression and neurodevelopment and confers schizophrenia risk in the Han Chinese population

doi: 10.1016/j.jgg.2020.04.001

Kaiqin Li^{a, b},
Yifan Li^{a, b},
Junyang Wang^{a, b},
Yongxia Huo^a,
Di Huang^a,
Shiwu Li^{a, b},
Jiewei Liu^a,
Xiaoyan Li^{a, b},
Rong Liu^{a, c},
Xiaogang Chen^d,
Yong-Gang Yao^{a, b, e, f},
Ceshi Chen^a,
Xiao Xiao^a,
Ming Li^{a, b, e, f},
Xiong-Jian Luo^{a, b, c, e}

a
Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650223, China
b
Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, 650204, China
c
Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming, 650223, China
d
Institute of Mental Health, National Clinical Research Center for Mental Health Disorders and National Technology Institute of Psychiatry, The Second Xiangya Hospital, Central South University, Changsha, 410011, China
e
KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650223, China
f
CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, 200031, China

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Corresponding author: E-mail address: wudaliming@163.com (Ming Li); E-mail address: luoxiongjian@mail.kiz.ac.cn (Xiong-Jian Luo)
Publish Date: 2020-05-25

Abstract

Abstract

The Psychiatric Genomics Consortium (PGC) has recently identified 10 potential functional coding variants for schizophrenia. However, how these coding variants confer schizophrenia risk remains largely unknown. Here, we investigate the associations between eight potential functional coding variants identified by PGC and schizophrenia in a large Han Chinese sample (n = 4022 cases and 9270 controls). Among the eight tested single nucelotide polymorphisms (SNPs), rs3617 (a missense variant, p.K315Q in the ITIH3 gene) showed genome-wide significant association with schizophrenia in the Han Chinese population (P = 8.36 × 10⁻¹⁶), with the same risk allele as in PGC. Interestingly, rs3617 is located in a genomic region that is highly evolutionarily conserved, and its schizophrenia risk allele (C allele) was associated with lower ITIH3 mRNA and protein expression. Intriguingly, mouse neural stem cells stably overexpressing ITIH3 with different alleles of rs3617 exhibited significant differences in proliferation, migration, and differentiation, suggesting the impact of rs3617 on neurodevelopment. Subsequent transcriptome analysis found that the differentially expressed genes in neural stem cells stably overexpressing different alleles of rs3617 were significantly enriched in schizophrenia-related pathways, including cell adhesion, synapse assembly, MAPK and PI3K-AKT pathways. Our study provides convergent lines of evidence suggesting that rs3617 in ITIH3 likely affects protein function and neurodevelopment and thereby confers risk of schizophrenia.
- Schizophrenia,
- ITIH3,
- Missense variant,
- Association,
- Neurodevelopment,
- Neural stem cells

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References(76)

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