ArticleMolecular psychiatry2021
A missense variant in NDUFA6 confers schizophrenia risk by affecting YY1 binding and NAGA expression.
Article in Molecular psychiatry, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers, 1 of them a synthesis that pooled it.
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Who cites it
18 citing papers in PubMed, 1 synthesis or guideline pooled it, 28 citations in OpenAlex.
- Genetic overlap and causality between depression and preterm birth: a large-scale genome-wide cross-trait analysis.Psychological medicine · 2025Pooled it
- eQTL analysis: A bridge from genome to mechanism.Genes & diseases · 2026Review
- Functional variants at 1p36.23 confer risk of schizophrenia through modulating RERE.Nature communications · 2026Article
- Potentially causal associations between placental DNA methylation and schizophrenia and other neuropsychiatric disorders.Nature communications · 2025Article
- Identification of Schizophrenia-Risk Regulatory Variant rs1399178 in the Non-coding Region With Its Impact on NRF1 Binding.CNS neuroscience & therapeutics · 2025Article
- Comprehensive Bioinformatics Analysis for the Identification of Hub Genes and Critical Signaling Pathways Differentiating Latent and Active Tuberculosis.Combinatorial chemistry & high throughput screening · 2025Article
- rs2736098, a synonymous polymorphism, is associated with carcinogenesis and cell count in multiple tissue types by regulatingHeliyon · 2024Article
- Functional genomics identify causal variant underlying the protective CTSH locus for Alzheimer's disease.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2023Article
- Genetic regulatory and biological implications of the 10q24.32 schizophrenia risk locus.Brain : a journal of neurology · 2023Article
- Article
- The schizophrenia-associated missense variant rs13107325 regulates dendritic spine density.Translational psychiatry · 2022Article
- Functional variant rs2270363 on 16p13.3 confers schizophrenia risk by regulating NMRAL1.Brain : a journal of neurology · 2022Article
- Functional genomic analysis delineates regulatory mechanisms of GWAS-identified bipolar disorder risk variants.Genome medicine · 2022Article
- Functional genomics elucidates regulatory mechanisms of Parkinson's disease-associated variants.BMC medicine · 2022Article
- Article
- The synergistic interaction landscape of chromatin regulators reveals their epigenetic regulation mechanisms across five cancer cell lines.Computational and structural biotechnology journal · 2022Article
- The schizophrenia susceptibility gene NAGA regulates dendritic spine density: further evidence for the dendritic spine pathology of schizophrenia.Molecular psychiatry · 2021Article
- Chromatin Alterations in Neurological Disorders and Strategies of (Epi)Genome Rescue.Pharmaceuticals (Basel, Switzerland) · 2021Review
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Authors and funding
16 authors at 3 institutions in 2 countries.
Funding
Abstract
Genome-wide association studies (GWASs) have revealed that genetic variants at the 22q13.2 risk locus were robustly associated with schizophrenia. However, the causal variants at this risk locus and their roles in schizophrenia remain elusive. Here we identify the risk missense variant rs1801311 (located in the 1st exon of NDUFA6 gene) as likely causal for schizophrenia at 22q13.2 by disrupting binding of YY1, TAF1, and POLR2A. We systematically elucidated the regulatory mechanisms of rs1801311 and validated the regulatory effect of this missense variant. Intriguingly, rs1801311 physically interacted with NAGA (encodes the alpha-N-acetylgalactosaminidase, which is mainly involved in regulating metabolisms of glycoproteins and glycolipids in lysosome) and showed the most significant association with NAGA expression in the human brain, with the risk allele (G) associated with higher NAGA expression. Consistent with eQTL analysis, expression analysis showed that NAGA was significantly upregulated in brains of schizophrenia cases compared with controls, further supporting that rs1801311 may confer schizophrenia risk by regulating NAGA expression. Of note, we found that NAGA regulates important neurodevelopmental processes, including proliferation and differentiation of neural stem cells. Transcriptome analysis corroborated that NAGA regulates pathways associated with neuronal differentiation. Finally, we independently confirmed the association between rs1801311 and schizophrenia in a large Chinese cohort. Our study elucidates the regulatory mechanisms of the missense schizophrenia risk variant rs1801311 and provides mechanistic links between risk variant and schizophrenia etiology. In addition, this study also revealed the novel role of coding variants in gene regulation and schizophrenia risk, i.e., genetic variant in coding region of a specific gene may confer disease risk through regulating distal genes (act as regulatory variant for distal genes).
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