Altered HCAR3 expression may underlying the blunted niacin responses of the psychiatric disorders and the risk of schizophrenia

Author:

Jiang Jie1,Wang Dandan1,Gao Yan1,Sun Liya2,Li Shuhui1,Hu Xiaowen1,Li Zhuyun1,Zhang Juan1,Ji Feng3,Tian Yusheng4,Guan Lili5,Li Zhiqiang16,He Lin1,Wan Chunling12ORCID

Affiliation:

1. Bio‐X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education Shanghai Jiao Tong University Shanghai China

2. Shanghai Mental Health Center, Shanghai Key Laboratory of Psychiatry Disorders Shanghai Jiao Tong University Shanghai China

3. Institute of Mental Health Jining Medical University Jining China

4. National Clinical Research Center for Mental Disorders, Department of Psychiatry and Hunan Medical Center for Mental Health The Second Xiangya Hospital of Central South University Changsha China

5. Peking University Sixth Hospital Peking University Institute of Mental Health Beijing China

6. The Affiliated Hospital of Qingdao University and the Biomedical Sciences Institute of Qingdao University, Qingdao Branch of SJTU Bio‐X Institutes Qingdao University Qingdao China

Abstract

AimBlunted niacin response (BNR) was an endophenotype of schizophrenia, but the underlying mechanism remains unclarified. The objective of this study was to verify whether genes associated with BNR pathway constitute the genetic basis and the pathological mechanism of BNR phenotypic psychiatric patients.MethodsTwo independent sample sets consisting of 971 subjects were enrolled in this study. A total of 62 variants were genotyped in the discovery set, then the related variants were verified in the verification set. The published PGC GWAS data were used to validate the associations between the variants and psychiatry disorders. RT‐PCR analysis, eQTL data, and Dual‐Luciferase Reporter experiment were used to investigate the potential molecular mechanisms of the variants underlying BNR.ResultsThe results showed that two SNPs, rs56959712 in HCAR2 and rs2454721 in HCAR3 were significantly associated with niacin response. The risk allele T of rs2454721 could affect the niacin responses of psychiatric patients through elevated HCAR3 gene expression. These two genes, especially HCAR3, were significantly associated with the risk of schizophrenia, as identified in this study and verified using the published GWAS data.ConclusionHCAR3 is a novel schizophrenia susceptibility gene which is significantly associated with blunted niacin response in schizophrenia. In‐depth investigation of HCAR3 is of great significance for uncovering the pathogenesis and propose new therapeutic targets for psychiatric disorders, especially for the BNR subgroup patients.

Funder

China Postdoctoral Science Foundation

National Natural Science Foundation of China

Shanghai Key Laboratory of Psychotic Disorders

Publisher

Wiley

Subject

Psychiatry and Mental health,Neurology (clinical),Neurology,General Medicine,General Neuroscience

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