Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London SE5 8AF, UK; Psychiatric Neuroscience Group, Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari 'Aldo Moro', Bari, Italy.
Psychiatric Imaging Group, MRC London Institute of Medical Sciences, Hammersmith Hospital, London W12 0NN, UK; Institute of Clinical Sciences, Faculty of Medicine, Imperial College London, Hammersmith Hospital, London, W12 0NN, UK; Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford OX37 JX, UK.
Psychiatry Res Neuroimaging. 2019 Sep 30;291:34-41. doi: 10.1016/j.pscychresns.2019.07.005. Epub 2019 Jul 19.
One of the most statistically significant loci to result from large-scale GWAS of schizophrenia is 10q24.32. However, it is still unclear how this locus is involved in the pathoaetiology of schizophrenia. The hypothesis that presynaptic dopamine dysfunction underlies schizophrenia is one of the leading theories of the pathophysiology of the disorder. Supporting this, molecular imaging studies show evidence for elevated dopamine synthesis and release capacity. Thus, altered dopamine function could be a potential mechanism by which this genetic variant acts to increase the risk of schizophrenia. We therefore tested the hypothesis that the 10q24.32 region confers genetic risk for schizophrenia through an effect on striatal dopamine function. To this aim we investigated the in vivo relationship between a GWAS schizophrenia-associated SNP within this locus and dopamine synthesis capacity measured using [F]-DOPA PET in healthy controls. 92 healthy volunteers underwent [F]-DOPA PET scans to measure striatal dopamine synthesis capacity (indexed as K) and were genotyped for the SNP rs7085104. We found a significant association between rs7085104 genotype and striatal K. Our findings indicate that the mechanism mediating the 10q24.32 risk locus for schizophrenia could involve altered dopaminergic function. Future studies are needed to clarify the neurobiological pathway implicated in this association.
大规模全基因组关联研究（GWAS）发现精神分裂症的一个最具统计学意义的基因座是 10q24.32。然而，目前尚不清楚该基因座如何参与精神分裂症的病理生理学。突触前多巴胺功能障碍是精神分裂症病理生理学的主要理论之一。支持这一假说的是，分子影像学研究表明多巴胺合成和释放能力增加。因此，多巴胺功能的改变可能是这种遗传变异增加精神分裂症风险的潜在机制。因此，我们测试了以下假设，即 10q24.32 区域通过对纹状体多巴胺功能的影响，为精神分裂症提供遗传风险。为此，我们研究了该基因座内与全基因组关联研究（GWAS）相关的 SNP 与健康对照者中使用 [F]-DOPA PET 测量的多巴胺合成能力之间的体内关系。92 名健康志愿者接受了 [F]-DOPA PET 扫描，以测量纹状体多巴胺合成能力（以 K 表示），并对 SNP rs7085104 进行了基因分型。我们发现 rs7085104 基因型与纹状体 K 之间存在显著关联。我们的研究结果表明，介导精神分裂症 10q24.32 风险基因座的机制可能涉及多巴胺能功能的改变。需要进一步的研究来阐明该关联所涉及的神经生物学途径。
