NORMENT, Centre for Mental Disorders Research, Division of Mental Health and Addiction, Oslo University Hospital, and Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
Schizophr Bull. 2023 Nov 29;49(6):1654-1664. doi: 10.1093/schbul/sbad063.
Low vitamin D (vitD) levels have been consistently reported in schizophrenia (SCZ) suggesting a role in the etiopathology. However, little is known about the role of underlying shared genetic mechanisms. We applied a conditional/conjunctional false discovery rate approach (FDR) on large, nonoverlapping genome-wide association studies for SCZ (N cases = 53 386, N controls = 77 258) and vitD serum concentration (N = 417 580) to evaluate shared common genetic variants. The identified genomic loci were characterized using functional analyses and biological repositories. We observed cross-trait SNP enrichment in SCZ conditioned on vitD and vice versa, demonstrating shared genetic architecture. Applying the conjunctional FDR approach, we identified 72 loci jointly associated with SCZ and vitD at conjunctional FDR < 0.05. Among the 72 shared loci, 40 loci have not previously been reported for vitD, and 9 were novel for SCZ. Further, 64% had discordant effects on SCZ-risk and vitD levels. A mixture of shared variants with concordant and discordant effects with a predominance of discordant effects was in line with weak negative genetic correlation (rg = -0.085). Our results displayed shared genetic architecture between SCZ and vitD with mixed effect directions, suggesting overlapping biological pathways. Shared genetic variants with complex overlapping mechanisms may contribute to the coexistence of SCZ and vitD deficiency and influence the clinical picture.
低维生素 D（vitD）水平在精神分裂症（SCZ）中一直有报道，表明其在发病机制中起作用。然而，对于潜在的共同遗传机制的作用知之甚少。我们应用条件/联合假发现率方法（FDR）对大规模、不重叠的精神分裂症全基因组关联研究（病例 N = 53386，对照 N = 77258）和维生素 D 血清浓度（N = 417580）进行了分析，以评估共同的常见遗传变异。使用功能分析和生物资源库对鉴定出的基因组位点进行了特征描述。我们观察到在 SCZ 条件下，与 vitD 相关的 SNP 富集，反之亦然，表明存在共同的遗传结构。应用联合 FDR 方法，我们在联合 FDR < 0.05 的条件下鉴定出了 72 个与 SCZ 和 vitD 共同相关的基因座。在 72 个共同的基因座中，有 40 个以前没有报道过与 vitD 相关，有 9 个是与 SCZ 相关的新基因座。此外，64%的基因座对 SCZ 风险和 vitD 水平的影响不一致。具有一致和不一致效应的共同变异体的混合，与弱负遗传相关性（rg = -0.085）一致。我们的结果显示了 SCZ 和 vitD 之间存在共同的遗传结构，效应方向混合，表明存在重叠的生物学途径。具有复杂重叠机制的共同遗传变异体可能有助于 SCZ 和 vitD 缺乏的共存，并影响临床特征。
