Research has shown differences in subcortical brain volumes between participants with schizophrenia and healthy controls. However, none of these differences have been found to associate with schizophrenia polygenic risk. Here, in a large sample (n = 14,701) of unaffected participants from the UK Biobank, we test whether schizophrenia polygenic risk scores (PRS) limited to specific gene-sets predict subcortical brain volumes. We compare associations with schizophrenia PRS at the whole genome level (‘genomic’, including all SNPs associated with the disorder at a p-value threshold < 0.05) with ‘genic’ PRS (based on SNPs in the vicinity of known genes), ‘intergenic’ PRS (based on the remaining SNPs), and genic PRS limited to SNPs within 7 gene-sets previously found to be enriched for genetic association with schizophrenia (‘abnormal behaviour,’ ‘abnormal long-term potentiation,’ ‘abnormal nervous system electrophysiology,’ ‘FMRP targets,’ ‘5HT2C channels,’ ‘CaV2 channels’ and ‘loss-of-function intolerant genes’). We observe a negative association between the ‘abnormal behaviour’ gene-set PRS and volume of the right thalamus that survived correction for multiple testing (ß = −0.031, p_FDR = 0.005) and was robust to different schizophrenia PRS p-value thresholds. In contrast, the only association with genomic PRS surviving correction for multiple testing was for right pallidum, which was observed using a schizophrenia PRS p-value threshold < 0.01 (ß = −0.032, p = 0.0003, p_FDR = 0.02), but not when using other PRS P-value thresholds. We conclude that schizophrenia PRS limited to functional gene sets may provide a better means of capturing differences in subcortical brain volume than whole genome PRS approaches.

研究表明，精神分裂症患者和健康对照者的皮质下脑容量存在差异。然而，尚未发现这些差异与精神分裂症多基因风险相关。在这里，我们在来自英国生物银行的未受影响参与者的大样本（ n = 14,701）中测试了仅限于特定基因集的精神分裂症多基因风险评分（PRS）是否可以预测皮质下脑体积。我们在全基因组水平（“基因组”，包括与p值阈值 < 0.05 的疾病相关的所有 SNP）与“基因”PRS（基于已知基因附近的 SNP）比较与精神分裂症 PRS 的关联，“基因间的 PRS（基于剩余的 SNP），以及基因 PRS 仅限于先前发现与精神分裂症遗传相关的 7 个基因组内的 SNP（“异常行为”、“异常长时程增强”、“异常神经系统”）电生理学”、“FMRP 目标”、“5HT2C 通道”、“CaV2 通道”和“功能丧失不耐受基因”）。我们观察到“异常行为”基因组 PRS 与右侧丘脑体积之间存在负相关，该相关性在多次测试校正后幸存下来（ß = -0.031，p _FDR = 0.005），并且对不同的精神分裂症 PRS p值阈值具有鲁棒性。相比之下，与基因组PRS在多次测试中幸存校正的唯一关联是右侧苍白球，这是使用精神分裂症PRS p值阈值<0.01（ß = -0.032， p = 0.0003，p _FDR = 0.02）观察到的，但不是当使用其他 PRS P值阈值时。 我们得出的结论是，与全基因组 PRS 方法相比，仅限于功能基因集的精神分裂症 PRS 可能提供更好的捕获皮层下大脑体积差异的方法。