A rare microcephalin 1 gene (MCPH1) variant rs61749465A>G (p.Asp61Gly) with prior evidence for association with schizophrenia (p = 3.78 × 10-7 ) was tested for association in 2,300 bipolar disorder (BPD) participants, 1,930 SCZ participants and 1,820 normal comparison subjects. We report evidence for association of rs61749465A>G with BPD (p = 0.0009). rs61749465 is located in the N-terminal of the BRCT1 domain of MCPH1. Bioinformatic analysis predicted the Asp61Gly substitution to be damaging to MCPH1 function. A second MCPH1 BRCT1 domain variant (rs199422124C>G; p.Thr27Arg), reported to cause autosomal recessive microcephaly, was not detected in the participants tested here. We sought to characterize the functional effects of these variants on MCPH1 function. Cell count assays indicated that rs199422124 allele G had a greater impact on cell survival compared to the G allele of rs61749465. Gene expression analysis combined with gene network and pathway analysis indicated that rs61749465 allele G may impact protein translation and cell cycle control. The evidence for association between rs61749465A>G and psychosis in both BPD and SCZ warrants further replication. Likewise, the data from the functional analyses point to molecular mechanisms that may underlie the proposed MCPH1 mediated risk of psychosis and pathogenesis in autosomal recessive microcephaly require additional experimental validation.

中文翻译：

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双相情感障碍和精神分裂症中 MCPH1 基因变异的遗传关联和功能特征。

在 2,300 名双相情感障碍 (BPD) 参与者、1,930 名 SCZ 参与者和1,820 名正常对照受试者。我们报告了 rs61749465A>G 与 BPD 关联的证据 (p = 0.0009)。rs61749465 位于 MCPH1 BRCT1 结构域的 N 端。生物信息分析预测 Asp61Gly 取代会损害 MCPH1 功能。据报道，第二种 MCPH1 BRCT1 结构域变异（rs199422124C>G；p.Thr27Arg）会导致常染色体隐性遗传性小头畸形，但在此测试的参与者中未检测到。我们试图表征这些变异对 MCPH1 功能的功能影响。细胞计数分析表明，与 rs61749465 的 G 等位基因相比，rs199422124 等位基因 G 对细胞存活的影响更大。基因表达分析结合基因网络和通路分析表明rs61749465等位基因G可能影响蛋白质翻译和细胞周期控制。rs61749465A>G 与 BPD 和 SCZ 中精神病之间关联的证据值得进一步复制。同样，功能分析的数据指出了可能是 MCPH1 介导的精神病风险和常染色体隐性小头畸形发病机制的分子机制，需要额外的实验验证。