Department of Psychiatry, Mount Sinai School of Medicine, New York, NY 10029, USA.
Schizophr Res. 2010 Dec;124(1-3):208-15. doi: 10.1016/j.schres.2010.08.040. Epub 2010 Sep 26.
The AMACR gene is located in the schizophrenia susceptibility locus on chromosome 5p13, previously identified in a large Puerto Rican pedigree of Spanish origin. The AMACR-encoded protein is an enzyme involved in the metabolism of branched-chain fatty and bile acids. The enzyme deficiency causes structural and functional brain changes, and disturbances in fatty acid and oxidative phosphorylation pathways observed in individuals with schizophrenia. Therefore, AMACR is both a positional and functional candidate gene for susceptibility to schizophrenia.
The study had a two-step design: we performed mutation analysis of the coding and flanking regions of AMACR in affected members of the pedigree, and tested the detected sequence variants for association with schizophrenia in a Puerto Rican case-control sample (n=383) of Spanish descent.
We identified three missense variants segregating with the disorder in the family, rs2278008, rs2287939 and rs10941112. Two of them, rs2278008 and rs2287939, demonstrated significant differences in genotype (P = 4 × 10-4, P = 4 × 10-4) and allele (P = 1 × 10-4, P = 9.5 × 10-5) frequencies in unrelated male patients compare to controls, with the odds ratios (OR) 2.24 (95% CI: 1.48-3.40) and 2.25 (95% CI: 1.49-3.38), respectively. The G-C-G haplotype of rs2278008-rs2287939-rs10941112 revealed the most significant association with schizophrenia (P = 4.25 × 10-6, OR = 2.96; 95% CI: 1.85-4.76) in male subjects. There were no statistically significant differences in genotype, allele, and haplotype frequencies between female schizophrenia subjects and controls. Our results suggest that AMACR may play a significant role in susceptibility to schizophrenia in male patients.
AMACR 基因位于染色体 5p13 上的精神分裂症易感基因座，先前在一个起源于西班牙的大型波多黎各家族中被发现。AMACR 编码的蛋白是一种参与支链脂肪酸和胆汁酸代谢的酶。该酶的缺乏导致结构性和功能性脑改变，以及在精神分裂症患者中观察到的脂肪酸和氧化磷酸化途径的紊乱。因此，AMACR 既是精神分裂症易感性的候选基因之一。
本研究采用两步设计：我们对家系中受影响成员的 AMACR 编码和侧翼区域进行突变分析，并在具有西班牙血统的波多黎各病例对照样本（n=383）中测试检测到的序列变异与精神分裂症的相关性。
我们在家系中发现了三个与疾病共分离的错义变异体，rs2278008、rs2287939 和 rs10941112。其中两个，rs2278008 和 rs2287939，在与对照组相比，在无关男性患者中的基因型（P=4×10-4，P=4×10-4）和等位基因（P=1×10-4，P=9.5×10-5）频率上存在显著差异，优势比（OR）分别为 2.24（95%CI：1.48-3.40）和 2.25（95%CI：1.49-3.38）。rs2278008-rs2287939-rs10941112 的 G-C-G 单倍型与精神分裂症的关联最为显著（P=4.25×10-6，OR=2.96；95%CI：1.85-4.76）在男性受试者中。在女性精神分裂症患者和对照组之间，基因型、等位基因和单倍型频率没有统计学上的显著差异。我们的结果表明，AMACR 可能在男性患者的精神分裂症易感性中发挥重要作用。
