Palmer Christina G S, Turunen Joni A, Sinsheimer Janet S, Minassian Sonia, Paunio Tiina, Lönnqvist Jouko, Peltonen Leena, Woodward J Arthur
Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, 90095, USA.
Am J Hum Genet. 2002 Dec;71(6):1312-9. doi: 10.1086/344659. Epub 2002 Nov 18.
Fetal events and obstetric complications are associated with schizophrenia. Here we report the results of a family-based candidate-gene study that assesses the role of maternal-fetal genotype incompatibility at the RHD locus in schizophrenia. We adapted the case-parent-trio log-linear modeling approach to test for RHD maternal-fetal genotype incompatibility and to distinguish this effect from a high-risk allele at or near the RHD locus and from a direct maternal effect alone. Eighty-eight patient-parent trios, 72 patient-mother pairs, and 21 patient-father pairs were genotyped at the RHD locus. Of the 181 patients, 62% were male and 81% were second born or later. Only three patients were born after prophylaxis against maternal isoimmunization had become common practice. There was significant evidence for an RHD maternal-fetal genotype incompatibility, and the incompatibility parameter was estimated at 2.6. There was no evidence to support linkage/association with schizophrenia at or near the RHD locus nor any evidence to support the role of maternal genotype effect alone. Our results replicate previous findings that implicate the RHD locus in schizophrenia, and the candidate-gene design of this study allows the elimination of alternative explanations for the role of this locus in disease. Thus, the present study provides increasing evidence that the RHD locus increases schizophrenia risk through a maternal-fetal genotype incompatibility mechanism that increases risk of an adverse prenatal environment (e.g., Rh incompatibility) rather than through linkage/association with the disorder, linkage disequilibrium with an unknown nearby susceptibility locus, or a direct maternal effect alone. This is the first candidate-gene study to explicitly test for and provide evidence of a maternal-fetal genotype incompatibility mechanism in schizophrenia.
胎儿期事件和产科并发症与精神分裂症有关。在此，我们报告一项基于家系的候选基因研究结果，该研究评估了RHD基因座上母胎基因型不相容性在精神分裂症中的作用。我们采用病例-父母三联体对数线性建模方法来检测RHD母胎基因型不相容性，并将这种效应与RHD基因座或其附近的高危等位基因以及单独的直接母体效应区分开来。对88个患者-父母三联体、72个患者-母亲对和21个患者-父亲对进行了RHD基因座基因分型。在181名患者中，62%为男性，81%为第二胎或更晚出生。只有3名患者是在预防母体血型同种免疫成为常规做法后出生的。有显著证据表明存在RHD母胎基因型不相容性，不相容参数估计为2.6。没有证据支持RHD基因座或其附近与精神分裂症存在连锁/关联，也没有证据支持单独的母体基因型效应的作用。我们的结果重复了先前将RHD基因座与精神分裂症联系起来的研究发现，并且本研究的候选基因设计能够排除对该基因座在疾病中作用的其他解释。因此，本研究提供了越来越多的证据表明，RHD基因座通过母胎基因型不相容机制增加精神分裂症风险，这种机制增加了不良产前环境（如Rh不相容）的风险，而不是通过与该疾病的连锁/关联、与附近未知易感基因座的连锁不平衡或单独的直接母体效应。这是第一项明确检测并提供精神分裂症中母胎基因型不相容机制证据的候选基因研究。
