Heilbronner Urs, Malzahn Dörthe, Strohmaier Jana, Maier Sandra, Frank Josef, Treutlein Jens, Mühleisen Thomas W, Forstner Andreas J, Witt Stephanie H, Cichon Sven, Falkai Peter, Nöthen Markus M, Rietschel Marcella, Schulze Thomas G
Institute of Psychiatric Phenomics and Genomics, Ludwig-Maximilians-University Munich, Germany.
Department of Genetic Epidemiology, University Medical Center, Georg-August-University, Göttingen, Germany.
Eur Neuropsychopharmacol. 2015 Dec;25(12):2262-70. doi: 10.1016/j.euroneuro.2015.09.012. Epub 2015 Oct 9.
Sex is a powerful modulator of disease susceptibility, course and outcome. The gene CACNA1C is among the best replicated vulnerability genes of bipolar disorder and schizophrenia. The aim of the present study was to investigate whether sex and a variant in CACNA1C (rs10774035 as a proxy for the well-acknowledged risk variant rs1006737) influence psychosocial adaptation in a large German patient sample with schizophrenia-spectrum (n=297) and bipolar (n=516) disorders. We analyzed Global Assessment of Functioning (GAF) scores, retrospectively collected for different time points during disease course. We investigated whether CACNA1C sex-dependently modulates longitudinal GAF scores and recovery from episodes of psychiatric disturbance in the above mentioned disorders. Psychosocial recovery was measured as difference score between the current GAF score (assessing the last remission) and the worst GAF score ever during an illness episode. Covariate- adjusted association analyses revealed a sex × rs10774035 genotype interaction on longitudinal GAF and recovery from illness episodes only in schizophrenia-spectrum but not in bipolar disorders. In schizophrenia-spectrum affected males, rs10774035 minor allele (T) carriers had higher GAF scores at three time points (premorbid, worst ever, current). In contrast, females carrying rs10774035 minor alleles had impaired recovery from schizophrenia-spectrum episodes. These results encourage further investigations of gene × sex interactions and longitudinal quantitative phenotypes to unravel the rich variety of behavioral consequences of genetic individuality.
性别是疾病易感性、病程和转归的有力调节因素。基因CACNA1C是双相情感障碍和精神分裂症中复制性最强的易损基因之一。本研究的目的是调查性别以及CACNA1C基因的一个变体（rs10774035作为公认风险变体rs1006737的替代指标）是否会影响一个大型德国精神分裂症谱系患者样本（n = 297）和双相情感障碍患者样本（n = 516）的心理社会适应情况。我们分析了在病程中不同时间点回顾性收集的功能总体评定量表（GAF）得分。我们研究了CACNA1C基因是否以性别依赖的方式调节上述疾病中GAF得分的纵向变化以及从精神障碍发作中恢复的情况。心理社会恢复情况通过当前GAF得分（评估最后一次缓解时）与疾病发作期间最差GAF得分之间的差值来衡量。协变量调整后的关联分析显示，仅在精神分裂症谱系障碍中，性别×rs10774035基因型相互作用对GAF得分纵向变化及疾病发作恢复情况有影响，而在双相情感障碍中则无此影响。在患有精神分裂症谱系障碍的男性中，rs10774035次要等位基因（T）携带者在三个时间点（病前、最差时、当前）的GAF得分较高。相比之下，携带rs10774035次要等位基因的女性从精神分裂症谱系发作中恢复的情况较差。这些结果鼓励进一步研究基因×性别相互作用以及纵向定量表型，以揭示遗传个体性所带来的丰富多样的行为后果。
