Centre for Clinical Research in Neuropsychiatry, School of Psychiatry and Clinical Neurosciences, University of Western Australia, MRF Building, 50 Murray Street, Perth 6000, Australia; Cooperative Research Centre for Mental Health, Carlton South, Victoria, Australia; Harry Perkins Institute of Medical Research and Centre for Medical Research, The University of Western Australia, 6 Verdun Street, Nedlands, WA 6009, Australia.
Centre for Clinical Research in Neuropsychiatry, School of Psychiatry and Clinical Neurosciences, University of Western Australia, MRF Building, 50 Murray Street, Perth 6000, Australia; Cooperative Research Centre for Mental Health, Carlton South, Victoria, Australia.
Schizophr Res. 2018 Mar;193:348-353. doi: 10.1016/j.schres.2017.06.054. Epub 2017 Jul 1.
Cognitive impairment is a core feature of schizophrenia and impacts negatively the functioning of affected individuals. Cognitive decline correlates with aging, and is the primary cause of loss of independence and reduced quality of life. The klotho gene is a key modulator of aging, with expression deficiency resulting in premature aging, while overexpression extends lifespan and enhances cognition. A haplotype and functional human variant of the gene, KL-VS, increases expression and promotes longevity. KL-VS heterozygosity is associated with enhanced cognition and a larger volume of the right dorsolateral prefrontal cortex, a region involved in planning and decision-making, which is especially susceptible to shrinkage with age. We examined the effect of KL-VS heterozygosity on cognition in 497 schizophrenia patients and 316 healthy controls from the Western Australian Family Study of Schizophrenia (WAFSS) who had been comprehensively characterised by neurocognitive tests and classified into cognitively deficient (CD) and cognitively "spared" (CS) clusters. An older, cognitively normal population sample from the Health in Men Study (HIMS) was included to allow assessment of heterozygosity and memory in aged individuals. We show that heterozygosity is associated with better learning and memory in the younger WAFSS healthy controls but not in the aging HIMS sample. However, in schizophrenia patients, KL-VS has a selective effect on memory, with heterozygotes in CD and CS clusters performing worse than non-carriers. This effect was significant and more severe in the CD cluster, reinforcing the utility of subtyping patients into CD and CS clusters that may differ in their genetic underpinnings.
认知障碍是精神分裂症的核心特征，对患者的功能产生负面影响。认知能力下降与年龄相关，是导致独立性丧失和生活质量下降的主要原因。klotho 基因是衰老的关键调节剂，表达缺陷导致早衰，而过表达则延长寿命并增强认知能力。该基因的一种单倍型和功能性人类变体 KL-VS 增加了表达，并促进了长寿。KL-VS 杂合性与增强的认知能力和更大的右侧背外侧前额叶皮层体积相关，该区域参与计划和决策，随着年龄的增长特别容易缩小。我们研究了 KL-VS 杂合性对来自西澳大利亚精神分裂症家庭研究（WAFSS）的 497 名精神分裂症患者和 316 名健康对照者认知的影响，这些患者通过神经认知测试进行了全面评估，并分为认知缺陷（CD）和认知“未受影响”（CS）两个亚组。我们还纳入了来自男性健康研究（HIMS）的年龄较大、认知正常的人群样本，以评估杂合性和老年人的记忆力。我们发现，杂合性与年轻的 WAFSS 健康对照组更好的学习和记忆相关，但与老龄化的 HIMS 样本无关。然而，在精神分裂症患者中，KL-VS 对记忆有选择性影响，CD 和 CS 亚组的杂合子患者比非携带者的表现更差。这种影响在 CD 亚组中更为显著和严重，这进一步强调了将患者分为 CD 和 CS 亚组的重要性，这两个亚组的遗传基础可能不同。
