The Genetic Basis of Quality of Life in Healthy Swedish Women: A Candidate Gene Approach

Background
Quality of life (QoL) is an increasingly important parameter in clinical practice as it predicts mortality and poor health outcomes. It is hypothesized that one may have a genetic predisposition for QoL. We therefore related 139 candidate genes, selected through a literature search, to QoL in healthy females.
Methods
In 5,142 healthy females, background characteristics (i.e. demographic, clinical, lifestyle, and psychological factors) were assessed. QoL was measured by the EORTC QLQ-C30, which consists of 15 domains. For all women genotype information was available. For each candidate gene, single nucleotide polymorphisms (SNPs) were identified based on their functional (n = 2,663) and physical annotation (n = 10,649). SNPs were related to each QoL-domain, while controlling for background characteristics and population stratification. Finally, gene-based analyses were performed relating the combined effect of 10,649 SNPs (selected based on physical annotation) for each gene, to QoL using the statistical software package VEGAS.
Results
Overall, we found no relation between genetic variations (SNPs and genes) and 14 out of 15 QoL-domains. The strongest association was found between cognitive functioning and the top SNP rs1468951 (p = 1.21E-05) in the GSTZ1 gene. Furthermore, results of the gene-based test showed that the combined effect of 11 SNPs within the GSTZ1 gene is significantly associated with cognitive functioning (p = 2.60E-05).
Conclusion
If validated, the involvement of GSTZ1 in cognitive functioning underscores its heritability which is likely the result of differences in the dopamine pathway, as GSTZ1 contributes to the equilibrium between dopamine and its neurotoxic metabolites via the glutathione redox cycle.

研究背景
生活质量（Quality of Life, QoL）在临床实践中的重要性日益凸显，其可预测死亡率与不良健康结局。有假说认为，个体的生活质量可能存在遗传易感性。本研究针对通过文献检索筛选出的139个候选基因，分析其与健康女性生活质量的关联。

研究方法
本研究共纳入5142名健康女性，评估了其人口统计学、临床、生活方式及心理等背景特征。采用包含15个维度的EORTC QLQ-C30量表评估研究对象的生活质量。所有研究对象均提供了基因型信息。针对每个候选基因，基于功能注释（共2663个）与物理注释（共10649个）筛选得到单核苷酸多态性（Single Nucleotide Polymorphisms, SNPs）。将SNPs与各生活质量维度进行关联分析，同时校正背景特征与人群分层因素。最后，采用统计软件包VEGAS开展基于基因的关联分析，将每个基因对应的10649个（基于物理注释筛选的）SNPs的联合效应与生活质量进行关联。

研究结果
整体而言，未发现遗传变异（单核苷酸多态性与基因）与15个生活质量维度中的14个存在关联。认知功能与GSTZ1基因中最显著的SNP rs1468951之间存在最强关联（p=1.21×10^-5）。此外，基于基因的分析结果显示，GSTZ1基因内11个SNPs的联合效应与认知功能存在显著关联（p=2.60×10^-5）。

研究结论
若该结果得以验证，GSTZ1参与认知功能这一发现将进一步证实其遗传易感性，这可能与多巴胺通路的差异有关——GSTZ1可通过谷胱甘肽氧化还原循环维持多巴胺与其神经毒性代谢产物之间的平衡。