Chen Daniel Tzu-Li, Cheng Szu-Wei, Chen Tiffany, Chang Jane Pei-Chen, Hwang Bing-Fang, Chang Hen-Hong, Chuang Eric Y, Chen Che-Hong, Su Kuan-Pin
School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung 404, Taiwan.
Department of Psychiatry and Mind-Body Interface Laboratory (MBI-Lab), China Medical University Hospital, Taichung 404, Taiwan.
J Clin Med. 2022 Jun 23;11(13):3622. doi: 10.3390/jcm11133622.
Nicotinamide adenine dinucleotide (NAD) is an important coenzyme in various physiological processes, including sirtuins (SIRTs) and kynurenine pathway (KP). Previous studies have shown that lower NAD levels can be indicative of increased risks of cancer and psychiatric disorders. However, there has been no prior study exploring the link between NAD homeostasis and psychiatric disorders from a genetic perspective. Therefore, we aimed to investigate the association of genetic polymorphism in the pathways of NAD biosynthesis with major depressive disorder (MDD). A total of 317 patients were included in the case group and were compared with sex-matched control group of 1268 participants (1:4 ratio) from Taiwan Biobank (TWB). All subjects in the control group were over 65 years old, which is well past the average age of onset of MDD. Genomic DNA extracted from patients' blood buffy coat was analyzed using the Affymetrix TWB array. Full-model tests were conducted for the analysis of single nucleotide polymorphism (SNPs) in all candidate genes. We focused on genes within the NAD-related candidate pathways, including 15 in KP, 12 in nicotinate metabolism, 7 in SIRTs, and 19 in aldehyde dehydrogenases (ALDHs). A total of 508 SNPs were analyzed in this study. After significant SNPs were determined, 5000 genome-wide max(T) permutations were performed in Plink. Finally, we built a predictive model with logistic regression and assessed the interactions of SNPs with the haplotype association tests. We found three SNPs that were significantly associated with MDD in our NAD-related candidate pathways, one within the KP (rs12622574 in ACMSD) and two within the nicotinate metabolism (rs28532698 in BST1 and rs3733593 in CD38). The observed association with MDD was significant in the dominant model of inheritance with marital status, education level, and body mass index (BMI) adjusted as covariates. Lastly, in haplotype analysis, the three associated SNPs consisted of one haploblock in ACMSD, four haploblocks in BST1, and two haploblocks in CD38. This study provides the first evidence that genetic variations involved in NAD homeostasis in the KP and nicotinate metabolism may be associated with the occurrence of MDD.
烟酰胺腺嘌呤二核苷酸（NAD）是包括沉默调节蛋白（SIRTs）和犬尿氨酸途径（KP）在内的各种生理过程中的一种重要辅酶。先前的研究表明，较低的NAD水平可能表明患癌症和精神疾病的风险增加。然而，以前尚无研究从遗传学角度探讨NAD稳态与精神疾病之间的联系。因此，我们旨在研究NAD生物合成途径中的基因多态性与重度抑郁症（MDD）之间的关联。病例组共纳入317例患者，并与来自台湾生物银行（TWB）的1268名参与者（比例为1:4）的性别匹配对照组进行比较。对照组中的所有受试者均超过65岁，这远远超过了MDD的平均发病年龄。使用Affymetrix TWB阵列分析从患者血液白膜层中提取的基因组DNA。对所有候选基因中的单核苷酸多态性（SNP）进行全模型测试分析。我们重点关注NAD相关候选途径中的基因，包括KP中的15个、烟酸代谢中的12个、SIRTs中的7个以及醛脱氢酶（ALDHs）中的19个。本研究共分析了508个SNP。在确定显著的SNP后，在Plink中进行了5000次全基因组最大（T）置换。最后，我们构建了一个逻辑回归预测模型，并通过单倍型关联测试评估SNP之间的相互作用。我们在NAD相关候选途径中发现了三个与MDD显著相关的SNP，一个在KP内（ACMSD中的rs12622574），两个在烟酸代谢内（BST1中的rs28532698和CD38中的rs3733593）。在以婚姻状况、教育水平和体重指数（BMI）作为协变量进行调整的显性遗传模型中，观察到的与MDD的关联具有显著性。最后，在单倍型分析中，这三个相关的SNP在ACMSD中组成一个单倍型块，在BST1中组成四个单倍型块，在CD38中组成两个单倍型块。本研究提供了首个证据，表明KP和烟酸代谢中参与NAD稳态的基因变异可能与MDD的发生有关。
