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Importance: The high incidence of major depressive episodes during interferon-α (IFN-α) therapy is considered the most powerful supportive evidence for the inflammation theory of depression. As the kynurenine pathway plays an important role connecting inflammation and depression, it is plausible to investigate this pathway for predictive genetic markers for IFN-α-induced depression. Methods: In this prospective case-control study, we assessed 291 patients with chronic hepatitis C viral infection taking IFN-α therapy and analyzed the single nucleotide polymorphisms (SNPs) in genes in the kynurenine pathway. Our case group contained patients who developed IFN-α-induced depression during the treatment, and others were defined as the control group. Genomic DNA was extracted from leukocytes in the peripheral blood and analyzed by Affymetrix TWB array. We first tested allelic, dominant, and recessive models on each of our SNPs using Fisher’s exact test. We then conducted 5000 gene-wide max(T) permutations based on the best model of each SNP to provide strong gene-wide family-wise error rate control. Finally, we preformed logistic regression for the significant SNPs acquired in previous procedures, with sex and education level as covariates to build predictive models. Additional haplotype analyses were conducted with Haploview 4.2 to investigate the combining effect of multiple significant SNPs within a gene. Results: With sex and education level as covariates, rs8082252 (p = 0.0015, odds ratio = 2.716), rs8082142 (p = 0.0031, odds ratio = 2.499) in arylformamidase (AFMID), and rs12477181 (p = 0.0004, odds ratio = 0.3478) in kynureninase (KYNU) were significant in logistic regression models with dominant modes of inheritance. Haplotype analyses showed the two significant SNPs in AFMID to be in the same haploblock and highly correlated (r2 = 0.99). There were two significant haplotypes (by the sequence of rs8082252, rs8082142): AT (χ2 = 7.734, p = 0.0054) and GC (χ2 = 6.874, p = 0.0087). Conclusions: This study provided supportive evidence of the involvement of the kynurenine pathway in IFN-α-induced depression. SNPs in this pathway were also predictive of this disease.

Background and Objectives: 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). Methods: 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. Results: 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. Conclusions: 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.