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Author Notes:

Cobolsu@gmail.com; Tel.: +886-4-22062121 (ext. 4126); Fax: +886-4-22361230

Conceptualization, D.T.-L.C.; methodology, D.T.-L.C., S.-W.C., B.-F.H. and C.-H.C.; formal analysis, D.T.-L.C.; writing—original draft preparation, D.T.-L.C. and T.C.; writing—review and editing, D.T.-L.C., J.P.-C.C., C.-H.C., H.-H.C., E.Y.C. and K.-P.S.; supervision, H.-H.C. and K.-P.S.; project administration, K.-P.S. All authors have read and agreed to the published version of the manuscript.

The authors of this work were supported by the following grants: MOST 109-2320-B-038-057-MY3, 109-2320-B-039-066, 110-2321-B-006-004, 110-2811-B-039-507, 110-2320-B-039-048-MY2, 110-2314-B-039-029-MY3, 110-2813-C-039-327-B and 110-2320-B-039-047-MY3 from the Ministry of Science and Technology, Taiwan; ANHRF109-31, 109-40, 110-44, 110-45, 110-13, and 110-26 from An-Nan Hospital, China Medical University, Tainan, Taiwan; CMRC-CMA-2 from Higher Education Sprout Project by the Ministry of Education (MOE), Taiwan; Chinese Medicine Research Center, China Medical University from The Featured Areas Research Center Program within the framework of the Higher Education Sprout Project by the Ministry of Education (MOE) in Taiwan (CMRC-CMA-6); CMU108-SR-106 and CMU110-SR-73 from the China Medical University, Taichung, Taiwan; and CMU104-S-16-01, CMU103-BC-4-1, CMU110-N-17, CRS-108-048, DMR-102-076, DMR-103-084, DMR-106-225, DMR-107-204, DMR-108-216, DMR-109-102, DMR-109-244, DMR-HHC-109-11 and DMR-HHC-109-12, DMR-HHC-110-10, DMR-110-124 from the China Medical University Hospital, Taichung, Taiwan. C-HC was supported by the NIH award AAA11147 to Daria Mochly-Rosen at Stanford University, School of Medicine, U.S.A. Special thanks to Kai-Jie Yang (Mind-Body Interface Laboratory, China Medical University Hospital, Taichung, Taiwan) and Wan-Jung Chang (School of Chinese Medicine, College of Chinese Medicine, China Medical University) for the technical support

The authors declare no competing interests.

Subject:

Research Funding:

This research was funded by Ministry of Science and Technology, Taiwan: MOST 106-2314-B-039-027-MY3, 108-2320-B-039-048, 108-2813-C-039-133-B, 108-2314-B-039-016, 109-2320-B-038-057-MY3, and 109-2320-B-039-066, An Nan Hospital, China Medical University, Tainan, Taiwan: ANHRF109-31, Ministry of Education (MOE), Taiwan: CMRC-CMA-3, China Medical University, Taiwan: CMU108-SR-106, China Medical University Hospital, Taichung, Taiwan: CRS-108-048, DMR-108-216, DMR-109-102, DMR-109-244, DMR-HHC-109-11, DMR-HCC-109-12 and DMR-110-124.

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Medicine, General & Internal
  • General & Internal Medicine
  • kynurenine pathway (KP)
  • major depressive disorder (MDD)
  • nicotinamide adenine dinucleotide (NAD)
  • single nuclear polymorphism (SNPs)
  • METABOLISM
  • ANTIDEPRESSANTS
  • INFLAMMATION
  • PREVALENCE
  • SIRTUINS
  • STRESS
  • NIACIN
  • ONSET
  • TIME
  • AGE

Identification of Genetic Variations in the NAD-Related Pathways for Patients with Major Depressive Disorder: A Case-Control Study in Taiwan

Tools:

Journal Title:

JOURNAL OF CLINICAL MEDICINE

Volume:

Volume 11, Number 13

Publisher:

Type of Work:

Article | Final Publisher PDF

Abstract:

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.

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© 2022 by the authors.

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/rdf).
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