Epigenome-wide association study of DNA methylation in panic disorder.
Panic disorder (PD) is considered to be a multifactorial disorder emerging from interactions among multiple genetic and environmental factors. To date, although genetic studies reported several susceptibility genes with PD, few of them were replicated and the pathogenesis of PD remains to be clarified. Epigenetics is considered to play an important role in etiology of complex traits and diseases, and DNA methylation is one of the major forms of epigenetic modifications. In this study, we performed an epigenome-wide association study of PD using DNA methylation arrays so as to investigate the possibility that different levels of DNA methylation might be associated with PD.



The DNA methylation levels of CpG sites across the genome were examined with genomic DNA samples (PD,N= 48, control,N= 48) extracted from peripheral blood. Methylation arrays were used for the analysis.βvalues, which represent the levels of DNA methylation, were normalized via an appropriate pipeline. Then,βvalues were converted toMvalues via the logit transformation for epigenome-wide association study. The relationship between each DNA methylation site and PD was assessed by linear regression analysis with adjustments for the effects of leukocyte subsets.



Forty CpG sites showed significant association with PD at 5% FDR correction, though the differences of the DNA methylation levels were relatively small. Most of the significant CpG sites (37/40 CpG sites) were located in or around CpG islands. Many of the significant CpG sites (27/40 CpG sites) were located upstream of genes, and all such CpG sites with the exception of two were hypomethylated in PD subjects. A pathway analysis on the genes annotated to the significant CpG sites identified several pathways, including "positive regulation of lymphocyte activation."



Although future studies with larger number of samples are necessary to confirm the small DNA methylation abnormalities associated with PD, there is a possibility that several CpG sites might be associated, together as a group, with PD.
Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo Ward, Tokyo, 113-0033 Japan.
Mihoko
M
Shimada-Sugimoto
Graduate School of Clinical Psychology, Teikyo Heisei University Major of Professional Clinical Psychology, 2-51-4 Higashiikebukuro, Toshima Ward, Tokyo, 171-0014 Japan.
Takeshi
T
Otowa
Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo Ward, Tokyo, 113-0033 Japan.|Department of Psychiatry and Behavioral Sciences, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya Ward, Tokyo, 156-8506 Japan.
Taku
T
Miyagawa
Division for Environment, Health and Safety, The University of Tokyo, 7-3-1 Hongo, Bunkyo Ward, Tokyo, 113-0033 Japan.
Tadashi
T
Umekage
Department of Psychiatry, Shonan Kamakura General Hospital, 1370-1 Okamoto, Kamakura City, Kanagawa 247-8533 Japan.
Yoshiya
Y
Kawamura
Department of Molecular Brain Science, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo Ward, Kumamoto City, Kumamoto 860-8556 Japan.
Miki
M
Bundo
Department of Molecular Brain Science, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo Ward, Kumamoto City, Kumamoto 860-8556 Japan.
Kazuya
K
Iwamoto
Department of Neuropsychiatry, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi Ward, Tokyo, 173-0003 Japan.
Mamoru
M
Tochigi
Department of Neuropsychiatry, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo Ward, Tokyo, 113-0033 Japan.
Kiyoto
K
Kasai
Panic Disorder Research Center, Warakukai Med Corp, 3-9-18 Akasaka, Minato Ward, Tokyo, 107-0052 Japan.
Hisanobu
H
Kaiya
Department of Psychiatry, Institute of Medical Life Science, Graduate School of Medicine, Mie University, 2-174 Edobashi, Tsu City, Mie 514-8502 Japan.
Hisashi
H
Tanii
Department of Psychiatry, Koseikai Michinoo Hospital, 1-1 Nijigaokamachi, Nagasaki City, Nagasaki 852-8055 Japan.
Yuji
Y
Okazaki
Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo Ward, Tokyo, 113-0033 Japan.
Katsushi
K
Tokunaga
Department of Physical and Health Education, Graduate School of Education, The University of Tokyo, 7-3-1 Hongo, Bunkyo Ward, Tokyo, 113-0033 Japan.
Tsukasa
T
Sasaki
D016022:Case-Control Studies; D018899:CpG Islands; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D057890:Epigenomics / Q000379:methods; D005260:Female; D053263:Gene Regulatory Networks; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D055106:Genome-Wide Association Study / Q000379:methods; D006801:Humans; D016131:Lymphocyte Subsets; D008297:Male; D016584:Panic Disorder / Q000235:genetics*
DNA methylation; Epigenetics; Epigenome-wide association study; Panic disorder; Psychiatric disorder