Associations between the orexin (hypocretin) receptor 2 gene polymorphism Val308Ile and nicotine dependence in genome-wide and subsequent association studies.
BACKGROUND
Many genetic and environmental factors are involved in the etiology of nicotine dependence. Although several candidate gene variations have been reported by candidate gene studies or genome-wide association studies (GWASs) to be associated with smoking behavior and the vulnerability to nicotine dependence, such studies have been mostly conducted with subjects with European ancestry. However, genetic factors have rarely been investigated for the Japanese population as GWASs. To elucidate genetic factors involved in nicotine dependence in Japanese, the present study comprehensively explored genetic contributors to nicotine dependence by using whole-genome genotyping arrays with more than 200,000 markers in Japanese subjects.


RESULTS
The subjects for the GWAS and replication study were 148 and 374 patients, respectively. A two-stage GWAS was conducted using the Fagerström Test for Nicotine Dependence (FTND), Tobacco Dependence Screener (TDS), and number of cigarettes smoked per day (CPD) as indices of nicotine dependence. For the additional association analyses, patients who underwent major abdominal surgery, patients with methamphetamine dependence/psychosis, and healthy subjects with schizotypal personality trait data were recruited. Autopsy specimens with various diseases were also evaluated. After the study of associations between more than 200,000 marker single-nucleotide polymorphisms (SNPs) and the FTND, TDS, and CPD, the nonsynonymous rs2653349 SNP (located on the gene that encodes orexin [hypocretin] receptor 2) was selected as the most notable SNP associated with FTND, with a p value of 0.0005921 in the two-stage GWAS. This possible association was replicated for the remaining 374 samples. This SNP was also associated with postoperative pain, the initiation of methamphetamine use, schizotypal personality traits, and susceptibility to goiter.


CONCLUSIONS
Although the p value did not reach a conventional genome-wide level of significance in our two-stage GWAS, we obtained significant results in the subsequent analyses that suggest that the rs2653349 SNP (Val308Ile) could be a genetic factor that is related to nicotine dependence and possibly pain, schizotypal personality traits, and goiter in the Japanese population.
Addictive Substance Project, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo, 156-8506, Japan. nishizawa-ds@igakuken.or.jp.
Daisuke
D
Nishizawa
Addictive Substance Project, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo, 156-8506, Japan. kasai-sy@igakuken.or.jp.
Shinya
S
Kasai
Addictive Substance Project, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo, 156-8506, Japan. hasegawa-jk@igakuken.or.jp.
Junko
J
Hasegawa
Department of Clinical Nursing, Hamamatsu University School of Medicine, Hamamatsu, 431-3192, Japan. naomi25@hama-med.ac.jp.|Department of Tumor Pathology, Hamamatsu University School of Medicine, Hamamatsu, 431-3192, Japan. naomi25@hama-med.ac.jp.
Naomi
N
Sato
Department of Tumor Pathology, Hamamatsu University School of Medicine, Hamamatsu, 431-3192, Japan. h-yamada@hama-med.ac.jp.
Hidetaka
H
Yamada
Department of Pathology, Iwata City Hospital, Iwata, 438-8550, Japan. kyon8@juno.ocn.ne.jp.
Fumihiko
F
Tanioka
Department of Surgery, Toho University Sakura Medical Center, Sakura, 285-8741, Japan. nagashima@sakura.med.toho-u.ac.jp.
Makoto
M
Nagashima
Department of Surgery, Toho University Sakura Medical Center, Sakura, 285-8741, Japan. ryochan@sakura.med.toho-u.ac.jp.
Ryoji
R
Katoh
Department of Anesthesiology, Toho University Sakura Medical Center, Sakura, 285-8741, Japan. satoh-ane@sakura.med.toho-u.ac.jp.
Yasuo
Y
Satoh
Department of Anesthesiology, Toho University Sakura Medical Center, Sakura, 285-8741, Japan. tagami@sakura.med.toho-u.ac.jp.
Megumi
M
Tagami
Ujike Nishiguchi Clinic, Okayama, 700-0024, Japan. hujike-10@t.okadai.jp.|Japanese Genetics Initiative for Drug Abuse (JGIDA), Tokyo, Japan. hujike-10@t.okadai.jp.
Hiroshi
H
Ujike
Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan. ozaki-n@med.nagoya-u.ac.jp.|Japanese Genetics Initiative for Drug Abuse (JGIDA), Tokyo, Japan. ozaki-n@med.nagoya-u.ac.jp.
Norio
N
Ozaki
Department of Psychiatry, Seiwa Hospital, Institute of Neuropsychiatry, Tokyo, 162-0851, Japan. inada@seiwa-hp.com.|Japanese Genetics Initiative for Drug Abuse (JGIDA), Tokyo, Japan. inada@seiwa-hp.com.
Toshiya
T
Inada
Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, 470-1192, Japan. nakao@fujita-hu.ac.jp.|Japanese Genetics Initiative for Drug Abuse (JGIDA), Tokyo, Japan. nakao@fujita-hu.ac.jp.
Nakao
N
Iwata
Addictive Substance Project, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo, 156-8506, Japan. sora@med.kobe-u.ac.jp.|Department of Psychiatry, Kobe University Graduate School of Medicine, Kobe, 650-0017, Japan. sora@med.kobe-u.ac.jp.|Japanese Genetics Initiative for Drug Abuse (JGIDA), Tokyo, Japan. sora@med.kobe-u.ac.jp.
Ichiro
I
Sora
Department of Psychiatry, Graduate School of Medicine, Chiba University, Chiba, 260-8670, Japan. iyom@faculty.chiba-u.jp.|Japanese Genetics Initiative for Drug Abuse (JGIDA), Tokyo, Japan. iyom@faculty.chiba-u.jp.
Masaomi
M
Iyo
Department of Neuropsychopharmacology, National Institute of Mental Health, National Center of Neurology and Psychiatry, Tokyo, 187-8553, Japan. mitsu@ncnp-k.go.jp.|Japanese Genetics Initiative for Drug Abuse (JGIDA), Tokyo, Japan. mitsu@ncnp-k.go.jp.
Mitsuhiko
M
Yamada
Seimei Hospital, Fuji City, 417-0801, Japan. waveonlyjust@yahoo.co.jp.|Japanese Genetics Initiative for Drug Abuse (JGIDA), Tokyo, Japan. waveonlyjust@yahoo.co.jp.
Naoki
N
Kondo
Koujin Hospital, Nagoya, 463-8530, Japan. wonmj@hm10.aitai.ne.jp.|Japanese Genetics Initiative for Drug Abuse (JGIDA), Tokyo, Japan. wonmj@hm10.aitai.ne.jp.
Moo-Jun
MJ
Won
Saitama Seishin-iryo Center, Kita-adachi, Saitama, 362-0806, Japan. naruse.nobuya@pref.saitama.lg.jp.|Japanese Genetics Initiative for Drug Abuse (JGIDA), Tokyo, Japan. naruse.nobuya@pref.saitama.lg.jp.
Nobuya
N
Naruse
Kanagawa Psychiatric Center, Serigaya Hospital, Kanagawa, 233-0006, Japan. kums@ballade.plala.or.jp.|Japanese Genetics Initiative for Drug Abuse (JGIDA), Tokyo, Japan. kums@ballade.plala.or.jp.
Kumi
K
Uehara-Aoyama
Schizophrenia and Depression Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, 156-8506, Japan. itokawa-ms@igakuken.or.jp.
Masanari
M
Itokawa
Department of Psychiatry, Osaka University Graduate School of Medicine, Osaka, 565-0871, Japan. ohi@psy.med.osaka-u.ac.jp.|National Hospital Organization, Yamato Mental-Medical Center, Nara, 639-1042, Japan. ohi@psy.med.osaka-u.ac.jp.
Kazutaka
K
Ohi
Department of Psychiatry, Osaka University Graduate School of Medicine, Osaka, 565-0871, Japan. hashimor@psy.med.osaka-u.ac.jp.|Molecular Research Center for Children's Mental Development, United Graduate School of Child Development, Osaka University, Kanazawa University, Hamamatsu University, Chiba University, and Fukui University School of Medicine, Osaka, 565-0871, Japan. hashimor@psy.med.osaka-u.ac.jp.
Ryota
R
Hashimoto
Department of Genomics for Longevity and Health, Tokyo Metropolitan Institute of Gerontology, Tokyo, 173-0015, Japan. kunpei-tanisawa@fuji.waseda.jp.|Graduate School of Sport Sciences, Waseda University, Tokyo, 359-1192, Japan. kunpei-tanisawa@fuji.waseda.jp.
Kumpei
K
Tanisawa
Department of Pathology, Tokyo Metropolitan Geriatric Hospital, Tokyo, 173-0015, Japan. arai@tmig.or.jp.
Tomio
T
Arai
Center for Promotion of Clinical Investigation, Tokyo Metropolitan Geriatric Hospital, Tokyo, 173-0015, Japan. mori_seijiro@tmghig.jp.
Seijiro
S
Mori
Molecular Pathophysiology, Department of Molecular-genetic Sciences, Division of Biomedical Laboratory Sciences, Graduate School of Health Care Sciences, Tokyo Medical and Dental University, Tokyo, 101-0062, Japan. m.sawabe.mp@tmd.ac.jp.
Motoji
M
Sawabe
Department of Medical Informatics, Center for Information, Jichi Medical University, Shimotsuke, 329-0498, Japan. mnaka@jichi.ac.jp.
Makiko
M
Naka-Mieno
Department of Human Functional Genomics, Life Science Research Center, Mie University, Tsu, 514-8507, Japan. yamada@gene.mie-u.ac.jp.
Yoshiji
Y
Yamada
Department of Molecular Epidemiology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, 101-0062, Japan. myamada.epi@mri.tmd.ac.jp.
Miki
M
Yamada
Department of Molecular Epidemiology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, 101-0062, Japan. nsato.epi@mri.tmd.ac.jp.
Noriko
N
Sato
Department of Molecular Epidemiology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, 101-0062, Japan. muramatsu.epi@mri.tmd.ac.jp.
Masaaki
M
Muramatsu
Department of Genomics for Longevity and Health, Tokyo Metropolitan Institute of Gerontology, Tokyo, 173-0015, Japan. mtanaka@tmig.or.jp.|Department of Clinical Laboratory, Tokyo Metropolitan Geriatric Hospital, Tokyo, 173-0015, Japan. mtanaka@tmig.or.jp.
Masashi
M
Tanaka
International Institute of Integrative Sleep Medicine, Ibaraki, 305-8575, Japan. irukayama.yoko.fm@u.tsukuba.ac.jp.
Yoko
Y
Irukayama-Tomobe
Department of Molecular Neuroscience and Integrative Physiology, Faculty of Medicine, Kanazawa University, Ishikawa, 920-8640, Japan. y.cleo1115@gmail.com.
Yuki C
YC
Saito
Department of Molecular Neuroscience and Integrative Physiology, Faculty of Medicine, Kanazawa University, Ishikawa, 920-8640, Japan. tsakurai@med.kanazawa-u.ac.jp.
Takeshi
T
Sakurai
Department of Anesthesiology and Pain Medicine, Juntendo University School of Medicine, Tokyo, 113-8421, Japan. hayashidatoday@yahoo.co.jp.
Masakazu
M
Hayashida
Department of Tumor Pathology, Hamamatsu University School of Medicine, Hamamatsu, 431-3192, Japan. hsugimur@hama-med.ac.jp.
Haruhiko
H
Sugimura
Addictive Substance Project, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo, 156-8506, Japan. ikeda-kz@igakuken.or.jp.|Japanese Genetics Initiative for Drug Abuse (JGIDA), Tokyo, Japan. ikeda-kz@igakuken.or.jp.
Kazutaka
K
Ikeda
D000005:Abdomen / Q000601:surgery; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D044466:Asian People / Q000235:genetics; D001344:Autopsy; D005260:Female; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006042:Goiter / Q000235:genetics; D006801:Humans; D008297:Male; D008694:Methamphetamine; D008875:Middle Aged; D064446:Orexin Receptors / Q000235:genetics*; D010149:Postoperative Pain / Q000209:etiology / Q000235:genetics; D020161:Physical Chromosome Mapping; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D015203:Reproducibility of Results; D012569:Schizotypal Personality Disorder / Q000235:genetics; D014029:Tobacco Use Disorder / Q000235:genetics*; D055815:Young Adult
D064446:Orexin Receptors; D008694:Methamphetamine