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Genome-wide association study of schizophrenia using microsatellite markers in the Japanese population

Shibata, Hirokia*; Yamamoto, Kenb*; Sun, Zhua; Oka, Akirac; Inoko, Hidetoshic; Arinami, Tadaod; Inada, Toshiyaf; Ujike, Hiroshie; Itokawa, Masanarig; Tochigi, Mamoruh; Watanabe, Yuichiroj; Someya, Toshiyukij; Kunugi, Hiroshii; Suzuki, Tatsuyok; Iwata, Nakaok; Ozaki, Noriol; Fukumaki, Yasuyukia

doi: 10.1097/YPG.0b013e32835fe4f1
Original Articles

Objectives: To search for schizophrenia susceptibility loci, we carried out a case–control study using 28601 microsatellite markers distributed across the entire genome.

Materials and methods: To control the highly multiple testing, we designed three sequential steps of screening using three independent sets of pooled samples, followed by the confirmatory step using an independent sample set (>2200 case–control pairs).

Results: The first screening using pooled samples of 157 case–control pairs showed 2966 markers to be significantly associated with the disorder (P<0.05). After the second and the third screening steps using pooled samples of 150 pairs each, 374 markers remained significantly associated with the disorder. We individually genotyped all screening samples using a total of 1536 tag single nucleotide polymorphisms (SNPs) located in the vicinity of ∼200 kb from the 59 positive microsatellite markers. Of the 167 SNPs that replicated the significance, we selected 31 SNPs on the basis of the levels of P values for the confirmatory association test using an independent-sample set. The best association signal was observed in rs13404754, located in the upstream region of SLC23A3. We genotyped six additional SNPs in the vicinity of rs13404754. Significant associations were observed in rs13404754, rs6436122, and rs1043160 in the cumulative samples (2617 cases and 2698 controls) (P=0.005, 0.035, and 0.011, respectively). These SNPs are located in the linkage disequilibrium block of 20 kb in size containing SLC23A3, CNPPD1, and FAM134A genes.

Conclusion: Genome-wide association study using microsatellite markers suggested SLC23A3, CNPPD1, and FAM134A genes as candidates for schizophrenia susceptibility in the Japanese population.

aResearch Center for Genetic Information, Division of Human Molecular Genetics

bResearch Center for Genetic Information, Division of Genome Analysis, Medical Institute of Bioregulation, Kyushu University, Fukuoka

cDepartment of Molecular Life Science, Course of Basic Medical Science and Molecular Medicine, Tokai University, School of Medicine, Kanagawa

dDepartment of Medical Genetics, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba

eDepartment of Neuropsychiatry, Okayama University, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama

fInstitute of Neuropsychiatry, Seiwa Hospital

gDepartment of Schizophrenia Research, Tokyo Institute of Psychiatry

hDepartment of Neuropsychiatry, Graduate School of Medicine, The University of Tokyo

iDepartment of Mental Disorder Research, National Center of Neurology and Psychiatry, National Institute of Neuroscience, Tokyo

jDepartment of Psychiatry, Niigata University Graduate School of Medical and Dental Sciences, Niigata

kDepartment of Psychiatry, School of Medicine, Fujita Health University, Aichi

lDepartment of Psychiatry, Graduate School of Medicine, Nagoya University, Nagoya, Japan

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*Hiroki Shibata and Ken Yamamoto contributed equally to the writing of this article.

Correspondence to Yasuyuki Fukumaki, MD, PhD, Research Center for Genetic Information, Division of Human Molecular Genetics, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan Tel: +81 92 642 6167; fax: +81 92 632 2375; e-mail: yfukumak@gen.kyushu-u.ac.jp

Received December 22, 2011

Accepted October 27, 2012

© 2013 Lippincott Williams & Wilkins, Inc.