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Whole-genome-wide association study in the Bulgarian population reveals HHAT as schizophrenia susceptibility gene

Betcheva, Elitza T.a,f; Yosifova, Adelina G.a,f; Mushiroda, Taiseib; Kubo, Michiakic; Takahashi, Atsushid; Karachanak, Sena K.f; Zaharieva, Irina T.f; Hadjidekova, Savina P.f; Dimova, Ivanka I.f; Vazharova, Radoslava V.f; Stoyanov, Drozdstoy S.h; Milanova, Vihra K.g; Tolev, Todori; Kirov, Georgej; Kamatani, Naoyukid; Toncheva, Draga I.f; Nakamura, Yusukea,e

doi: 10.1097/YPG.0b013e3283586343
Original Articles

Objective: Schizophrenia, the most common major psychiatric disorder (or group of disorders), entails severe decline of higher functions, principally with alterations in cognitive functioning and reality perception. Both genetic and environmental factors are involved in its pathogenesis; however, its genetic background still needs to be clarified. The objective of the study was to reveal genetic markers associated with schizophrenia in the Bulgarian population.

Methods: We have conducted a genome-wide association study using 554 496 single nucleotide polymorphisms (SNPs) in 188 affected and 376 unaffected Bulgarian individuals. Subsequently, the 100 candidate SNPs that revealed the smallest P-values were further evaluated in an additional set of 99 case and 328 control samples.

Results: We found a significant association between schizophrenia and the intronic SNP rs7527939 in the HHAT gene (P-value of 6.49×10−9 with an odds ratio of 2.63, 95% confidence interval of 1.89–3.66). We also genotyped additional SNPs within a 58-kb linkage disequilibrium block surrounding the landmark SNP.

Conclusion: We suggest rs7527939 to be the strongest indicator of susceptibility to schizophrenia in the Bulgarian population within the HHAT locus.

aLaboratory for International Alliance

bLaboratory for Pharmacogenetics

cLaboratory for Genotyping Development, RIKEN Center for Genomic Medicine, Yokohama City, Kanagawa

dLaboratory of Statistical Analysis, RIKEN Center for Genomic Medicine

eLaboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan

fDepartment of Medical Genetics, Medical Faculty

gDepartment of Psychiatry, Aleksandrovska Hospital, Medical University, Sofia

hState Psychiatric Hospital “St. Ivan Rilski” – Ministry of Health of Republic of Bulgaria, Novi Iskar

iDepartment of Psychiatry, Dr Georgi Kisiov Hospital, Radnevo, Bulgaria

jDepartment of Psychological Medicine, Cardiff University, School of Medicine, Henry Wellcome Building, Heath Park, Cardiff, UK

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Correspondence to Draga I. Toncheva, MD, PhD, DSci, Department of Medical Genetics, Medical Faculty, Medical University Sofia, 1431Sofia, Bulgaria Tel/fax: +359 2 952 03 57; e-mail: dragatoncheva@yahoo.com

Received November 8, 2011

Accepted May 3, 2012

© 2013 Lippincott Williams & Wilkins, Inc.