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(Stroke. 2007;38:1368.)
© 2007 American Heart Association, Inc.

Research Reports

Combination of Linkage and Association Studies for Brain Arteriovenous Malformation

Sumiko Inoue, PhD; Wanyang Liu, MPH; Kayoko Inoue, MD, MPH, PhD; Youhei Mineharu, MD; Katsunobu Takenaka, MD, PhD; Hiroyasu Yamakawa, MD, PhD; Masamitsu Abe, MD, PhD; Jafar J. Jafar, MD; Roman Herzig, MD, PhD Akio Koizumi, MD, PhD

From the Department of Health and Environmental Sciences, Kyoto University Graduate School of Medicine (S.I., L.W., K.I., Y.M., A.K.), Japan; Department of Neurosurgery, Takayama Red Cross Hospital (K.T.), Japan; Department of Emergency Medicine, Chunou Kousei Hospital (H.Y.), Gifu, Japan; Department of Neurosurgery, Faculty of Medicine, Saga University (M.A.), Saga, Japan; Department of Neurosurgery, New York University Medical Center (J.J.J.), New York, USA; and Stroke Center, Department of Neurology, Palacky University Medical School and University Hospital (R.H.), Olomouc, Czech Republic.

Correspondence to Akio Koizumi, MD, PhD, Professor, Department of Health and Environmental Sciences, Kyoto University Graduate School of Medicine, Konoe-cho, Yoshida, Sakyo-ku, Kyoto, 606-8501 Japan. E-mail koizumi{at}pbh.med.kyoto-u.ac.jp

Background and Purpose— Genetic factors for brain arteriovenous malformation are unexplored because of the low incidence of familial cases, albeit local and familial clustering. We used a combination of a linkage study and an association study to explore the genetic background.

Methods— A genome-wide linkage analysis was performed in 12 patients from 6 unrelated families using the GENEHUNTER program. A genome-wide association analysis of 26 cases and 30 controls was performed using a GeneChip 10K mapping array. Significance levels for linkage and single single-nucleotide polymorphism association analyses were set at P<0.05 and P<0.0001, respectively. Genotyping was also performed using 58 960 single-nucleotide polymorphisms for 2 sets of discordant twins.

Results— The linkage analysis revealed 7 candidate regions, with the highest logarithm of odds score of 1.88 (P=0.002) at chromosome 6q25. A significant association was observed for 4 single-nucleotide polymorphisms and 2 haplotypes, but none of them overlapped with candidate linkage regions. Genotyping of the twins showed no genetic heterogeneity.

Conclusions— The present study failed to identify genetic factors for arteriovenous malformation although the low statistical power may have resulted in such evidence being missed.

Key Words: arteriovenous malformation • association • genome-wide • genetics • linkage • microarr