Common protein-altering variant in GFAP is associated with white matter lesions in the older Japanese population

Yoshihiko Furuta; Masato Akiyama; Naoki Hirabayashi; Takanori Honda; Mao Shibata; Tomoyuki Ohara; Jun Hata; Chikashi Terao; Yukihide Momozawa; Yasuko Tatewaki; Yasuyuki Taki; Shigeyuki Nakaji; Tetsuya Maeda; Kenjiro Ono; Masaru Mimura; Kenji Nakashima; Jun-Ichi Iga; Minoru Takebayashi; Toshiharu Ninomiya; Japan Prospective Studies for Aging and Dementia (JPSC-AD) Study Group

doi:10.1038/s41525-024-00431-x

Common protein-altering variant in GFAP is associated with white matter lesions in the older Japanese population

NPJ Genom Med. 2024 Nov 13;9(1):59. doi: 10.1038/s41525-024-00431-x.

Authors

Yoshihiko Furuta^#^{1

2}, Masato Akiyama^#³, Naoki Hirabayashi^{1

4

5}, Takanori Honda¹, Mao Shibata^{1

4

6}, Tomoyuki Ohara^{1

7}, Jun Hata^{6

8}, Chikashi Terao^{9

10

11}, Yukihide Momozawa¹², Yasuko Tatewaki¹³, Yasuyuki Taki¹³, Shigeyuki Nakaji¹⁴, Tetsuya Maeda¹⁵, Kenjiro Ono¹⁶, Masaru Mimura¹⁷, Kenji Nakashima¹⁸, Jun-Ichi Iga¹⁹, Minoru Takebayashi²⁰, Toshiharu Ninomiya^{1

6}; Japan Prospective Studies for Aging and Dementia (JPSC-AD) Study Group

Affiliations

¹ Department of Epidemiology and Public Health, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
² Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
³ Department of Ocular Pathology and Imaging Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. akiyama.masato.588@m.kyushu-u.ac.jp.
⁴ Department of Psychosomatic Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
⁵ Ito Clinic, Kyushu University, Fukuoka, Japan.
⁶ Center for Cohort Studies, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
⁷ Department of Neuropsychiatry, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
⁸ Department of Health Care Administration and Management, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
⁹ Laboratory for Statistical and Translational Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
¹⁰ Clinical Research Center, Shizuoka General Hospital, Shizuoka, Japan.
¹¹ The Department of Applied Genetics, The School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan.
¹² Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
¹³ Department of Aging Research and Geriatric Medicine, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan.
¹⁴ Department of Social Medicine, Graduate School of Medicine, Hirosaki University, Hirosaki, Japan.
¹⁵ Division of Neurology and Gerontology, Department of Internal Medicine, School of Medicine, Iwate Medical University, Yahaba, Japan.
¹⁶ Department of Neurology, Kanazawa University Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan.
¹⁷ Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan.
¹⁸ National Hospital Organization, Matsue Medical Center, Matsue, Japan.
¹⁹ Department of Neuropsychiatry, Ehime University Graduate School of Medicine, Ehime University, Toon, Japan.
²⁰ Department of Neuropsychiatry, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.

^# Contributed equally.

Abstract

The genetic architecture of white matter lesions (WMLs) in Asian populations has not been well-characterized. Here, we performed a genome-wide association study (GWAS) to identify loci associated with the WML volume. Brain MRI and DNA samples were collected from 9479 participants in the Japan Prospective Studies Collaboration for Aging and Dementia (JPSC-AD). The GWAS confirmed three known WML-associated loci (SH3PXD2A, GFAP, and TRIM47). The lead variant of GFAP was a common missense variant (p.D295N) in East Asians. Meta-GWAS using the publicly available summary statistics of UK Biobank identified one previously unreported locus 6q23.2 (SLC2A12). Integration with expression quantitative trait locus data implied the newly identified locus affects SLC2A12 expression. The effect sizes of 20 lead variants at the WML-associated loci were moderately correlated between JPSC-AD and UK Biobank. These results indicate that the alteration in GFAP protein caused by the common missense variant in East Asians influences the WML volume.