Genome-wide Association Study of Axial Length in Population-based Cohorts in Japan: The Tohoku Medical Megabank Organization Eye Study

Nobuo Fuse; Miyuki Sakurai; Ikuko N Motoike; Kaname Kojima; Takako Takai-Igarashi; Naoki Nakaya; Naho Tsuchiya; Tomohiro Nakamura; Mami Ishikuro; Taku Obara; Akiko Miyazawa; Kei Homma; Keisuke Ido; Makiko Taira; Tomoko Kobayashi; Ritsuko Shimizu; Akira Uruno; Eiichi N Kodama; Kichiya Suzuki; Yohei Hamanaka; Hiroaki Tomita; Junichi Sugawara; Yoichi Suzuki; Fuji Nagami; Soichi Ogishima; Fumiki Katsuoka; Naoko Minegishi; Atsushi Hozawa; Shinichi Kuriyama; Nobuo Yaegashi; Shigeo Kure; Kengo Kinoshita; Masayuki Yamamoto

doi:10.1016/j.xops.2022.100113

Genome-wide Association Study of Axial Length in Population-based Cohorts in Japan: The Tohoku Medical Megabank Organization Eye Study

Ophthalmol Sci. 2022 Jan 22;2(1):100113. doi: 10.1016/j.xops.2022.100113. eCollection 2022 Mar.

Authors

Nobuo Fuse¹, Miyuki Sakurai¹, Ikuko N Motoike¹, Kaname Kojima¹, Takako Takai-Igarashi¹, Naoki Nakaya¹, Naho Tsuchiya¹, Tomohiro Nakamura¹, Mami Ishikuro¹, Taku Obara¹, Akiko Miyazawa¹, Kei Homma¹, Keisuke Ido^{1

2}, Makiko Taira^{1

2}, Tomoko Kobayashi^{1

2}, Ritsuko Shimizu^{1

2}, Akira Uruno¹, Eiichi N Kodama^{1

3}, Kichiya Suzuki¹, Yohei Hamanaka¹, Hiroaki Tomita^{1

2}, Junichi Sugawara^{1

2}, Yoichi Suzuki¹, Fuji Nagami¹, Soichi Ogishima^{1

4}, Fumiki Katsuoka^{1

4}, Naoko Minegishi¹, Atsushi Hozawa¹, Shinichi Kuriyama^{1

3}, Nobuo Yaegashi^{1

2}, Shigeo Kure^{1

2}, Kengo Kinoshita^{1

4

5}, Masayuki Yamamoto^{1

2}

Affiliations

¹ Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan.
² Tohoku University Graduate School of Medicine, Sendai, Japan.
³ International Research Institute of Disaster Science, Tohoku University, Sendai, Japan.
⁴ Advanced Research Center for Innovations in Next-Generation Medicine, Tohoku University, Sendai, Japan.
⁵ Department of System Bioinformatics, Tohoku University Graduate School of Information Sciences, Sendai, Japan.

Abstract

Purpose: To elucidate the differences in ocular biometric parameters by generation and gender and to identify axial length (AL)-associated genetic variants in Japanese individuals, we analyzed Tohoku Medical Megabank Organization (ToMMo) Eye Study data.

Design: We designed the ToMMo Eye Study, examined AL variations, and conducted genome-wide association studies (GWASs).

Participants: In total, 33 483 participants aged > 18 years who were recruited into the community-based cohort (CommCohort) and the birth and three-generation cohort (BirThree Cohort) of the ToMMo Eye Study were examined.

Methods: Each participant was screened with an interview, ophthalmic examinations, and a microarray analysis. The GWASs were performed in 22 379 participants in the CommCohort (discovery stage) and 11 104 participants in the BirThree Cohort (replication stage). We evaluated the associations of single nucleotide polymorphisms (SNPs) with AL using a genome-wide significance threshold (5 × 10^-8) in each stage of the study and in the subsequent meta-analysis.

Main outcome measures: We identified the association of SNPs with AL and distributions of AL in right and left eyes and individuals of different sexes and ages.

Results: In the discovery stage, the mean AL of the right eye (23.99 mm) was significantly greater than that of the left eye (23.95 mm). This difference was reproducible across sexes and ages. The GWASs revealed 703 and 215 AL-associated SNPs with genome-wide significance in the discovery and validation stages, respectively, and many of the SNPs in the discovery stage were replicated in the validation stage. Validated SNPs and their associated loci were meta-analyzed for statistical significance (P < 5 × 10^-8). This study identified 1478 SNPs spread over 31 loci. Of the 31 loci, 5 are known AL loci, 15 are known refractive-error loci, 4 are known corneal-curvature loci, and 7 loci are newly identified loci that are not known to be associated with AL. Of note, some of them shared functional relationships with previously identified loci.

Conclusions: Our large-scale GWASs exploiting ToMMo Eye Study data identified 31 loci linked to variations in AL, 7 of which are newly reported in this article. The results revealed genetic heterogeneity and similarity in SNPs related to ethnic variations in AL.

Keywords: AL, axial length; Axial length; BirThree, birth and three-generation cohort; CommCohort, community-based cohort; GWAS, genome-wide association study; Genome-wide association study; MAF, minor allele frequency; PCA, principal component analysis; Population-based cohort study; TMM, Tohoku Medical Megabank; ToMMo, Tohoku Medical Megabank Organization.