Low-frequency coding variants in CETP and CFB are associated with susceptibility of exudative age-related macular degeneration in the Japanese population

Yukihide Momozawa, Masato Akiyama, Yoichiro Kamatani, Satoshi Arakawa, Miho Yasuda, Shigeo Yoshida, Yuji Oshima, Ryusaburo Mori, Koji Tanaka, Keisuke Mori, Satoshi Inoue, Hiroko Terasaki, Tetsuhiro Yasuma, Shigeru Honda, Akiko Miki, Maiko Inoue, Kimihiko Fujisawa, Kanji Takahashi, Tsutomu Yasukawa, Yasuo YanagiKazuaki Kadonosono, Koh Hei Sonoda, Tatsuro Ishibashi, Atsushi Takahashi, Michiaki Kubo

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Abstract

Age-related macular degeneration (AMD) is a major cause of blindness in the elderly. Previous sequencing studies of AMD susceptibility genes have revealed the association of rare coding variants in CFH, CFI, C3 and C9 in European population; however, the impact of rare or low-frequency coding variants on AMD susceptibility in other populations is largely unknown. To identify the role of low-frequency coding variants on exudative AMD susceptibility in a Japanese population, we analysed the association of coding variants of 34 AMD candidate genes in the two-stage design by a multiplex PCR-based target sequencing method. We used a total of 2,886 (1st: 827, 2nd: 2,059) exudative AMD cases including typical AMD, polypoidal choroidal vasculopathy, and retinal angiomatous proliferation and 9,337 (1st: 3,247 2nd: 6,090) controls. Gene-based analysis found a significant association of low-frequency variants (minor allele frequency (MAF)< 0.05) in CETP, C2 and CFB. The association of CETP remained after conditioned with all known genome-wide association study (GWAS) associated variants. In addition, when we included only disruptive variants, enrichment of rare variants (MAF < 0.01) was also observed after conditioned with all GWAS associated variants (P=1.03×10-6, odds ratio (OR)=2.48). Haplotype and conditional analysis of the C2-CFB-SKIV2L locus showed a low-frequency variant (R74H) in CFB would be individually associated with AMD susceptibility independent of the GWAS associated SNP. These findings highlight the importance of target sequencing to reveal the impact of rare or low-frequency coding variants on disease susceptibility in different ethnic populations.

Original languageEnglish
Pages (from-to)5027-5034
Number of pages8
JournalHuman molecular genetics
Volume25
Issue number22
DOIs
Publication statusPublished - 15-11-2016

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Macular Degeneration
Population
Genome-Wide Association Study
Gene Frequency
Genes
Multiplex Polymerase Chain Reaction
Disease Susceptibility
Blindness
Haplotypes
Single Nucleotide Polymorphism
Odds Ratio

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Momozawa, Yukihide ; Akiyama, Masato ; Kamatani, Yoichiro ; Arakawa, Satoshi ; Yasuda, Miho ; Yoshida, Shigeo ; Oshima, Yuji ; Mori, Ryusaburo ; Tanaka, Koji ; Mori, Keisuke ; Inoue, Satoshi ; Terasaki, Hiroko ; Yasuma, Tetsuhiro ; Honda, Shigeru ; Miki, Akiko ; Inoue, Maiko ; Fujisawa, Kimihiko ; Takahashi, Kanji ; Yasukawa, Tsutomu ; Yanagi, Yasuo ; Kadonosono, Kazuaki ; Sonoda, Koh Hei ; Ishibashi, Tatsuro ; Takahashi, Atsushi ; Kubo, Michiaki. / Low-frequency coding variants in CETP and CFB are associated with susceptibility of exudative age-related macular degeneration in the Japanese population. In: Human molecular genetics. 2016 ; Vol. 25, No. 22. pp. 5027-5034.
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title = "Low-frequency coding variants in CETP and CFB are associated with susceptibility of exudative age-related macular degeneration in the Japanese population",
abstract = "Age-related macular degeneration (AMD) is a major cause of blindness in the elderly. Previous sequencing studies of AMD susceptibility genes have revealed the association of rare coding variants in CFH, CFI, C3 and C9 in European population; however, the impact of rare or low-frequency coding variants on AMD susceptibility in other populations is largely unknown. To identify the role of low-frequency coding variants on exudative AMD susceptibility in a Japanese population, we analysed the association of coding variants of 34 AMD candidate genes in the two-stage design by a multiplex PCR-based target sequencing method. We used a total of 2,886 (1st: 827, 2nd: 2,059) exudative AMD cases including typical AMD, polypoidal choroidal vasculopathy, and retinal angiomatous proliferation and 9,337 (1st: 3,247 2nd: 6,090) controls. Gene-based analysis found a significant association of low-frequency variants (minor allele frequency (MAF)< 0.05) in CETP, C2 and CFB. The association of CETP remained after conditioned with all known genome-wide association study (GWAS) associated variants. In addition, when we included only disruptive variants, enrichment of rare variants (MAF < 0.01) was also observed after conditioned with all GWAS associated variants (P=1.03×10-6, odds ratio (OR)=2.48). Haplotype and conditional analysis of the C2-CFB-SKIV2L locus showed a low-frequency variant (R74H) in CFB would be individually associated with AMD susceptibility independent of the GWAS associated SNP. These findings highlight the importance of target sequencing to reveal the impact of rare or low-frequency coding variants on disease susceptibility in different ethnic populations.",
author = "Yukihide Momozawa and Masato Akiyama and Yoichiro Kamatani and Satoshi Arakawa and Miho Yasuda and Shigeo Yoshida and Yuji Oshima and Ryusaburo Mori and Koji Tanaka and Keisuke Mori and Satoshi Inoue and Hiroko Terasaki and Tetsuhiro Yasuma and Shigeru Honda and Akiko Miki and Maiko Inoue and Kimihiko Fujisawa and Kanji Takahashi and Tsutomu Yasukawa and Yasuo Yanagi and Kazuaki Kadonosono and Sonoda, {Koh Hei} and Tatsuro Ishibashi and Atsushi Takahashi and Michiaki Kubo",
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Momozawa, Y, Akiyama, M, Kamatani, Y, Arakawa, S, Yasuda, M, Yoshida, S, Oshima, Y, Mori, R, Tanaka, K, Mori, K, Inoue, S, Terasaki, H, Yasuma, T, Honda, S, Miki, A, Inoue, M, Fujisawa, K, Takahashi, K, Yasukawa, T, Yanagi, Y, Kadonosono, K, Sonoda, KH, Ishibashi, T, Takahashi, A & Kubo, M 2016, 'Low-frequency coding variants in CETP and CFB are associated with susceptibility of exudative age-related macular degeneration in the Japanese population', Human molecular genetics, vol. 25, no. 22, pp. 5027-5034. https://doi.org/10.1093/hmg/ddw335

Low-frequency coding variants in CETP and CFB are associated with susceptibility of exudative age-related macular degeneration in the Japanese population. / Momozawa, Yukihide; Akiyama, Masato; Kamatani, Yoichiro; Arakawa, Satoshi; Yasuda, Miho; Yoshida, Shigeo; Oshima, Yuji; Mori, Ryusaburo; Tanaka, Koji; Mori, Keisuke; Inoue, Satoshi; Terasaki, Hiroko; Yasuma, Tetsuhiro; Honda, Shigeru; Miki, Akiko; Inoue, Maiko; Fujisawa, Kimihiko; Takahashi, Kanji; Yasukawa, Tsutomu; Yanagi, Yasuo; Kadonosono, Kazuaki; Sonoda, Koh Hei; Ishibashi, Tatsuro; Takahashi, Atsushi; Kubo, Michiaki.

In: Human molecular genetics, Vol. 25, No. 22, 15.11.2016, p. 5027-5034.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Low-frequency coding variants in CETP and CFB are associated with susceptibility of exudative age-related macular degeneration in the Japanese population

AU - Momozawa, Yukihide

AU - Akiyama, Masato

AU - Kamatani, Yoichiro

AU - Arakawa, Satoshi

AU - Yasuda, Miho

AU - Yoshida, Shigeo

AU - Oshima, Yuji

AU - Mori, Ryusaburo

AU - Tanaka, Koji

AU - Mori, Keisuke

AU - Inoue, Satoshi

AU - Terasaki, Hiroko

AU - Yasuma, Tetsuhiro

AU - Honda, Shigeru

AU - Miki, Akiko

AU - Inoue, Maiko

AU - Fujisawa, Kimihiko

AU - Takahashi, Kanji

AU - Yasukawa, Tsutomu

AU - Yanagi, Yasuo

AU - Kadonosono, Kazuaki

AU - Sonoda, Koh Hei

AU - Ishibashi, Tatsuro

AU - Takahashi, Atsushi

AU - Kubo, Michiaki

PY - 2016/11/15

Y1 - 2016/11/15

N2 - Age-related macular degeneration (AMD) is a major cause of blindness in the elderly. Previous sequencing studies of AMD susceptibility genes have revealed the association of rare coding variants in CFH, CFI, C3 and C9 in European population; however, the impact of rare or low-frequency coding variants on AMD susceptibility in other populations is largely unknown. To identify the role of low-frequency coding variants on exudative AMD susceptibility in a Japanese population, we analysed the association of coding variants of 34 AMD candidate genes in the two-stage design by a multiplex PCR-based target sequencing method. We used a total of 2,886 (1st: 827, 2nd: 2,059) exudative AMD cases including typical AMD, polypoidal choroidal vasculopathy, and retinal angiomatous proliferation and 9,337 (1st: 3,247 2nd: 6,090) controls. Gene-based analysis found a significant association of low-frequency variants (minor allele frequency (MAF)< 0.05) in CETP, C2 and CFB. The association of CETP remained after conditioned with all known genome-wide association study (GWAS) associated variants. In addition, when we included only disruptive variants, enrichment of rare variants (MAF < 0.01) was also observed after conditioned with all GWAS associated variants (P=1.03×10-6, odds ratio (OR)=2.48). Haplotype and conditional analysis of the C2-CFB-SKIV2L locus showed a low-frequency variant (R74H) in CFB would be individually associated with AMD susceptibility independent of the GWAS associated SNP. These findings highlight the importance of target sequencing to reveal the impact of rare or low-frequency coding variants on disease susceptibility in different ethnic populations.

AB - Age-related macular degeneration (AMD) is a major cause of blindness in the elderly. Previous sequencing studies of AMD susceptibility genes have revealed the association of rare coding variants in CFH, CFI, C3 and C9 in European population; however, the impact of rare or low-frequency coding variants on AMD susceptibility in other populations is largely unknown. To identify the role of low-frequency coding variants on exudative AMD susceptibility in a Japanese population, we analysed the association of coding variants of 34 AMD candidate genes in the two-stage design by a multiplex PCR-based target sequencing method. We used a total of 2,886 (1st: 827, 2nd: 2,059) exudative AMD cases including typical AMD, polypoidal choroidal vasculopathy, and retinal angiomatous proliferation and 9,337 (1st: 3,247 2nd: 6,090) controls. Gene-based analysis found a significant association of low-frequency variants (minor allele frequency (MAF)< 0.05) in CETP, C2 and CFB. The association of CETP remained after conditioned with all known genome-wide association study (GWAS) associated variants. In addition, when we included only disruptive variants, enrichment of rare variants (MAF < 0.01) was also observed after conditioned with all GWAS associated variants (P=1.03×10-6, odds ratio (OR)=2.48). Haplotype and conditional analysis of the C2-CFB-SKIV2L locus showed a low-frequency variant (R74H) in CFB would be individually associated with AMD susceptibility independent of the GWAS associated SNP. These findings highlight the importance of target sequencing to reveal the impact of rare or low-frequency coding variants on disease susceptibility in different ethnic populations.

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