A multi-ethnic meta-analysis identifies novel genes, including ACSL5, associated with amyotrophic lateral sclerosis

被引：46

作者：

Nakamura, Ryoichi ^{[1
]}

Misawa, Kazuharu ^{[2
,3
]}

Tohnai, Genki ^{[1
]}

Nakatochi, Masahiro ^{[4
]}

Furuhashi, Sho ^{[2
]}

Atsuta, Naoki ^{[1
]}

Hayashi, Naoki ^{[1
]}

Yokoi, Daichi ^{[1
,5
]}

Watanabe, Hazuki ^{[1
,6
]}

Watanabe, Hirohisa ^{[7
,8
]}

Katsuno, Masahisa ^{[1
]}

Izumi, Yuishin ^{[9
]}

Kanai, Kazuaki ^{[10
,11
]}

Hattori, Nobutaka ^{[10
]}

Morita, Mitsuya ^{[12
]}

Taniguchi, Akira ^{[13
]}

Kano, Osamu ^{[14
]}

Oda, Masaya ^{[15
]}

Shibuya, Kazumoto ^{[16
]}

Kuwabara, Satoshi ^{[16
]}

Suzuki, Naoki ^{[17
]}

Aoki, Masashi ^{[17
]}

Ohta, Yasuyuki ^{[18
]}

Yamashita, Toru ^{[18
]}

Abe, Koji ^{[18
]}

Hashimoto, Rina ^{[19
]}

Aiba, Ikuko ^{[19
]}

Okamoto, Koichi ^{[20
]}

Mizoguchi, Kouichi ^{[21
]}

Hasegawa, Kazuko ^{[22
]}

Okada, Yohei ^{[23
]}

Ishihara, Tomohiko ^{[24
]}

Onodera, Osamu ^{[24
]}

Nakashima, Kenji ^{[25
]}

Kaji, Ryuji ^{[9
]}

Kamatani, Yoichiro ^{[26
]}

Ikegawa, Shiro ^{[27
]}

Momozawa, Yukihide ^{[28
]}

Kubo, Michiaki ^{[29
]}

Ishida, Noriko ^{[2
]}

Minegishi, Naoko ^{[2
]}

Nagasaki, Masao ^{[2
,30
,31
]}

Sobue, Gen ^{[1
,7
,32
]}

机构：

[1] Nagoya Univ, Dept Neurol, Grad Sch Med, Nagoya, Aichi, Japan

[2] Tohoku Univ, Tohoku Med Megabank Org, Sendai, Miyagi, Japan

[3] Kansai Med Univ, Inst Biomed Sci, Dept Mol Genome Anal, Hirakata, Osaka, Japan

[4] Nagoya Univ, Dept Nursing, Div Data Sci, Grad Sch Med, Nagoya, Aichi, Japan

[5] Kakeyu Hosp, Dept Neurol, Kakeyu Misayama Rehabil Ctr, Ueda, Nagano, Japan

[6] Japanese Red Cross Nagoya Daiichi Hosp, Dept Neurol, Nagoya, Aichi, Japan

[7] Nagoya Univ, Brain & Mind Res Ctr, Nagoya, Aichi, Japan

[8] Fujita Hlth Univ, Dept Neurol, Toyoake, Aichi, Japan

[9] Tokushima Univ, Inst Biomed Sci, Dept Neurol, Grad Sch, Tokushima, Japan

[10] Juntendo Univ, Dept Neurol, Grad Sch Med, Tokyo, Japan

[11] Fukushima Med Univ, Dept Neurol, Sch Med, Fukushima, Japan

[12] Jichi Med Univ, Dept Internal Med, Div Neurol, Shimotsuke, Tochigi, Japan

[13] Mie Univ, Dept Neurol, Grad Sch Med, Tsu, Mie, Japan

[14] Toho Univ, Dept Internal Med, Div Neurol, Fac Med, Tokyo, Japan

[15] Vihara Hananosato Hosp, Dept Neurol, Miyoshi, Hiroshima, Japan

[16] Chiba Univ, Grad Sch Med, Dept Neurol, Chiba, Japan

[17] Tohoku Univ, Dept Neurol, Sch Med, Sendai, Miyagi, Japan

[18] Okayama Univ, Dept Neurol, Grad Sch Med, Okayama, Japan

[19] Natl Hosp Org, Dept Neurol, Higashinagoya Natl Hosp, Nagoya, Aichi, Japan

[20] Geriatr Res Inst & Hosp, Dept Neurol, Maebashi, Gunma, Japan

[21] Natl Hosp Org, Dept Neurol, Shizuoka Med Ctr, Shizuoka, Japan

[22] Natl Hosp Org, Sagamihara Natl Hosp, Div Neurol, Sagamihara, Kanagawa, Japan

[23] Aichi Med Univ, Dept Neurol, Nagakute, Aichi, Japan

[24] Niigata Univ, Brain Res Inst, Dept Neurol, Niigata, Japan

[25] Natl Hosp Org, Matsue Med Ctr, Dept Neurol, Matsue, Shimane, Japan

[26] RIKEN, Lab Stat & Translat Genet, Ctr Integrat Med Sci, Yokohama, Kanagawa, Japan

[27] RIKEN, Lab Bone & Joint Dis, Ctr Integrat Med Sci, Tokyo, Japan

[28] RIKEN, Lab Genotyping Dev, Ctr Integrat Med Sci, Yokohama, Kanagawa, Japan

[29] RIKEN, Ctr Integrat Med Sci, Yokohama, Kanagawa, Japan

[30] Kyoto Univ, Ctr Promot Interdisciplinary Educ & Res, Sakyo Ku, Kyoto, Japan

[31] Kyoto Univ, Ctr Genom Med, Grad Sch Med, Sakyo Ku, Kyoto, Japan

[32] Aichi Med Univ, Nagakute, Aichi, Japan

来源：

COMMUNICATIONS BIOLOGY | 2020年 / 3卷 / 01期

基金：

日本学术振兴会;

关键词：

GENOME-WIDE ASSOCIATION; FOLLOW-UP; MR-GEF; EXPRESSION; RISK; SUSCEPTIBILITY; EXPANSIONS; VARIANTS; PROJECT; PROTEIN;

D O I：

10.1038/s42003-020-01251-2

中图分类号：

Q [生物科学];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Amyotrophic lateral sclerosis (ALS) is a devastating progressive motor neuron disease that affects people of all ethnicities. Approximately 90% of ALS cases are sporadic and thought to have multifactorial pathogenesis. To understand the genetics of sporadic ALS, we conducted a genome-wide association study using 1,173 sporadic ALS cases and 8,925 controls in a Japanese population. A combined meta-analysis of our Japanese cohort with individuals of European ancestry revealed a significant association at the ACSL5 locus (top SNP p=2.97x10(-8)). We validated the association with ACSL5 in a replication study with a Chinese population and an independent Japanese population (1941 ALS cases, 3821 controls; top SNP p=1.82x10(-4)). In the combined meta-analysis, the intronic ACSL5 SNP rs3736947 showed the strongest association (p=7.81x10(-11)). Using a gene-based analysis of the full multi-ethnic dataset, we uncovered additional genes significantly associated with ALS: ERGIC1, RAPGEF5, FNBP1, and ATXN3. These results advance our understanding of the genetic basis of sporadic ALS. Gen Sobue, Masao Nagasaki and colleagues report a genome-wide association study for amyotrophic lateral sclerosis (ALS) in a large, multi-ethnic cohort comprising Japanese, Chinese, and European ancestry populations. They find a significant association to variants within the ACSL5 gene and identify novel associations with 4 additional genes using a gene-based approach.

引用

页数：9

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