Genetic insights into ossification of the posterior longitudinal ligament of the spine.
Mendelian randomization
bone mineral density
genetics
genome-wide association study
genomics
human
obesity
ossification of the posterior longitudinal ligament of the spine
polygenic risk score
Journal
eLife
ISSN: 2050-084X
Titre abrégé: Elife
Pays: England
ID NLM: 101579614
Informations de publication
Date de publication:
18 07 2023
18 07 2023
Historique:
received:
30
01
2023
accepted:
22
05
2023
medline:
19
7
2023
pubmed:
18
7
2023
entrez:
18
7
2023
Statut:
epublish
Résumé
Ossification of the posterior longitudinal ligament of the spine (OPLL) is an intractable disease leading to severe neurological deficits. Its etiology and pathogenesis are primarily unknown. The relationship between OPLL and comorbidities, especially type 2 diabetes (T2D) and high body mass index (BMI), has been the focus of attention; however, no trait has been proven to have a causal relationship. We conducted a meta-analysis of genome-wide association studies (GWASs) using 22,016 Japanese individuals and identified 14 significant loci, 8 of which were previously unreported. We then conducted a gene-based association analysis and a transcriptome-wide Mendelian randomization approach and identified three candidate genes for each. Partitioning heritability enrichment analyses observed significant enrichment of the polygenic signals in the active enhancers of the connective/bone cell group, especially H3K27ac in chondrogenic differentiation cells, as well as the immune/hematopoietic cell group. Single-cell RNA sequencing of Achilles tendon cells from a mouse Achilles tendon ossification model confirmed the expression of genes in GWAS and post-GWAS analyses in mesenchymal and immune cells. Genetic correlations with 96 complex traits showed positive correlations with T2D and BMI and a negative correlation with cerebral aneurysm. Mendelian randomization analysis demonstrated a significant causal effect of increased BMI and high bone mineral density on OPLL. We evaluated the clinical images in detail and classified OPLL into cervical, thoracic, and the other types. GWAS subanalyses identified subtype-specific signals. A polygenic risk score for BMI demonstrated that the effect of BMI was particularly strong in thoracic OPLL. Our study provides genetic insight into the etiology and pathogenesis of OPLL and is expected to serve as a basis for future treatment development.
Identifiants
pubmed: 37461309
doi: 10.7554/eLife.86514
pii: 86514
pmc: PMC10353864
doi:
pii:
Banques de données
GEO
['GSE126060', 'GSE188758', 'GSE188760', 'GSE188759']
Types de publication
Meta-Analysis
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Investigateurs
Tsuji Takashi
(T)
Miyamoto Takeshi
(M)
Chiba Kazuhiro
(C)
Matsumoto Morio
(M)
Toyama Yoshiaki
(T)
Inose Hiroyuki
(I)
Yoshii Toshitaka
(Y)
Kawabata Shigenori
(K)
Okawa Atsushi
(O)
Yamazaki Masashi
(Y)
Masao Koda
(M)
Koike Yoshinao
(K)
Takahata Masahiko
(T)
Endo Tsutomu
(E)
Imagama Shiro
(I)
Kobayashi Kazuyoshi
(K)
Nakashima Hiroaki
(N)
Ando Kei
(A)
Kaito Takashi
(K)
Kashii Masafumi
(K)
Kato Satoshi
(K)
Kawaguchi Yoshiharu
(K)
Sakai Hiroaki
(S)
Shindo Shigeo
(S)
Taniguchi Yuki
(T)
Takeuchi Kazuhiro
(T)
Maeda Shingo
(M)
Ichiro Kawamura
(I)
Nakajima Hideaki
(N)
Baba Hisatoshi
(B)
Uchida Kenzo
(U)
Mori Kanji
(M)
Seichi Atsushi
(S)
Kimura Atsushi
(K)
Fujibayashi Shunsuke
(F)
Kanchiku Tsukasa
(K)
Watanabe Kei
(W)
Tanaka Toshihiro
(T)
Kida Kazunobu
(K)
Kobayashi Sho
(K)
Takahashi Masahito
(T)
Yamada Kei
(Y)
Terao Chikashi
(T)
Ikegawa Shiro
(I)
Informations de copyright
© 2023, Koike, Takahata, Nakajima et al.
Déclaration de conflit d'intérêts
YK, MT, MN, NO, HS, XL, TE, SI, KK, TK, SK, MK, HS, TT, TM, HI, TY, MK, HN, KA, YT, KT, SI, KT, KH, YI, YK, SM, HN, KM, AS, SF, TK, KW, TT, KK, SK, MT, KY, HT, HL, SN, KO, YM, AO, MM, NI, CT, SI No competing interests declared, YK Consulting fees from Medacta International, MY representatives of Japanese Organization of the Study for Ossification of Spinal Ligament
Références
PLoS Comput Biol. 2015 Apr 17;11(4):e1004219
pubmed: 25885710
Obes Rev. 2022 Oct;23(10):e13493
pubmed: 35822276
Nature. 2020 Jun;582(7811):240-245
pubmed: 32499647
J Orthop Surg (Hong Kong). 2004 Jun;12(1):45-54
pubmed: 15237122
Genome Res. 2012 Sep;22(9):1790-7
pubmed: 22955989
Nat Commun. 2017 Nov 28;8(1):1826
pubmed: 29184056
Osteoporos Int. 2014 Mar;25(3):1089-98
pubmed: 23974860
Orthop Traumatol Surg Res. 2017 Sep;103(5):733-740
pubmed: 28619269
Nat Genet. 2016 May;48(5):481-7
pubmed: 27019110
Curr Osteoporos Rep. 2016 Dec;14(6):292-309
pubmed: 27766484
Bioinformatics. 2016 May 15;32(10):1493-501
pubmed: 26773131
J Neurosurg Spine. 2022 Mar 4;:1-8
pubmed: 35245901
Genet Epidemiol. 2016 May;40(4):304-14
pubmed: 27061298
Nat Genet. 1996 Aug;13(4):450-7
pubmed: 8696340
Spine (Phila Pa 1976). 2004 May 1;29(9):1006-10
pubmed: 15105673
Endocr Rev. 2008 Aug;29(5):535-59
pubmed: 18436706
Calcif Tissue Int. 2013 Jan;92(1):28-34
pubmed: 23104450
Nat Genet. 2017 Oct;49(10):1458-1467
pubmed: 28892062
Eur J Epidemiol. 2017 May;32(5):377-389
pubmed: 28527048
Nature. 2015 Jun 4;522(7554):111-4
pubmed: 25849773
Skeletal Radiol. 1983;10(2):79-85
pubmed: 6612370
Annu Rev Genomics Hum Genet. 2015;16:327-50
pubmed: 25939054
Int J Endocrinol. 2014;2014:235060
pubmed: 25147565
J Epidemiol. 2017 Mar;27(3S):S9-S21
pubmed: 28190657
Spine (Phila Pa 1976). 1989 Nov;14(11):1184-91
pubmed: 2513651
Nat Genet. 2016 Oct;48(10):1284-1287
pubmed: 27571263
J Epidemiol. 2017 Mar;27(3S):S2-S8
pubmed: 28189464
J Bone Miner Metab. 1999;17(4):296-300
pubmed: 10575595
Nat Genet. 2015 Mar;47(3):291-5
pubmed: 25642630
Nat Genet. 2018 Mar;50(3):390-400
pubmed: 29403010
Nucleic Acids Res. 2012 Jan;40(Database issue):D930-4
pubmed: 22064851
Elife. 2018 May 30;7:
pubmed: 29846171
J Inherit Metab Dis. 2018 Sep;41(5):865-876
pubmed: 29460029
J Rheumatol. 2007 Dec;34(12):2460-2
pubmed: 18050374
Nat Genet. 2014 Sep;46(9):1012-6
pubmed: 25064007
PLoS One. 2017 May 03;12(5):e0174881
pubmed: 28467440
Ann Rheum Dis. 1998 Jul;57(7):429-33
pubmed: 9797571
Cell. 2021 Jun 24;184(13):3573-3587.e29
pubmed: 34062119
BMC Genomics. 2008 Jul 17;9:340
pubmed: 18637193
Sci Adv. 2022 Aug 19;8(33):eabn2138
pubmed: 35984875
Clin Spine Surg. 2018 Nov;31(9):E460-E465
pubmed: 30113323
Exp Ther Med. 2010 Jul;1(4):603-610
pubmed: 22993583
BMC Musculoskelet Disord. 2016 Dec 1;17(1):492
pubmed: 27903251
J Bone Joint Surg Am. 2001 Oct;83(10):1537-44
pubmed: 11679606
Genet Epidemiol. 2016 Nov;40(7):597-608
pubmed: 27625185
Spine (Phila Pa 1976). 1999 May 15;24(10):937-8; discussion 939
pubmed: 10332781
Nucleic Acids Res. 2010 Sep;38(16):e164
pubmed: 20601685
Hum Hered. 2019;84(6):256-271
pubmed: 32721961
Int J Epidemiol. 2015 Apr;44(2):512-25
pubmed: 26050253
Nature. 2015 Feb 19;518(7539):317-30
pubmed: 25693563
Stat Med. 2008 Apr 15;27(8):1133-63
pubmed: 17886233
JCI Insight. 2017 Nov 2;2(21):
pubmed: 29093266
Spine (Phila Pa 1976). 2012 Mar 1;37(5):E309-14
pubmed: 22146284
Genet Epidemiol. 2009 Nov;33(7):581-98
pubmed: 19278015
Spine (Phila Pa 1976). 1991 Nov;16(11):1249-52
pubmed: 1749995
J Bone Miner Res. 2018 Feb;33(2):269-282
pubmed: 28986986
Nat Genet. 2015 Nov;47(11):1228-35
pubmed: 26414678
Bioinformatics. 2010 Sep 1;26(17):2190-1
pubmed: 20616382
Nat Genet. 2020 Jul;52(7):669-679
pubmed: 32514122
Elife. 2020 May 27;9:
pubmed: 32459176
Cell. 2018 Nov 29;175(6):1507-1519.e16
pubmed: 30415835
PLoS Genet. 2006 Dec;2(12):e190
pubmed: 17194218
Am J Hum Genet. 2007 Sep;81(3):559-75
pubmed: 17701901
Nat Genet. 2018 Sep;50(9):1219-1224
pubmed: 30104762
Arch Orthop Trauma Surg (1978). 1987;106(2):89-93
pubmed: 3494437
Nat Genet. 2016 Nov;48(11):1443-1448
pubmed: 27694958
Bioinformatics. 2010 Sep 15;26(18):2336-7
pubmed: 20634204
Nat Genet. 2019 Dec;51(12):1664-1669
pubmed: 31784727
Spine (Phila Pa 1976). 2013 Oct 15;38(22):E1388-96
pubmed: 23883825
Nat Commun. 2019 Sep 27;10(1):4393
pubmed: 31562340
J Biol Chem. 2017 Jul 7;292(27):11178-11188
pubmed: 28500134
PLoS Genet. 2020 Jun 4;16(6):e1008805
pubmed: 32497039
Nat Commun. 2020 Feb 5;11(1):722
pubmed: 32024825
J Bone Miner Metab. 2020 Jan;38(1):63-69
pubmed: 31290005
Nat Genet. 2017 Oct;49(10):1468-1475
pubmed: 28869591
Science. 2015 May 8;348(6235):648-60
pubmed: 25954001
Nat Genet. 2020 Dec;52(12):1303-1313
pubmed: 33199917
J Bone Miner Res. 2021 Jul;36(7):1281-1287
pubmed: 33784428
EMBO J. 2007 Jul 25;26(14):3373-83
pubmed: 17581632
Nature. 2021 May;593(7858):238-243
pubmed: 33828297
Hum Mol Genet. 2019 Jan 1;28(1):166-174
pubmed: 30239722
Nature. 2015 Feb 12;518(7538):197-206
pubmed: 25673413
Nat Genet. 2016 May;48(5):510-8
pubmed: 26974007
Am J Hum Genet. 2016 Jul 7;99(1):202-7
pubmed: 27374772
Nat Genet. 2019 Feb;51(2):258-266
pubmed: 30598549
J Neurosurg Spine. 2007 Aug;7(2):174-83
pubmed: 17688057
J Orthop Translat. 2022 May 14;34:42-59
pubmed: 35615641
Exp Dermatol. 2019 Oct;28(10):1122-1130
pubmed: 30118182
J Orthop Sci. 2019 Jan;24(1):35-41
pubmed: 30243519
Calcif Tissue Int. 2020 Nov;107(5):440-445
pubmed: 32989491