GWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes.

TitleGWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes.
Publication TypeJournal Article
Year of Publication2018
AuthorsFranceschini, N, Giambartolomei, C, de Vries, PS, Finan, C, Bis, JC, Huntley, RP, Lovering, RC, Tajuddin, SM, Winkler, TW, Graff, M, Kavousi, M, Dale, C, Smith, AV, Hofer, E, van Leeuwen, EM, Nolte, IM, Lu, L, Scholz, M, Sargurupremraj, M, Pitkänen, N, Franzén, O, Joshi, PK, Noordam, R, Marioni, RE, Hwang, S-J, Musani, SK, Schminke, U, Palmas, W, Isaacs, A, Correa, A, Zonderman, AB, Hofman, A, Teumer, A, Cox, AJ, Uitterlinden, AG, Wong, A, Smit, AJ, Newman, AB, Britton, A, Ruusalepp, A, Sennblad, B, Hedblad, B, Pasaniuc, B, Penninx, BW, Langefeld, CD, Wassel, CL, Tzourio, C, Fava, C, Baldassarre, D, O'Leary, DH, Teupser, D, Kuh, D, Tremoli, E, Mannarino, E, Grossi, E, Boerwinkle, E, Schadt, EE, Ingelsson, E, Veglia, F, Rivadeneira, F, Beutner, F, Chauhan, G, Heiss, G, Snieder, H, Campbell, H, Völzke, H, Markus, HS, Deary, IJ, J Jukema, W, de Graaf, J, Price, J, Pott, J, Hopewell, JC, Liang, J, Thiery, J, Engmann, J, Gertow, K, Rice, K, Taylor, KD, Dhana, K, Kiemeney, LALM, Lind, L, Raffield, LM, Launer, LJ, Holdt, LM, Dörr, M, Dichgans, M, Traylor, M, Sitzer, M, Kumari, M, Kivimaki, M, Nalls, MA, Melander, O, Raitakari, O, Franco, OH, Rueda-Ochoa, OL, Roussos, P, Whincup, PH, Amouyel, P, Giral, P, Anugu, P, Wong, Q, Malik, R, Rauramaa, R, Burkhardt, R, Hardy, R, Schmidt, R, de Mutsert, R, Morris, RW, Strawbridge, RJ, S Wannamethee, G, Hägg, S, Shah, S, McLachlan, S, Trompet, S, Seshadri, S, Kurl, S, Heckbert, SR, Ring, S, Harris, TB, Lehtimäki, T, Galesloot, TE, Shah, T, de Faire, U, Plagnol, V, Rosamond, WD, Post, W, Zhu, X, Zhang, X, Guo, X, Saba, Y, Dehghan, A, Seldenrijk, A, Morrison, AC, Hamsten, A, Psaty, BM, van Duijn, CM, Lawlor, DA, Mook-Kanamori, DO, Bowden, DW, Schmidt, H, Wilson, JF, Wilson, JG, Rotter, JI, Wardlaw, JM, Deanfield, J, Halcox, J, Lyytikäinen, L-P, Loeffler, M, Evans, MK, Debette, S, Humphries, SE, Völker, U, Gudnason, V, Hingorani, AD, Björkegren, JLM, Casas, JP, O'Donnell, CJ
Corporate AuthorsMEGASTROKE Consortium
JournalNat Commun
Volume9
Issue1
Pagination5141
Date Published2018 12 03
ISSN2041-1723
KeywordsADAMTS9 Protein, Amino Acid Oxidoreductases, Carotid Intima-Media Thickness, Coronary Disease, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Lod Score, Plaque, Atherosclerotic, Polymorphism, Single Nucleotide, Protein-Lysine 6-Oxidase, Quantitative Trait Loci, Risk Factors
Abstract

Carotid artery intima media thickness (cIMT) and carotid plaque are measures of subclinical atherosclerosis associated with ischemic stroke and coronary heart disease (CHD). Here, we undertake meta-analyses of genome-wide association studies (GWAS) in 71,128 individuals for cIMT, and 48,434 individuals for carotid plaque traits. We identify eight novel susceptibility loci for cIMT, one independent association at the previously-identified PINX1 locus, and one novel locus for carotid plaque. Colocalization analysis with nearby vascular expression quantitative loci (cis-eQTLs) derived from arterial wall and metabolic tissues obtained from patients with CHD identifies candidate genes at two potentially additional loci, ADAMTS9 and LOXL4. LD score regression reveals significant genetic correlations between cIMT and plaque traits, and both cIMT and plaque with CHD, any stroke subtype and ischemic stroke. Our study provides insights into genes and tissue-specific regulatory mechanisms linking atherosclerosis both to its functional genomic origins and its clinical consequences in humans.
DOI10.1038/s41467-018-07340-5
Alternate JournalNat Commun
PubMed ID30510157
PubMed Central IDPMC6277418
Grant ListUH3 NS100605 / NS / NINDS NIH HHS / United States
U01 CA194393 / CA / NCI NIH HHS / United States
U41 HG002273 / HG / NHGRI NIH HHS / United States
G1001245 / MRC_ / Medical Research Council / United Kingdom
T32 HL129982 / HL / NHLBI NIH HHS / United States
G0701120 / MRC_ / Medical Research Council / United Kingdom
RG/13/5/30112 / BHF_ / British Heart Foundation / United Kingdom
U01 AG052409 / AG / NIA NIH HHS / United States
RG/13/16/30528 / BHF_ / British Heart Foundation / United Kingdom
MR/R024227/1 / MRC_ / Medical Research Council / United Kingdom
R01 NS017950 / NS / NINDS NIH HHS / United States
PG/13/66/30442 / BHF_ / British Heart Foundation / United Kingdom
RG/13/13/30194 / BHF_ / British Heart Foundation / United Kingdom
R01 AG054076 / AG / NIA NIH HHS / United States
R01 HL120393 / HL / NHLBI NIH HHS / United States
R21 HL140385 / HL / NHLBI NIH HHS / United States
U01 HL130114 / HL / NHLBI NIH HHS / United States
U01 HL120393 / HL / NHLBI NIH HHS / United States
R56 DK104806 / DK / NIDDK NIH HHS / United States
R01 DK117445 / DK / NIDDK NIH HHS / United States
PG/09/024/26857 / BHF_ / British Heart Foundation / United Kingdom
T32 NS048004 / NS / NINDS NIH HHS / United States
R01 HG006399 / HG / NHGRI NIH HHS / United States
01/37/03 / DH_ / Department of Health / United Kingdom
MR/K026992/1 / MRC_ / Medical Research Council / United Kingdom
MR/L003120/1 / MRC_ / Medical Research Council / United Kingdom
R01 HL105756 / HL / NHLBI NIH HHS / United States
RG/16/11/32334 / BHF_ / British Heart Foundation / United Kingdom
G1001357 / MRC_ / Medical Research Council / United Kingdom
MC_UU_12015/1 / MRC_ / Medical Research Council / United Kingdom
MC_UU_12019/2 / MRC_ / Medical Research Council / United Kingdom
MR/M006638/1 / MRC_ / Medical Research Council / United Kingdom
R21 HL123677 / HL / NHLBI NIH HHS / United States
FS/14/55/30806 / BHF_ / British Heart Foundation / United Kingdom
MR/K013351/1 / MRC_ / Medical Research Council / United Kingdom
R01 HG009120 / HG / NHGRI NIH HHS / United States
R01 MD012765 / MD / NIMHD NIH HHS / United States
P30 AG010129 / AG / NIA NIH HHS / United States
MC_UU_12013/5 / MRC_ / Medical Research Council / United Kingdom
U54 GM115428 / GM / NIGMS NIH HHS / United States