GWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes.
Franceschini 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., Jukema JW., 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., Wannamethee SG., 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., MEGASTROKE Consortium None., 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.
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.