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., Okada Y., Mishra A., Rutten-Jacobs L., Giese A-K., van der Laan SW., Gretarsdottir S., Anderson CD., Chong M., Adams HHH., Ago T., Almgren P., Amouyel P., Ay H., Bartz TM., Benavente OR., Bevan S., Boncoraglio GB., Brown RD., Butterworth AS., Carrera C., Carty CL., Chasman DI., Chen W-M., Cole JW., Cotlarciuc I., Cruchaga C., Danesh J., de Bakker PIW., DeStefano AL., den Hoed M., Duan Q., Engelter ST., Falcone GJ., Gottesman RF., Grewal RP., Gustafsson S., Haessler J., Harris TB., Hassan A., Havulinna AS., Holliday EG., Howard G., Hsu F-C., Hyacinth HI., Ikram MA., Irvin MR., Jian X., Jiménez-Conde J., Johnson JA., Jukema JW., Kanai M., Keene KL., Kissela BM., Kleindorfer DO., Kooperberg C., Kubo M., Lange L., Langefeld CD., Langenberg C., Lee J-M., Lemmens R., Leys D., Lewis CM., Lin W-Y., Lindgren AG., Lorentzen E., Magnusson PK., Maguire J., Manichaikul A., McArdle PF., Meschia JF., Mosley TH., Ninomiya T., O’Donnell MJ., Pulit SL., Rannikmäe K., Reiner AP., Rexrode KM., Rich SS., Ridker PM., Rost NS., Rothwell PM., Rundek T., Sacco RL., Sakaue S., Sale MM., Salomaa V., Sapkota BR., Schmidt R., Schmidt CO., Schminke U., Sharma P., Slowik A., Sudlow CLM., Tanislav C., Tatlisumak T., Thijs VNS., Thorleifsson G., Thorsteinsdottir U., Tiedt S., Trompet S., Walters M., Wareham NJ., Wassertheil-Smoller S., Wiggins KL., Yang Q., Yusuf S., Pastinen T., Ruusalepp A., Schadt EE., Koplev S., Codoni V., Civelek M., Smith N., Trégouët DA., Christophersen IE., Roselli C., Lubitz SA., Ellinor PT., Tai ES., Kooner JS., Kato N., He J., van der Harst P., Elliott P., Chambers JC., Takeuchi F., Johnson AD., Sanghera DK., Melander O., Jern C., Strbian D., Fernandez-Cadenas I., Longstreth WT., Rolfs A., Hata J., Woo D., Rosand J., Pare G., Saleheen D., Stefansson K., Worrall BB., Kittner SJ., Howson JMM., Kamatani 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.
AbstractCarotid 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.