Article

Large-scale gene-centric analysis identifies novel variants for coronary artery disease

Butterworth AS, Braund PS, Farrall M, Hardwick RJ, Saleheen D, Peden JF, Soranzo N, Chambers JC, Sivapalaratnam S, Kleber ME, Keating B, Qasim A, Klopp N, Erdmann J, Assimes TL, Ball SG, Balmforth AJ, Barnes TA, Basart H, Baumert J, Bezzina CR, Boerwinkle E, Boehm BO, Brocheton J, Bugert P, Cambien F, Clarke R, Codd V, Collins R, Couper D, Cupples LA, de Jong JS, Diemert P, Ejebe K, Elbers CC, Elliott P, Fornage M, Franzosi MG, Frossard P, Garner S, Goel A, Goodall AH, Hengstenberg C, Hunt SE, Kastelein JJ, Klungel OH, Klüter H, Koch K, König IR, Kooner AS, Laaksonen R, Lathrop M, Li M, Liu K, McPherson R, Musameh MD, Musani S, Nelson CP, O'Donnell CJ, Ongen H, Papanicolaou G, Peters A, Peters BJ, Potter S, Psaty BM, Qu L, Rader DJ, Rasheed A, Rice C, Scott J, Seedorf U, Sehmi JS, Sotoodehnia N, Stark K, Stephens J, van der Schoot CE, van der Schouw YT, Thorsteinsdottir U, Tomaszewski M, van der Harst P, Vasan RS, Wilde AA, Willenborg C, Winkelmann BR, Zaidi M, Zhang W, Ziegler A, de Bakker PI, Koenig W, Mätz W, Trip MD, Reilly MP, Kathiresan S, Schunkert H, Hamsten A, Hall AS, Kooner JS, Thompson SG, Thompson JR, Deloukas P, Ouwehand WH, Watkins H, Danesh J, Samani NJ, Barnes T, Rafelt S, Bruinsma N, Dekker LR, Henriques JP, Koch KT, de Winter RJ, Alings M, Allaart CF, Gorgels AP, Verheugt FW, Mueller M, Meisinger C, DerOhannessian S, Mehta NN, Ferguson J, Hakonarson H, Matthai W, Wilensky R, Hopewell JC, Parish S, Linksted P, Notman J, Gonzalez H, Young A, Ostley T, Munday A, Goodwin N, Verdon V, Shah S, Cobb L, Edwards C, Mathews C, Gunter R, Benham J, Davies C, Cobb M, Crowther J, Richards A, Silver M, Tochlin S, Mozley S, Clark S, Radley M, Kourellias K, Silveira A, Söderholm B, Olsson P, Barlera S, Tognoni G, Rust S, Assmann G, Heath S, Zelenika D, Gut I, Green F, Peden J, Aly A, Anner K, Björklund K, Blomgren G, Cederschiöld B, Danell-Toverud K, Eriksson P, Grundstedt U, Heinonen M, Hellénius ML, van't Hooft F, Husman K, Lagercrantz J, Larsson A, Larsson M, Mossfeldt M, Mälarstig A, Olsson G, Sabater-Lleal M, Sennblad B, Strawbridge R, Öhrvik J, Zaman KS, Mallick NH, Azhar M, Samad A, Ishaq M, Shah N, Samuel M, Reilly M, Holm H, Preuss M, Stewart AF, Barbalic M, Gieger C, Absher D, Aherrahrou Z, Allayee H, Altshuler D, Anand S, Andersen K, Anderson JL, Ardissino D, Becker LC, Becker DM, Berger K, Bis JC, Boekholdt SM, Brown MJ, Burnett MS, Buysschaert I, Carlquist JF, Chen L, Davies RW, Dedoussis G, Dehghan A, Demissie S, Devaney J, Do R, Doering A, El Mokhtari NE, Ellis SG, Elosua R, Engert JC, Epstein S, de Faire U, Fischer M, Folsom AR, Freyer J, Gigante B, Girelli D, Gretarsdottir S, Gudnason V, Gulcher JR, Tennstedt S, Halperin E, Hammond N, Hazen SL, Hofman A, Horne BD, Illig T, Iribarren C, Jones GT, Jukema JW, Kaiser MA, Kaplan LM, Khaw KT, Knowles JW, Kolovou G, Kong A, Lambrechts D, Leander K, Lieb W, Lettre G, Loley C, Lotery AJ, Mannucci PM, Maouche S, Martinelli N, McKeown PP, Meitinger T, Melander O, Merlini PA, Mooser V, Morgan T, Mühleisen TW, Muhlestein JB, Musunuru K, Nahrstaedt J, Nöthen MM, Olivieri O, Peyvandi F, Patel RS, Patterson CC, Quyyumi AA, Rallidis LS, Roosendaal FR, Rubin D, Salomaa V, Sampietro ML, Sandhu MS, Schadt E, Schäfer A, Schillert A, Schreiber S, Schrezenmeir J, Schwartz SM, Siscovick DS, Sivananthan M, Smith AV, Smith TB, Snoep JD, Spertus JA, Stefansson K, Stirrups K, Stoll M, Tang WH, Thorgeirsson G, Thorleifsson G, Uitterlinden AG, van Rij AM, Voight BF, Wareham NJ, AWells G, Wichmann HE, Witteman JC, Wright BJ, Ye S, Quertermous T, März W, Blankenberg S, Roberts R, Onland-Moret NC, van Setten J, Verschuren WM, Boer JM, Wijmenga C, Hofker MH, Maitland-van der Zee AH, de Boer A, Grobbee DE, Attwood T, Belz S, Braund P, Cooper J, Crisp-Hihn A, Foad N, Gracey J, Gray E, Gwilliams R, Heimerl S, Jolley J, Krishnan U, Lloyd-Jones H, Lugauer I, Lundmark P, Moore JS, Muir D, Murray E, Neudert J, Niblett D, O'Leary K, Pollard H, Rankin A, Rice CM, Sager H, Sambrook J, Schmitz G, Scholz M, Schroeder L, Syvannen AC, Wallace C

PLoS Genetics (impact factor: 8.69). 09/2011; 7(9):e1002260. pp.e1002260

ABSTRACT Coronary artery disease (CAD) has a significant genetic contribution that is incompletely characterized. To complement genome-wide association (GWA) studies, we conducted a large and systematic candidate gene study of CAD susceptibility, including analysis of many uncommon and functional variants. We examined 49,094 genetic variants in ∼2,100 genes of cardiovascular relevance, using a customised gene array in 15,596 CAD cases and 34,992 controls (11,202 cases and 30,733 controls of European descent; 4,394 cases and 4,259 controls of South Asian origin). We attempted to replicate putative novel associations in an additional 17,121 CAD cases and 40,473 controls. Potential mechanisms through which the novel variants could affect CAD risk were explored through association tests with vascular risk factors and gene expression. We confirmed associations of several previously known CAD susceptibility loci (eg, 9p21.3:p<10(-33); LPA:p<10(-19); 1p13.3:p<10(-17)) as well as three recently discovered loci (COL4A1/COL4A2, ZC3HC1, CYP17A1:p<5×10(-7)). However, we found essentially null results for most previously suggested CAD candidate genes. In our replication study of 24 promising common variants, we identified novel associations of variants in or near LIPA, IL5, TRIB1, and ABCG5/ABCG8, with per-allele odds ratios for CAD risk with each of the novel variants ranging from 1.06-1.09. Associations with variants at LIPA, TRIB1, and ABCG5/ABCG8 were supported by gene expression data or effects on lipid levels. Apart from the previously reported variants in LPA, none of the other ∼4,500 low frequency and functional variants showed a strong effect. Associations in South Asians did not differ appreciably from those in Europeans, except for 9p21.3 (per-allele odds ratio: 1.14 versus 1.27 respectively; P for heterogeneity = 0.003). This large-scale gene-centric analysis has identified several novel genes for CAD that relate to diverse biochemical and cellular functions and clarified the literature with regard to many previously suggested genes.

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Keywords

24 promising common variants
 
additional 17,121 CAD cases
 
CAD candidate genes
 
cardiovascular relevance
 
customised gene array
 
diverse biochemical
 
functional variants
 
gene expression data
 
genome-wide association
 
large-scale gene-centric analysis
 
novel associations
 
novel genes
 
novel variants
 
replicate putative novel associations
 
reported variants
 
significant genetic contribution
 
South Asian origin
 
South Asians
 
suggested genes
 
systematic candidate gene study
 

Butterworth AS