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101. Cervical artery dissection in patients ≥60 years: Often painless, few mechanical triggers

Author: Traenka, C, Dougoud, D, Simonetti, B, Metso, T, Debette, S, Pezzini, A, Kloss, M, Grond Ginsbach, C, Majersik, J, Worrall, B, Leys, D, Baumgartner, R, Caso, V, Béjot, Y, Compter, A, Reiner, P, Thijs, V, Southerland, A, Bersano, A, Brandt, T, Gensicke, H, Touzé, E, Martin, J, Chabriat, H, Tatlisumak, T, Lyrer, P, Arnold, M, Engelter, ST, Abboud S, Pandolfo M, Bodenant M, Louillet F, Mas JL, Leder S, Léger A, Deltour S, Crozier S, Méresse I, Canaple S, Godefroy O, Giroud M, Decavel P, Medeiros E, Montiel P, Moulin T, Vuillier F, Amouyel P, Wiest T, Werner I, Arnold ML, Santos MD, Dichgans M, Thomas Feles C, Weber R, Del Zotto E, Giossi A, Volonghi I, Padovani A, Poli L, Morotti A, Lanfranconi S, Baron P, Beretta S, Giacolone G, Fluri F, Hatz F, Gisler D, Bonati, Amort M, Markus H, Meschia JF, Cole J, Kittner S, Buffon F, Mawet J, Heldner MR, Mattle HP, Gralla J., FERRARESE, CARLO, Neurologian yksikkö, Clinicum, Department of Neurosciences, HUS Neurocenter, Traenka, C, Dougoud, D, Simonetti, B, Metso, T, Debette, S, Pezzini, A, Kloss, M, Grond Ginsbach, C, Majersik, J, Worrall, B, Leys, D, Baumgartner, R, Caso, V, Béjot, Y, Compter, A, Reiner, P, Thijs, V, Southerland, A, Bersano, A, Brandt, T, Gensicke, H, Touzé, E, Martin, J, Chabriat, H, Tatlisumak, T, Lyrer, P, Arnold, M, Engelter, S, Abboud, S, Pandolfo, M, Bodenant, M, Louillet, F, Mas, J, Leder, S, Léger, A, Deltour, S, Crozier, S, Méresse, I, Canaple, S, Godefroy, O, Giroud, M, Decavel, P, Medeiros, E, Montiel, P, Moulin, T, Vuillier, F, Amouyel, P, Wiest, T, Werner, I, Santos, M, Dichgans, M, Thomas Feles, C, Weber, R, Del Zotto, E, Giossi, A, Volonghi, I, Padovani, A, Poli, L, Morotti, A, Lanfranconi, S, Baron, P, Beretta, S, Ferrarese, C, Giacolone, G, Fluri, F, Hatz, F, Gisler, D, Bonati, Amort, M, Markus, H, Meschia, J, Cole, J, Kittner, S, Buffon, F, Mawet, J, Heldner, M, Mattle, H, and Gralla, J
Subjects: Adult, Male, medicine.medical_specialty, Vertebral artery dissection, FEATURES, 030204 cardiovascular system & hematology, 3124 Neurology and psychiatry, Brain Ischemia, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Modified Rankin Scale, Internal medicine, YOUNG-ADULTS, CADISP, Odds Ratio, medicine, Humans, Risk factor, Young adult, 610 Medicine & health, Stroke, VASCULAR RISK-FACTORS, Aged, Vertebral Artery Dissection, Neck pain, Neck Pain, business.industry, Age Factors, Middle Aged, medicine.disease, BRAIN-SUPPLYING ARTERIES, 3. Good health, Surgery, PREVALENCE, MIGRAINE, VERTEBRAL ARTERY, Cohort, Female, Neurology (clinical), medicine.symptom, business, CAROTID-ARTERY, 030217 neurology & neurosurgery, ISCHEMIC-STROKE PATIENTS, Cohort study
Abstract: Objective:In a cohort of patients diagnosed with cervical artery dissection (CeAD), to determine the proportion of patients aged ≥60 years and compare the frequency of characteristics (presenting symptoms, risk factors, and outcome) in patients aged Methods:We combined data from 3 large cohorts of consecutive patients diagnosed with CeAD (i.e., Cervical Artery Dissection and Ischemic Stroke Patients–Plus consortium). We dichotomized cases into 2 groups, age ≥60 and Results:Among 2,391 patients diagnosed with CeAD, we identified 177 patients (7.4%) aged ≥60 years. In this age group, cervical pain (ORadjusted 0.47 [0.33–0.66]), headache (ORadjusted 0.58 [0.42–0.79]), mechanical trigger events (ORadjusted 0.53 [0.36–0.77]), and migraine (ORadjusted 0.58 [0.39–0.85]) were less frequent than in younger patients. In turn, hypercholesterolemia (ORadjusted 1.52 [1.1–2.10]) and hypertension (ORadjusted 3.08 [2.25–4.22]) were more frequent in older patients. Key differences between age groups were confirmed in secondary analyses. In multivariable, adjusted analyses, favorable outcome (i.e., modified Rankin Scale score 0–2) was less frequent in the older age group (ORadjusted 0.45 [0.25, 0.83]).Conclusion:In our study population of patients diagnosed with CeAD, 1 in 14 was aged ≥60 years. In these patients, pain and mechanical triggers might be missing, rendering the diagnosis more challenging and increasing the risk of missed CeAD diagnosis in older patients.
Published: 2017
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102. Publisher Correction: Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits (vol 50, pg 1412, 2018)

Author: Evangelou, E, Warren, HR, Mosen-Ansorena, D, Mifsud, B, Pazoki, R, Gao, H, Ntritsos, G, Dimou, N, Cabrera, CP, Karaman, I, Fu, LN, Evangelou, M, Witkowska, K, Tzanis, E, Hellwege, JN, Giri, A, Edwards, DRV, Sun, YV, Cho, K, Gaziano, JM, Wilson, PWF, Tsao, PS, Kovesdy, CP, Esko, T, Magi, R, Milani, L, Almgren, P, Boutin, T, Debette, S, Ding, J, Giulianini, F, Holliday, EG, Jackson, AU, Li-Gao, R, Lin, W-Y, Luan, J, Mangino, M, Oldmeadow, C, Prins, BP, Qian, Y, Sargurupremraj, M, Shah, N, Surendran, P, Theriault, S, Verweij, N, Willems, SM, Zhao, J-H, Amouyel, P, Connell, J, De Mutsert, R, Doney, ASF, Farrall, M, Menni, C, Morris, AD, Noordam, R, Pare, G, Poulter, NR, Shields, DC, Stanton, A, Thom, S, Abecasis, G, Amin, N, Arking, DE, Ayers, KL, Barbieri, CM, Batini, C, Bis, JC, Blake, T, Bochud, M, Boehnke, M, Boerwinkle, E, Boomsma, DI, Bottinger, EP, Braund, PS, Brumat, M, Campbell, A, Campbell, H, Chakravarti, A, Chambers, JC, Chauhan, G, Ciullo, M, Cocca, M, Collins, F, Cordell, HJ, Davies, G, De Borst, MH, De Geus, EJ, Deary, IJ, Deelen, J, Del Greco, FM, Demirkale, CY, Dorr, M, Ehret, GB, Elosua, R, Enroth, S, Erzurumluoglu, AM, Ferreira, T, Franberg, M, Franco, OH, Gandin, I, Gasparini, P, Giedraitis, V, Gieger, C, Girotto, G, Goel, A, Gow, AJ, Gudnason, V, Guo, X, Gyllensten, U, Hamsten, A, Harris, TB, Harris, SE, Hartman, CA, Havulinna, AS, Hicks, AA, Hofer, E, Hofman, A, Hottenga, J-J, Huffman, JE, Hwang, S-J, Ingelsson, E, James, A, Jansen, R, Jarvelin, M-R, Joehanes, R, Johansson, A, Johnson, AD, Joshi, PK, Jousilahti, P, Jukema, JW, Jula, A, Kahonen, M, Kathiresan, S, Keavney, BD, Khaw, K-T, Knekt, P, Knight, J, Kolcic, I, Kooner, JS, Koskinen, S, Kristiansson, K, Kutalik, Z, Laan, M, Larson, M, Launer, LJ, Lehne, B, Lehtimaki, T, Liewald, DCM, Lin, L, Lind, L, Lindgren, CM, Liu, Y, Loos, RJF, Lopez, LM, Lu, Y, Lyytikainen, L-P, Mahajan, A, Mamasoula, C, Marrugat, J, Marten, J, Milaneschi, Y, Morgan, A, Morris, AP, Morrison, AC, Munson, PJ, Nalls, MA, Nandakumar, P, Nelson, CP, Niiranen, T, Nolte, IM, Nutile, T, Oldehinkel, AJ, Oostra, BA, O'Reilly, PF, Org, E, Padmanabhan, S, Palmas, W, Palotie, A, Pattie, A, Penninx, BWJH, Perola, M, Peters, A, Polasek, O, Pramstaller, PP, Quang, TN, Raitakari, OT, Ren, M, Rettig, R, Rice, K, Ridker, PM, Ried, JS, Riese, H, Ripatti, S, Robino, A, Rose, LM, Rotter, JI, Rudan, I, Ruggiero, D, Saba, Y, Sala, CF, Salomaa, V, Samani, NJ, Sarin, A-P, Schmidt, R, Schmidt, H, Shrine, N, Siscovick, D, Smith, AV, Snieder, H, Sober, S, Sorice, R, Starr, JM, Stott, DJ, Strachan, DP, Strawbridge, RJ, Sundstrom, J, Swertz, MA, Taylor, KD, Teumer, A, Tobin, MD, Tomaszewski, M, Toniolo, D, Traglia, M, Trompet, S, Tuomilehto, J, Tzourio, C, Uitterlinden, AG, Vaez, A, Van der Most, PJ, Van Duijn, CM, Vergnaud, A-C, Verwoert, GC, Vitart, V, Volker, U, Vollenweider, P, Vuckovic, D, Watkins, H, Wild, SH, Willemsen, G, Wilson, JF, Wright, AF, Yao, J, Zemunik, T, Zhang, W, Attia, JR, Butterworth, AS, Chasman, DI, Conen, D, Cucca, F, Danesh, J, Hayward, C, Howson, JMM, Laakso, M, Lakatta, EG, Langenberg, C, Melander, O, Mook-Kanamori, DO, Palmer, CNA, Risch, L, Scott, RA, Scott, RJ, Sever, P, Spector, TD, Van der Harst, P, Wareham, NJ, Zeggini, E, Levy, D, Munroe, PB, Newton-Cheh, C, Brown, MJ, Metspalu, A, Hung, AM, O'Donnell, CJ, Edwards, TL, Psaty, BM, Tzoulaki, I, Barnes, MR, Wain, LV, Elliott, P, and Caulfield, MJ
Subjects: Genetics & Heredity, Science & Technology, Million Veteran Program, 06 Biological Sciences, Life Sciences & Biomedicine, 11 Medical and Health Sciences, Developmental Biology
Abstract: Correction to: Nature Genetics https://doi.org/10.1038/s41588-018-0205-x, published online 17 September 2018.
Published: 2018

103. Genetic determinants of risk in pulmonary arterial hypertension: international case-control studies and meta-analysis

Author: Rhodes, CJ, Batai, K, Bleda, M, Haimel, M, Southgate, L, Germain, M, Pauciulo, MW, Hadinnapola, C, Aman, J, Girerd, B, Arora, A, Robbins, I, Roden, DM, Rosenzweig, EB, Saydain, G, Scelsi, L, Schilz, R, Seeger, W, Shaffer, CM, Simms, RW, Simon, M, Walter, RE, Sitbon, O, Suntharalingam, J, Tang, H, Tchourbanov, AY, Thenappan, T, Torres, F, Toshner, MR, Treacy, CM, Noordegraaf, AV, Waisfisz, Q, Wharton, J, Walsworth, AK, White, RJ, Wilt, J, Wort, SJ, Yung, D, Lawrie, A, Humbert, M, Soubrier, F, Trégouët, D-A, Knight, J, Prokopenko, I, Kittles, R, Gräf, S, Nichols, WC, Trembath, RC, Desai, AA, Morrell, NW, Wilkins, MR, UK NIHR BioResource Rare Diseases Consortium, UK PAH Cohort Study Consortium, Hanscombe, KB, US PAH Biobank Consortium, Karnes, JH, Kaakinen, M, Gall, H, Ulrich, A, Harbaum, L, Cebola, I, Ferrer, J, Lutz, K, Swietlik, EM, Ahmad, F, Amouyel, P, Archer, SL, Argula, R, Austin, ED, Badesch, D, Bakshi, S, Barnett, C, Benza, R, Bhatt, N, Bogaard, HJ, Burger, CD, Chakinala, M, Church, C, Coghlan, JG, Condliffe, R, Corris, PA, Danesino, C, Debette, S, Elliott, CG, Elwing, J, Eyries, M, Fortin, T, Franke, A, Frantz, RP, Frost, A, Garcia, JGN, Ghio, S, Ghofrani, H-A, Gibbs, JSR, Harley, J, He, H, Hill, NS, Hirsch, R, Houweling, AC, Howard, LS, Ivy, D, Kiely, DG, Klinger, J, Kovacs, G, Lahm, T, Laudes, M, Machado, RD, Ross, RVM, Marsolo, K, Martin, LJ, Moledina, S, Montani, D, Nathan, SD, Newnham, M, Olschewski, A, Olschewski, H, Oudiz, RJ, Ouwehand, WH, Peacock, AJ, Pepke-Zaba, J, Rehman, Z, British Heart Foundation, Wellcome Trust, and Medical Research Council (MRC)
Subjects: ALPHA, Science & Technology, US PAH Biobank Consortium, Critical Care Medicine, ENDODERM FORMATION, General & Internal Medicine, UK NIHR BioResource Rare Diseases Consortium, Respiratory System, UK PAH Cohort Study Consortium, SUSCEPTIBILITY, SOX17, Life Sciences & Biomedicine, DISEASE
Abstract: Background Rare genetic variants cause pulmonary arterial hypertension, but the contribution of common genetic variation to disease risk and natural history is poorly characterised. We tested for genome-wide association for pulmonary arterial hypertension in large international cohorts and assessed the contribution of associated regions to outcomes. Methods We did two separate genome-wide association studies (GWAS) and a meta-analysis of pulmonary arterial hypertension. These GWAS used data from four international case-control studies across 11 744 individuals with European ancestry (including 2085 patients). One GWAS used genotypes from 5895 whole-genome sequences and the other GWAS used genotyping array data from an additional 5849 individuals. Cross-validation of loci reaching genome-wide significance was sought by meta-analysis. Conditional analysis corrected for the most significant variants at each locus was used to resolve signals for multiple associations. We functionally annotated associated variants and tested associations with duration of survival. All-cause mortality was the primary endpoint in survival analyses. Findings A locus near SOX17 (rs10103692, odds ratio 1·80 [95% CI 1·55–2·08], p=5·13 × 10–15) and a second locus in HLA-DPA1 and HLA-DPB1 (collectively referred to as HLA-DPA1/DPB1 here; rs2856830, 1·56 [1·42–1·71], p=7·65 × 10–20) within the class II MHC region were associated with pulmonary arterial hypertension. The SOX17 locus had two independent signals associated with pulmonary arterial hypertension (rs13266183, 1·36 [1·25–1·48], p=1·69 × 10–12; and rs10103692). Functional and epigenomic data indicate that the risk variants near SOX17 alter gene regulation via an enhancer active in endothelial cells. Pulmonary arterial hypertension risk variants determined haplotype-specific enhancer activity, and CRISPR-mediated inhibition of the enhancer reduced SOX17 expression. The HLA-DPA1/DPB1 rs2856830 genotype was strongly associated with survival. Median survival from diagnosis in patients with pulmonary arterial hypertension with the C/C homozygous genotype was double (13·50 years [95% CI 12·07 to >13·50]) that of those with the T/T genotype (6·97 years [6·02–8·05]), despite similar baseline disease severity. Interpretation This is the first study to report that common genetic variation at loci in an enhancer near SOX17 and in HLA-DPA1/DPB1 is associated with pulmonary arterial hypertension. Impairment of SOX17 function might be more common in pulmonary arterial hypertension than suggested by rare mutations in SOX17. Further studies are needed to confirm the association between HLA typing or rs2856830 genotyping and survival, and to determine whether HLA typing or rs2856830 genotyping improves risk stratification in clinical practice or trials.
Published: 2018

104. Meta-analysis of genetic association with diagnosed Alzheimer's disease identifies novel risk loci and implicates Abeta, Tau, immunity and lipid processing

Author: Kunkle, BW, Grenier-Boley, B, Sims, R, Bis, JC, Naj, AC, Boland, A, Vronskaya, M, van der Lee, SJ, Amlie-Wolf, A, Bellenguez, C, Frizatti, A, Chouraki, V, Martin, ER, Sleegers, K, Badarinarayan, N, Jakobsdottir, J, Hamilton-Nelson, KL, Aloso, R, Raybould, R, Chen, Y, Kuzma, AB, Hiltunen, M, Morgan, T, Ahmad, S, Vardarajan, BN, Epelbaum, J, Hoffmann, P, Boada, M, Beecham, GW, Garnier, JG, Harold, D, Fitzpatrick, AL, Valladares, O, Moutet, ML, Gerrish, A, Smith, AV, Qu, L, Bacq, D, Denning, N, Jian, X, Zhao, Y, Zompo, MD, Fox, NC, Grove, ML, Choi, SH, Mateo, I, Hughes, JT, Adams, HH, Malamon, J, Garcia, FS, Patel, Y, Brody, JA, Dombroski, B, Naranjo, MCD, Daniilidou, M, Eiriksdottir, G, Mukherjee, S, Wallon, D, Uphill, J, Aspelund, T, Cantwell, LB, Garzia, F, Galimberti, D, Hofer, E, Butkiewics, M, Fin, B, Scarpini, E, Sarnowski, C, Bush, W, Meslage, S, Kornhuber, J, White, CC, Song, Y, Barber, RC, Engelborghs, S, Pichler, S, Voijnovic, D, Adams, PM, Vandenberghe, R, Mayhaus, M, Cupples, LA, Albert, MS, De Deyn, PP, Gu, W, Himali, JJ, Beekly, D, Squassina, A, Hartmann, AM, Orellana, A, Blacker, D, Rodriguez-Rodriguez, E, Lovestone, S, Garcia, ME, Doody, RS, Fernadez, CM, Sussams, R, Lin, H, Fairchild, TJ, Benito, YA, Holmes, C, Comic, H, Frosch, MP, Thonberg, H, Maier, W, Roschupkin, G, Ghetti, B, Giedraitis, V, Kawalia, A, Li, S, Huebinger, RM, Kilander, L, Moebus, S, Hernández, I, Kamboh, MI, Brundin, R, Turton, J, Yang, Q, Katz, MJ, Concari, L, Lord, J, Beiser, AS, Keene, CD, Helisalmi, S, Kloszewska, I, Kukull, WA, Koivisto, AM, Lynch, A, Tarraga, L, Larson, EB, Haapasalo, A, Lawlor, B, Mosley, TH, Lipton, RB, Solfrizzi, V, Gill, M, Longstreth Jr, WT, Montine, TJ, Frisardi, V, Ortega-Cubero, S, Rivadeneira, F, Petersen, RC, Deramecourt, V, Ciaramella, A, Boerwinkle, E, Reiman, EM, Fievet, N, Caltagirone, C, Rotter, JI, Reisch, JS, Hanon, O, Cupidi, C, Uitterlinden, AG, Royall, DR, Dufouil, C, Maletta, RG, Moreno-Grau, S, Sano, M, Brice, A, Cecchetti, R, St George-Hyslop, P, Ritchie, K, Tsolaki, M, Tsuang, DW, Dubois, B, Craig, D, Wu, CK, Soininen, H, Avramidou, D, Albin, RL, Fratiglioni, L, Germanou, A, Apostolova, LG, Keller, L, Koutroumani, M, Arnold, SE, Panza, F, Gkatzima, O, Asthana, S, Hannequin, D, Whitehead, P, Atwood, CS, Caffarra, P, Hampel, H, Baldwin, CT, Lannfelt, L, Rubinsztein, DC, Barnes, LL, Pasquier, F, Frölich, L, Barral, S, McGuinness, B, Beach, TG, Johnston, JI, Becker, JT, Passmore, P, Bigio, EH, Schott, JM, Bird, TD, Warren, JD, Boeve, BF, Lupton, MK, Bowen, JD, Proitsi, P, Boxer, A, Powell, JF, Burke, JR, Kauwe, JK, Burns, JM, Mancuso, M, Buxbaum, JD, Bonuccelli, U, Cairns, NJ, McQuillin, A, Cao, C, Livingston, G, Carlson, CS, Bass, NJ, Carlsson, CM, Hardy, J, Carney, RM, Bras, J, Carrasquillo, MM, Guerreiro, R, Allen, M, Chui, HC, Fisher, E, Cribbs, DH, Masullo, C, Crocco, EA, DeCarli, C, Bisceglio, G, Dick, M, Ma, L, Duara, R, Graff-Radford, NR, Evans, DA, Hodges, A, Faber, KM, Scherer, M, Fallon, KB, Riemenschneider, M, Fardo, DW, Heun, R, Farlow, MR, Ferris, S, Leber, M, Foroud, TM, Heuser, I, Galasko, DR, Giegling, I, Gearing, M, Hüll, M, Geschwind, DH, Gilbert, JR, Morris, J, Green, RC, Mayo, K, Growdon, JH, Feulner, T, Hamilton, RL, Harrell, LE, Drichel, D, Honig, LS, Cushion, TD, Huentelman, MJ, Hollingworth, P, Hulette, CM, Hyman, BT, Marshall, R, Jarvik, GP, Meggy, A, Abner, E, Menzies, G, Jin, LW, Leonenko, G, Jun, G, Grozeva, D, Karydas, A, Russo, G, Kaye, JA, Kim, R, Jessen, F, Kowall, NW, Vellas, B, Kramer, JH, Vardy, E, LaFerla, FM, Jöckel, KH, Lah, JJ, Dichgans, M, Leverenz, JB, Mann, D, Levey, AI, Pickering-Brown, S, Lieberman, AP, Klopp, N, Lunetta, KL, Wichmann, HE, Lyketsos, CG, Morgan, K, Marson, DC, Brown, K, Martiniuk, F, Medway, C, Mash, DC, Nöthen, MM, Masliah, E, Hooper, NM, McCormick, WC, Daniele, A, McCurry, SM, Bayer, A, McDavid, AN, Gallacher, J, McKee, AC, van den Bussche, H, Mesulam, M, Brayne, C, Miller, BL, Riedel-Heller, S, Miller, CA, Miller, JW, Al-Chalabi, A, Morris, JC, Shaw, CE, Myers, AJ, Wiltfang, J, O’Bryant, S, Coto, E, Olichney, JM, Alvarez, V, Parisi, JE, Singleton, AB, Paulson, HL, Collinge, J, Perry, W, Mead, S, Peskind, E, Rosser, M, Pierce, A, Ryan, N, Poon, WW, Nacmias, B, Potter, H, Sorbi, S, Quinn, JF, Sacchinelli, E, Raj, A, Spalletta, G, Raskind, M, Bossù, P, Reisberg, B, Clarke, R, Reitz, C, Smith, AD, Ringman, JM, Warden, D, Roberson, ED, Wilcock, G, Rogaeva, E, Bruni, AC, Rosen, HJ, Gallo, M, Rosenberg, RN, Ben-Shlomo, Y, Sager, MA, Mecocci, P, Saykin, AJ, Pastor, P, Cuccaro, ML, Vance, JM, Schneider, JA, Schneider, LS, Seeley, WW, Smith, AG, Sonnen, JA, Spina, S, Stern, RA, Swerdlow, RH, Tanzi, RE, Trojanowski, JQ, Troncoso, JC, Van Deerlin, VM, Van Eldik, LJ, Vinters, HV, Vonsattel, JP, Weintraub, S, Welsh-Bohmer, KA, Wilhelmsen, KC, Williamson, J, Wingo, TS, Woltjer, RL, Wright, CB, Yu, CE, Yu, L, Crane, PK, Bennett, DA, Boccardi, V, De Jager, PL, Warner, N, Lopez, OL, McDonough, S, Ingelsson, M, Deloukas, P, Cruchaga, C, Graff, C, Gwilliam, R, Fornage, M, Goate, AM, Sanchez-Juan, P, Kehoe, PG, Amin, N, Ertekin-Taner, N, Berr, C, Debette, S, Love, S, Launer, LJ, Younkin, SG, Dartigues, JF, Corcoran, C, Ikram, MA, Dickson, DW, Campion, D, Tschanz, J, Schmidt, H, Hakonarson, H, Munger, R, Schmidt, R, Farrer, LA, Van Broeckhoven, C, O’Donovan, MC, DeStefano, AL, Jones, L, Haines, JL, Deleuze, JF, Owen, MJ, Gudnason, V, Mayeux, R, Escott-Price, V, Psaty, BM, Ruiz, A, Ramirez, A, Wang, LS, van Duijn, CM, Holmans, PA, Seshadri, S, Williams, J, Amouyel, P, Schellenberg, GD, Lambert, JC, Pericak-Vance, MA, Bis, JC [0000-0002-3409-1110], Garnier, JG [0000-0003-4991-763X], Smith, AV [0000-0001-9088-234X], Denning, N [0000-0001-8467-7382], Vandenberghe, R [0000-0001-6237-2502], Himali, JJ [0000-0003-1391-9481], Rodriguez-Rodriguez, E [0000-0001-7742-677X], Frisardi, V [0000-0003-0764-7387], Ortega-Cubero, S [0000-0003-0520-9439], Hanon, O [0000-0002-4697-122X], Brice, A [0000-0002-0941-3990], Albin, RL [0000-0002-0629-608X], Buxbaum, JD [0000-0001-8898-8313], Bass, NJ [0000-0002-4481-778X], Fisher, E [0000-0003-2850-9936], Bayer, A [0000-0002-7514-248X], Gallacher, J [0000-0002-2394-5299], Brayne, C [0000-0001-5307-663X], Riedel-Heller, S [0000-0003-4321-6090], Al-Chalabi, A [0000-0002-4924-7712], and Apollo - University of Cambridge Repository
Subjects: Aging, 4202 Epidemiology, Genome-wide association study, Disease, Neurodegenerative, Biology, 3101 Biochemistry and Cell Biology, Alzheimer's Disease, 3105 Genetics, 03 medical and health sciences, 0302 clinical medicine, Clinical Research, Acquired Cognitive Impairment, Genetics, medicine, 2.1 Biological and endogenous factors, Dementia, Gene, 030304 developmental biology, Genetic association, 2 Aetiology, 0303 health sciences, Prevention, Human Genome, 42 Health Sciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Lipid metabolism, medicine.disease, Brain Disorders, 3. Good health, Meta-analysis, Neurological, Alzheimer's disease, 030217 neurology & neurosurgery, 31 Biological Sciences
Abstract: IntroductionLate-onset Alzheimer’s disease (LOAD, onset age > 60 years) is the most prevalent dementia in the elderly1, and risk is partially driven by genetics2. Many of the loci responsible for this genetic risk were identified by genome-wide association studies (GWAS)3–8. To identify additional LOAD risk loci, the we performed the largest GWAS to date (89,769 individuals), analyzing both common and rare variants. We confirm 20 previous LOAD risk loci and identify four new genome-wide loci (IQCK, ACE, ADAM10, and ADAMTS1). Pathway analysis of these data implicates the immune system and lipid metabolism, and for the first time tau binding proteins and APP metabolism. These findings show that genetic variants affecting APP and Aβ processing are not only associated with early-onset autosomal dominant AD but also with LOAD. Analysis of AD risk genes and pathways show enrichment for rare variants (P = 1.32 × 10−7) indicating that additional rare variants remain to be identified.
Published: 2018
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105. Genetics of the thrombomodulin-endothelial cell protein C receptor system and the risk of early-onset ischemic stroke

Author: Cole, J, Xu, H, Ryan, K, Jaworek, T, Dueker, N, McArdle, P, Gaynor, B, Cheng, Y, O'Connell, J, Bevan, S, Malik, R, Ahmed, N, Amouyel, P, Anjum, S, Bis, J, Crosslin, D, Danesh, J, Engelter, S, Fornage, M, Frossard, P, Gieger, C, Giese, A, Grond-Ginsbach, C, Ho, W, Holliday, E, Hopewell, J, Hussain, M, Iqbal, W, Jabeen, S, Jannes, J, Kamal, A, Kamatani, Y, Kanse, S, Kloss, M, Lathrop, M, Leys, D, Lindgren, A, Longstreth, W, Mahmood, K, Meisinger, C, Metso, T, Mosley, T, Müller-Nurasyid, M, Norrving, B, Parati, E, Peters, A, Pezzini, A, Quereshi, I, Rasheed, A, Rauf, A, Salam, T, Shen, J, Słowik, A, Stanne, T, Strauch, K, Tatlisumak, T, Thijs, V, Tiedt, S, Traylor, M, Waldenberger, M, Walters, M, Zhao, W, Boncoraglio, G, Debette, S, Jern, C, Levi, C, Markus, H, Meschia, J, Rolfs, A, Rothwell, P, Saleheen, D, Seshadri, S, Sharma, P, Sudlow, C, Worrall, B, Isgc, Metastroke Consortium Of The, Consortium, Wtccc-2, Stine, O, Kittner, S, Mitchell, B, Cole, John W [0000-0001-9263-8930], Gaynor, Brady [0000-0002-4142-0613], Pezzini, Alessandro [0000-0001-8629-3315], Thijs, Vincent N [0000-0002-6614-8417], Apollo - University of Cambridge Repository, Faculty of Medicine, Neurologian yksikkö, Clinicum, Department of Neurosciences, HUS Neurocenter, Bordeaux population health (BPH), and Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Oncology, Male, Thrombomodulin, Social Sciences, Genome-wide association study, 030204 cardiovascular system & hematology, Cardiovascular Medicine, Vascular Medicine, 3124 Neurology and psychiatry, Brain Ischemia, Brain ischemia, 0302 clinical medicine, Sociology, Consortia, YOUNG-ADULTS, Medicine and Health Sciences, Medicine, FACTOR-V-LEIDEN, Ethnicities, Age of Onset, African American people, POPULATION, education.field_of_study, Endothelial protein C receptor, Multidisciplinary, Endothelial Protein C Receptor, Genomics, Middle Aged, Population groupings, 3. Good health, Stroke, Hemorrhagic Stroke, VINTAGE, Neurology, Cardiovascular Diseases, Female, Research Article, Adult, medicine.medical_specialty, Adolescent, Science, Cerebrovascular Diseases, Population, Single-nucleotide polymorphism, Polymorphism, Single Nucleotide, CLASSIFICATION, White People, MECHANISMS, Molecular Genetics, 03 medical and health sciences, Young Adult, Internal medicine, Factor V Leiden, Genome-Wide Association Studies, Genetics, Humans, Genetic Predisposition to Disease, ddc:610, GENOME-WIDE ASSOCIATION, education, Molecular Biology, POLYMORPHISMS, METAANALYSIS, Genetic Association Studies, Ischemic Stroke, business.industry, MORTALITY, Case-control study, 3112 Neurosciences, Biology and Life Sciences, Computational Biology, Human Genetics, medicine.disease, Genome Analysis, Black or African American, MYOCARDIAL-INFARCTION, Case-Control Studies, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, 3111 Biomedicine, Age of onset, People and places, business, 030217 neurology & neurosurgery
Abstract: Background and purpose Polymorphisms in coagulation genes have been associated with early-onset ischemic stroke. Here we pursue an a priori hypothesis that genetic variation in the endothelial-based receptors of the thrombomodulin−protein C system (THBD and PROCR) may similarly be associated with early-onset ischemic stroke. We explored this hypothesis utilizing a multi-stage design of discovery and replication. Methods Discovery was performed in the Genetics-of-Early-Onset Stroke (GEOS) Study, a biracial population-based case-control study of ischemic stroke among men and women aged 15–49 including 829 cases of first ischemic stroke (42.2% African-American) and 850 age-comparable stroke-free controls (38.1% African-American). Twenty-four single-nucleotide-polymorphisms (SNPs) in THBD and 22 SNPs in PROCR were evaluated. Following LD pruning (r2≥0.8), we advanced uncorrelated SNPs forward for association analyses. Associated SNPs were evaluated for replication in an early-onset ischemic stroke population (onset-age Results Among GEOS Caucasians, PROCR rs9574, which was in strong LD with 8 other SNPs, and one additional independent SNP rs2069951, were significantly associated with ischemic stroke (rs9574, OR = 1.33, p = 0.003; rs2069951, OR = 1.80, p = 0.006) using an additive-model adjusting for age, gender and population-structure. Adjusting for risk factors did not change the associations; however, associations were strengthened among those without risk factors. PROCR rs9574 also associated with early-onset ischemic stroke in the replication sample (OR = 1.08, p = 0.015), but not older-onset stroke. There were no PROCR associations in African-Americans, nor were there any THBD associations in either ethnicity. Conclusion PROCR polymorphisms are associated with early-onset ischemic stroke in Caucasians.
Published: 2018
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106. Erratum: Allelic differences between Europeans and Chinese for CREB1 SNPs and their implications in gene expression regulation, hippocampal structure and function, and bipolar disorder susceptibility

Author: Li, M, Luo, X-j, Rietschel, M, Lewis, C M, Mattheisen, M, Müller-Myhsok, B, Jamain, S, Leboyer, M, Landén, M, Thompson, P M, Cichon, S, Nöthen, M M, Schulze, T G, Sullivan, P F, Bergen, S E, Donohoe, G, Morris, D W, Hargreaves, A, Gill, M, Corvin, A, Hultman, C, Toga, A W, Shi, L, Lin, Q, Shi, H, Gan, L, Meyer-Lindenberg, A, Czamara, D, Henry, C, Etain, B, Bis, J C, Ikram, M A, Fornage, M, Debette, S, Launer, L J, Seshadri, S, Erk, S, Walter, H, Heinz, A, Bellivier, F, Stein, J L, Medland, S E, Vasquez, A A, Hibar, D P, Franke, B, Martin, N G, and Wright, M J
Published: 2014
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107. Prognostic significance of pulsatile tinnitus in cervical artery dissection

Author: Kellert, L., Kloss, M., Pezzini, Alessandro, Debette, S., Leys, D., Caso, V., Thijs, V. N., Bersano, A., Touzé, E., Tatlisumak, T., Traenka, C., Lyrer, P. A., Engelter, S. T., Metso, T. M., Grond Ginsbach, C., Pandolfo, Massimo, Bodenant, Marie, Louillet, Fabien, Mas, Jean Louis, Deltour, Sandrine, Léger, Anne, Canaple, Sandrine, Godefroy, Olivier, Béjot, Yannick, Moulin, Thierry, Vuillier, Fabrice, Dos Santos, Michael, Malik, Rainer, Hausser, Ingrid, Brandt, Tobias, Thomas Feles, Constanze, Weber, Ralf, Costa, Paolo, Poli, Loris, Morotti, Andrea, Padovani, Alessandro, Lanfranconi, Silvia, Baron, Pierluigi, Ferrarese, Carlo, Giacolone, Giacomo, Paolucci, Stefano, Fluri, Felix, Hatz, Florian, Gisler, Dominique, Amort, Margareth, Bevan, Steve, Altintas, Ayse, Heidelberg University Hospital [Heidelberg], Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Troubles cognitifs dégénératifs et vasculaires - U 1171 (TCDV), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Università degli Studi di Perugia = University of Perugia (UNIPG), University Hospitals Leuven [Leuven], Physiopathologie et imagerie des troubles neurologiques (PhIND), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Neurologie [CHU Caen], Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Laboratoire de Neurosciences Fonctionnelles et Pathologies - UR UPJV 4559 (LNFP), Université de Picardie Jules Verne (UPJV), CHU Amiens-Picardie, Cervical Artery Dissection and Ischemic Stroke Patients (CADISP) study group, Kellert, L, Kloss, M, Pezzini, A, Debette, S, Leys, D, Caso, V, Thijs, V, Bersano, A, Touzé, E, Tatlisumak, T, Traenka, C, Lyrer, P, Engelter, S, Metso, T, Grond Ginsbach, C, Pandolfo, M, Bodenant, M, Louillet, F, Mas, J, Deltour, S, Léger, A, Canaple, S, Godefroy, O, Béjot, Y, Moulin, T, Vuillier, F, Dos Santos, M, Malik, R, Hausser, I, Brandt, T, Thomas Feles, C, Weber, R, Costa, P, Poli, L, Morotti, A, Padovani, A, Lanfranconi, S, Baron, P, Ferrarese, C, Giacolone, G, Paolucci, S, Fluri, F, Hatz, F, Gisler, D, Amort, M, Bevan, S, and Altintas, A
Subjects: Adult, Male, medicine.medical_specialty, Cervical Artery, Vertebral artery dissection, acute ischaemic stroke, cervical artery dissection, outcome, pulsatile tinnitus, Neurology (clinical), Neurology, Dissection (medical), 030204 cardiovascular system & hematology, Brain Ischemia, Tinnitus, 03 medical and health sciences, Sex Factors, 0302 clinical medicine, Modified Rankin Scale, medicine.artery, Internal medicine, medicine, Humans, Stroke, Vertebral Artery Dissection, business.industry, Odds ratio, Middle Aged, Prognosis, medicine.disease, Confidence interval, Surgery, Cardiology, Female, Internal carotid artery, business, pulsatile tinnitu, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Background and purpose Our aim was to investigate whether pulsatile tinnitus (PT) in cervical artery dissection (CeAD) has prognostic significance. Methods All CeAD patients from the CADISP (Cervical Artery Dissection and Ischemic Stroke Patients) study with documentation of PT were analysed. The presence of PT was systematically assessed using a standardized questionnaire. Stroke severity at admission was defined according to the National Institutes of Health Stroke Scale (NIHSS). Excellent outcome after 3 months was defined as a modified Rankin Scale of 0–1. Results Sixty-three of 778 patients (8.1%) reported PT. PT+ patients presented less often with ischaemic stroke (41.3% vs. 63.9%, P < 0.001), more often with dissection in the internal carotid artery (85.7% vs. 64.2%, P = 0.001), less often with vessel occlusion (19.0% vs. 34.1%, P = 0.017) and more often with excellent outcome at 3 months (92.1% vs. 75.4%, P = 0.002). Logistic regression analysis identified PT as an independent predictor of excellent outcome after 3 months [odds ratio (OR) 3.96, 95% confidence interval (CI) 1.22–12.87] adjusted to significant outcome predictors NIHSS on admission (OR 0.82, 95% CI 0.79–0.86), Horner syndrome (OR 1.95, 95% CI 1.16–3.29) and vessel occlusion (OR 0.62, 95% CI 0.40–0.94) and to non-significant predictors age, sex, pain and location of CeAD. Conclusion The presence of PT in CeAD is associated with a benign clinical course and predicts a favourable outcome.
Published: 2016
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108. Epidemiology, aetiology, and management of ischaemic stroke in young adults

Author: Ekker, M.S., Boot, E.M., Singhal, A.B., Tan, K.S., Debette, S., Tuladhar, A.M., Leeuw, F.E. de, Ekker, M.S., Boot, E.M., Singhal, A.B., Tan, K.S., Debette, S., Tuladhar, A.M., and Leeuw, F.E. de
Abstract: Contains fulltext : 196605.pdf (publisher's version ) (Closed access), Epidemiological evidence suggests that the incidence of ischaemic stroke in young adults (18-50 years) has increased substantially. These patients have a long life expectancy after stroke, and the costs of long-term care pose huge challenges to health-care systems. Although the current recommendations for treatment of young and old (>50 years) patients with stroke are similar, the optimal management of young adult patients with stroke is unknown. They are usually not included in trials, and specific subanalyses limited to young adult patients with stroke are usually not done, owing to lower incidence of stroke and lower prevalence of vascular risk factors in young adults. Progress has been made in identifying patients with a considerable risk of stroke occurrence, such as those with patent foramen ovale. Future prevention studies might result in a decrease in the incidence of stroke and its sequelae in young adults. The development of guidelines specifically devoted to the management of stroke in young adults will be an important step in achieving this aim.
Published: 2018

109. Erratum to: Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits

Author: Evangelou, E. (Evangelos), Warren, H. (Helen), Mosen-Ansorena, D. (David), Mifsud, B. (Borbala), Pazoki, R. (Raha), Gao, H. (He), Ntritsos, G. (Georgios), Dimou, N. (Niki), Cabrera, C.P. (Claudia P.), Karaman, I. (Ibrahim), Ng, F.L. (Fu Liang), Evangelou, M. (Marina), Witkowska, K. (Katarzyna), Tzanis, E. (Evan), Hellwege, J.N. (Jacklyn N.), Giri, A. (Ayush), Velez Edwards, D.R. (Digna R.), Sun, Y.V. (Yan V.), Cho, K. (Kelly), Gaziano, J.M. (J. Michael), Wilson, P.W.F. (Peter W. F.), Tsao, P.S. (Philip S.), Kovesdy, C.P. (Csaba P.), Esko, T. (Tonu), Mägi, R. (Reedik), Milani, L. (Lili), Almgren, P. (Peter), Boutin, T. (Thibaud), Debette, S. (Stéphanie), Ding, J. (Jun), Giulianini, F. (Franco), Holliday, E.G. (Elizabeth), Jackson, A.U. (Anne), Li-Gao, R. (Ruifang), Lin, W.-Y. (Wei-Yu), Luan, J., Mangino, M. (Massimo), Oldmeadow, C. (Christopher), Prins, B.P. (Bram Peter), Qian, Y. (Yong), Sargurupremraj, M. (Muralidharan), Shah, N. (Nisha), Surendran, P. (Praveen), Thériault, S. (Sébastien), Verweij, N. (Niek), Willems, S.M. (Sara), Zhao, J.-H. (Jing-Hua), Amouyel, P. (Philippe), Connell, J. (John), Mutsert, R. (Reneé) de, Doney, A.S.F. (Alex), Farrall, M. (Martin), Menni, C. (Cristina), Morris, A.D. (Andrew), Noordam, R. (Raymond), Pare, G. (Guillame), Poulter, N.R. (Neil), Shields, D.C. (Denis C.), Stanton, A. (Alice), McG Thom, S.A., Abecasis, G. (Gonçalo), Amin, N. (Najaf), Arking, D.E. (Dan), Ayers, K.L. (Kristin), Barbieri, C.M. (Caterina M.), Batini, C. (Chiara), Bis, J.C. (Joshua), Blake, T. (Tineka), Bochud, M. (Murielle), Boehnke, M. (Michael), Boerwinkle, E. (Eric), Boomsma, D.I. (Dorret I.), Bottinger, E.P. (Erwin P.), Braund, P.S. (Peter), Brumat, M. (Marco), Campbell, A. (Archie), Campbell, H. (Harry), Chakravarti, A. (Aravinda), Chambers, J.C. (John C.), Chauhan, G. (Ganesh), Ciullo, M. (Marina), Cocca, M. (Massimiliano), Collins, F. (Francis), Cordell, H.J. (Heather), Davies, G. (Gail), de Borst, M.H. (Martin H.), Geus, E.J.C. (Eco) de, Deary, I.J. (Ian), Deelen, J. (Joris), Del Greco M, F. (Fabiola), Demirkale, C.Y. (Cumhur Yusuf), Dörr, M. (Marcus), Ehret, G.B. (Georg B.), Elosua, R. (Roberto), Enroth, S. (Stefan), Erzurumluoglu, A.M. (A. Mesut), Ferreira, T. (Teresa), Frånberg, M. (Mattias), Franco, O.H. (Oscar), Gandin, I. (Ilaria), Gasparini, P. (Paolo), Giedraitis, V. (Vilmantas), Gieger, C. (Christian), Girotto, G. (Giorgia), Goel, A. (Anuj), Gow, A.J. (Alan J.), Gudnason, V. (Vilmundur), Guo, X. (Xiuqing), Gyllensten, U. (Ulf), Hamsten, A. (Anders), Harris, T.B. (Tamara), Harris, S.E. (Sarah), Hartman, C.A. (Catharina A.), Havulinna, A.S. (Aki), Hicks, A.A. (Andrew A.), Hofer, E. (Edith), Hofman, A. (Albert), Hottenga, J.J. (Jouke Jan), Huffman, J.E. (Jennifer E.), Hwang, S.-J. (Shih-Jen), Ingelsson, E. (Erik), James, A. (Alan), Jansen, R. (Rick), Jarvelin, M.-R. (Marjo-Riitta), Joehanes, R. (Roby), Johansson, A. (Åsa), Johnson, A.D. (Andrew), Joshi, P.K. (Peter K.), Jousilahti, P. (Pekka), Jukema, J.W. (Jan Wouter), Jula, A. (Antti), Kähönen, M. (Mika), Kathiresan, S. (Sekar), Keavney, B.D. (Bernard D.), Khaw, K.-T. (Kay-Tee), Knekt, P., Knight, J. (Joanne), Kolcic, I. (Ivana), Kooner, J.S. (Jaspal S.), Koskinen, S. (Seppo), Kristiansson, K. (Kati), Kutalik, Z. (Zoltán), Laan, M. (Maris), Larson, M.G. (Martin), Launer, L.J. (Lenore), Lehne, B. (Benjamin), Lehtimäki, T. (Terho), Liewald, D.C.M. (David C. M.), Lin, L. (Li), Kao, W.H.L. (Wen), Lindgren, C.M. (Cecilia M.), Liu, Y. (YongMei), Loos, R.J.F. (Ruth), Lopez, L.M. (Lorna), Lu, Y. (Yingchang), Lyytikäinen, L.-P. (Leo-Pekka), Mahajan, A. (Anubha), Mamasoula, C. (Chrysovalanto), Marrugat, J. (Jaume), Marten, J. (Jonathan), Milaneschi, Y. (Yuri), Morgan, A. (Anna), Morris, A.P. (Andrew), Morrison, A.C. (Alanna), Munson, P.J. (Peter), Nalls, M.A. (Michael), Nandakumar, P. (Priyanka), Nelson, C.P. (Christopher P.), Niiranen, T. (Teemu), Nolte, I.M. (Ilja), Nutile, T. (Teresa), Oldehinkel, A.J. (Albertine), Oostra, B.A. (Ben), O’Reilly, P.F. (Paul F.), Org, E. (Elin), Padmanabhan, S. (Sandosh), Palmas, W. (Walter), Palotie, A. (Aarno), Pattie, A. (Alison), Penninx, B.W.J.H. (Brenda), Perola, M. (Markus), Peters, A. (Annette), Polasek, O. (Ozren), Pramstaller, P.P. (Peter Paul), Nguyen, Q.T. (Quang Tri), Raitakari, O. (Olli), Ren, M. (Meixia), Rettig, R. (Rainer), Rice, K.M. (Kenneth), Ridker, P.M. (Paul), Ried, J.S. (Janina S.), Riese, H. (Harriëtte), Ripatti, S. (Samuli), Robino, A. (Antonietta), Rose, L.M. (Lynda M.), Rotter, J.I. (Jerome I.), Rudan, I. (Igor), Ruggiero, D., Saba, Y. (Yasaman), Sala, C. (Cinzia), Salomaa, V. (Veikko), Samani, N.J. (Nilesh J.), Sarin, A.-P., Schmidt, R. (Reinhold), Schmidt, H. (Helena), Shrine, N.R.G. (Nick), Siscovick, D. (David), Smith, A.V. (Albert), Snieder, H. (Harold), Sõber, S. (Siim), Sorice, R., Starr, J.M. (John), Stott, D.J. (David. J.), Strachan, D.P. (David), Strawbridge, R.J. (Rona), Sundström, J. (Johan), Swertz, M.A. (Morris A.), Taylor, K.D. (Kent), Teumer, A. (Alexander), Tobin, M.D. (Martin), Tomaszewski, M. (Maciej), Toniolo, D. (Daniela), Traglia, M. (Michela), Trompet, S. (Stella), Tuomilehto, J. (Jaakko), Tzourio, C. (Christophe), Uitterlinden, A.G. (André), Vaez, A. (Ahmad), Most, P.J. (Peter) van der, Duijn, C.M. (Cornelia) van, Vergnaud, A.-C. (Anne-Claire), Verwoert, G.C. (Germaine C.), Vitart, V. (Veronique), Völker, U. (Uwe), Vollenweider, P. (Peter), Vuckovic, D. (Dragana), Watkins, H. (Hugh), Wild, S.H. (Sarah), Willemsen, G. (Gonneke), Wilson, J.F. (James F.), Wright, A.F. (Alan), Yao, J. (Jie), Zemunik, T. (Tatijana), Zhang, W. (Weihua), Attia, J. (John), Butterworth, A.S. (Adam S.), Chasman, D.I. (Daniel), Conen, D. (David), Cucca, F. (Francesco), Danesh, J. (John), Hayward, C. (Caroline), Howson, J.M.M. (Joanna M. M.), Laakso, M. (Markku), Lakatta, E.G. (Edward G.), Langenberg, C. (Claudia), Melander, O. (Olle), Mook-Kanamori, D.O. (Dennis O.), Palmer, C.N.A. (Colin N. A.), Risch, L. (Lorenz), Scott, R.A. (Robert), Scott, R.J. (Rodney J.), Sever, P. (Peter), Spector, T.D. (Timothy), van der Harst, P. (Pim), Wareham, N.J. (Nick), Zeggini, E. (Eleftheria), Levy, D. (Daniel), Munroe, P. (Patricia), Newton-Cheh, C. (Christopher), Brown, M.J. (Morris), Metspalu, A. (Andres), Hung, A.M. (Adriana M.), Ódonnell, C.J. (Christopher), Edwards, T.L. (Todd L.), Psaty, B.M. (Bruce), Tzoulaki, I., Barnes, M.J. (Michael), Wain, L.V. (Louise V.), Elliott, P. (Paul), Caulfield, M. (Mark), Evangelou, E. (Evangelos), Warren, H. (Helen), Mosen-Ansorena, D. (David), Mifsud, B. (Borbala), Pazoki, R. (Raha), Gao, H. (He), Ntritsos, G. (Georgios), Dimou, N. (Niki), Cabrera, C.P. (Claudia P.), Karaman, I. (Ibrahim), Ng, F.L. (Fu Liang), Evangelou, M. (Marina), Witkowska, K. (Katarzyna), Tzanis, E. (Evan), Hellwege, J.N. (Jacklyn N.), Giri, A. (Ayush), Velez Edwards, D.R. (Digna R.), Sun, Y.V. (Yan V.), Cho, K. (Kelly), Gaziano, J.M. (J. Michael), Wilson, P.W.F. (Peter W. F.), Tsao, P.S. (Philip S.), Kovesdy, C.P. (Csaba P.), Esko, T. (Tonu), Mägi, R. (Reedik), Milani, L. (Lili), Almgren, P. (Peter), Boutin, T. (Thibaud), Debette, S. (Stéphanie), Ding, J. (Jun), Giulianini, F. (Franco), Holliday, E.G. (Elizabeth), Jackson, A.U. (Anne), Li-Gao, R. (Ruifang), Lin, W.-Y. (Wei-Yu), Luan, J., Mangino, M. (Massimo), Oldmeadow, C. (Christopher), Prins, B.P. (Bram Peter), Qian, Y. (Yong), Sargurupremraj, M. (Muralidharan), Shah, N. (Nisha), Surendran, P. (Praveen), Thériault, S. (Sébastien), Verweij, N. (Niek), Willems, S.M. (Sara), Zhao, J.-H. (Jing-Hua), Amouyel, P. (Philippe), Connell, J. (John), Mutsert, R. (Reneé) de, Doney, A.S.F. (Alex), Farrall, M. (Martin), Menni, C. (Cristina), Morris, A.D. (Andrew), Noordam, R. (Raymond), Pare, G. (Guillame), Poulter, N.R. (Neil), Shields, D.C. (Denis C.), Stanton, A. (Alice), McG Thom, S.A., Abecasis, G. (Gonçalo), Amin, N. (Najaf), Arking, D.E. (Dan), Ayers, K.L. (Kristin), Barbieri, C.M. (Caterina M.), Batini, C. (Chiara), Bis, J.C. (Joshua), Blake, T. (Tineka), Bochud, M. (Murielle), Boehnke, M. (Michael), Boerwinkle, E. (Eric), Boomsma, D.I. (Dorret I.), Bottinger, E.P. (Erwin P.), Braund, P.S. (Peter), Brumat, M. (Marco), Campbell, A. (Archie), Campbell, H. (Harry), Chakravarti, A. (Aravinda), Chambers, J.C. (John C.), Chauhan, G. (Ganesh), Ciullo, M. (Marina), Cocca, M. (Massimiliano), Collins, F. (Francis), Cordell, H.J. (Heather), Davies, G. (Gail), de Borst, M.H. (Martin H.), Geus, E.J.C. (Eco) de, Deary, I.J. (Ian), Deelen, J. (Joris), Del Greco M, F. (Fabiola), Demirkale, C.Y. (Cumhur Yusuf), Dörr, M. (Marcus), Ehret, G.B. (Georg B.), Elosua, R. (Roberto), Enroth, S. (Stefan), Erzurumluoglu, A.M. (A. Mesut), Ferreira, T. (Teresa), Frånberg, M. (Mattias), Franco, O.H. (Oscar), Gandin, I. (Ilaria), Gasparini, P. (Paolo), Giedraitis, V. (Vilmantas), Gieger, C. (Christian), Girotto, G. (Giorgia), Goel, A. (Anuj), Gow, A.J. (Alan J.), Gudnason, V. (Vilmundur), Guo, X. (Xiuqing), Gyllensten, U. (Ulf), Hamsten, A. (Anders), Harris, T.B. (Tamara), Harris, S.E. (Sarah), Hartman, C.A. (Catharina A.), Havulinna, A.S. (Aki), Hicks, A.A. (Andrew A.), Hofer, E. (Edith), Hofman, A. (Albert), Hottenga, J.J. (Jouke Jan), Huffman, J.E. (Jennifer E.), Hwang, S.-J. (Shih-Jen), Ingelsson, E. (Erik), James, A. (Alan), Jansen, R. (Rick), Jarvelin, M.-R. (Marjo-Riitta), Joehanes, R. (Roby), Johansson, A. (Åsa), Johnson, A.D. (Andrew), Joshi, P.K. (Peter K.), Jousilahti, P. (Pekka), Jukema, J.W. (Jan Wouter), Jula, A. (Antti), Kähönen, M. (Mika), Kathiresan, S. (Sekar), Keavney, B.D. (Bernard D.), Khaw, K.-T. (Kay-Tee), Knekt, P., Knight, J. (Joanne), Kolcic, I. (Ivana), Kooner, J.S. (Jaspal S.), Koskinen, S. (Seppo), Kristiansson, K. (Kati), Kutalik, Z. (Zoltán), Laan, M. (Maris), Larson, M.G. (Martin), Launer, L.J. (Lenore), Lehne, B. (Benjamin), Lehtimäki, T. (Terho), Liewald, D.C.M. (David C. M.), Lin, L. (Li), Kao, W.H.L. (Wen), Lindgren, C.M. (Cecilia M.), Liu, Y. (YongMei), Loos, R.J.F. (Ruth), Lopez, L.M. (Lorna), Lu, Y. (Yingchang), Lyytikäinen, L.-P. (Leo-Pekka), Mahajan, A. (Anubha), Mamasoula, C. (Chrysovalanto), Marrugat, J. (Jaume), Marten, J. (Jonathan), Milaneschi, Y. (Yuri), Morgan, A. (Anna), Morris, A.P. (Andrew), Morrison, A.C. (Alanna), Munson, P.J. (Peter), Nalls, M.A. (Michael), Nandakumar, P. (Priyanka), Nelson, C.P. (Christopher P.), Niiranen, T. (Teemu), Nolte, I.M. (Ilja), Nutile, T. (Teresa), Oldehinkel, A.J. (Albertine), Oostra, B.A. (Ben), O’Reilly, P.F. (Paul F.), Org, E. (Elin), Padmanabhan, S. (Sandosh), Palmas, W. (Walter), Palotie, A. (Aarno), Pattie, A. (Alison), Penninx, B.W.J.H. (Brenda), Perola, M. (Markus), Peters, A. (Annette), Polasek, O. (Ozren), Pramstaller, P.P. (Peter Paul), Nguyen, Q.T. (Quang Tri), Raitakari, O. (Olli), Ren, M. (Meixia), Rettig, R. (Rainer), Rice, K.M. (Kenneth), Ridker, P.M. (Paul), Ried, J.S. (Janina S.), Riese, H. (Harriëtte), Ripatti, S. (Samuli), Robino, A. (Antonietta), Rose, L.M. (Lynda M.), Rotter, J.I. (Jerome I.), Rudan, I. (Igor), Ruggiero, D., Saba, Y. (Yasaman), Sala, C. (Cinzia), Salomaa, V. (Veikko), Samani, N.J. (Nilesh J.), Sarin, A.-P., Schmidt, R. (Reinhold), Schmidt, H. (Helena), Shrine, N.R.G. (Nick), Siscovick, D. (David), Smith, A.V. (Albert), Snieder, H. (Harold), Sõber, S. (Siim), Sorice, R., Starr, J.M. (John), Stott, D.J. (David. J.), Strachan, D.P. (David), Strawbridge, R.J. (Rona), Sundström, J. (Johan), Swertz, M.A. (Morris A.), Taylor, K.D. (Kent), Teumer, A. (Alexander), Tobin, M.D. (Martin), Tomaszewski, M. (Maciej), Toniolo, D. (Daniela), Traglia, M. (Michela), Trompet, S. (Stella), Tuomilehto, J. (Jaakko), Tzourio, C. (Christophe), Uitterlinden, A.G. (André), Vaez, A. (Ahmad), Most, P.J. (Peter) van der, Duijn, C.M. (Cornelia) van, Vergnaud, A.-C. (Anne-Claire), Verwoert, G.C. (Germaine C.), Vitart, V. (Veronique), Völker, U. (Uwe), Vollenweider, P. (Peter), Vuckovic, D. (Dragana), Watkins, H. (Hugh), Wild, S.H. (Sarah), Willemsen, G. (Gonneke), Wilson, J.F. (James F.), Wright, A.F. (Alan), Yao, J. (Jie), Zemunik, T. (Tatijana), Zhang, W. (Weihua), Attia, J. (John), Butterworth, A.S. (Adam S.), Chasman, D.I. (Daniel), Conen, D. (David), Cucca, F. (Francesco), Danesh, J. (John), Hayward, C. (Caroline), Howson, J.M.M. (Joanna M. M.), Laakso, M. (Markku), Lakatta, E.G. (Edward G.), Langenberg, C. (Claudia), Melander, O. (Olle), Mook-Kanamori, D.O. (Dennis O.), Palmer, C.N.A. (Colin N. A.), Risch, L. (Lorenz), Scott, R.A. (Robert), Scott, R.J. (Rodney J.), Sever, P. (Peter), Spector, T.D. (Timothy), van der Harst, P. (Pim), Wareham, N.J. (Nick), Zeggini, E. (Eleftheria), Levy, D. (Daniel), Munroe, P. (Patricia), Newton-Cheh, C. (Christopher), Brown, M.J. (Morris), Metspalu, A. (Andres), Hung, A.M. (Adriana M.), Ódonnell, C.J. (Christopher), Edwards, T.L. (Todd L.), Psaty, B.M. (Bruce), Tzoulaki, I., Barnes, M.J. (Michael), Wain, L.V. (Louise V.), Elliott, P. (Paul), and Caulfield, M. (Mark)
Abstract: In the version of this article originally published, the name of author Martin H. de Borst was coded incorrectly in the XML. The error has now been corrected in the HTML version of the paper.
Published: 2018
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110. GWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes

Author: Franceschini, N. (Nora), Giambartolomei, C. (Claudia), Vries, P.S. (Paul) de, Finan, C. (Chris), Bis, J.C. (Joshua), Huntley, R.P. (Rachael P.), Lovering, R.C. (Ruth C.), Tajuddin, S.M. (Salman M.), Winkler, T.W. (Thomas W.), Graff, M. (Misa), Kavousi, M. (Maryam), Dale, C. (Caroline), Smith, A.V. (Albert), Hofer, E. (Edith), Leeuwen, E.M. (Elisa) van, Nolte, I.M. (Ilja), Lu, L. (Lingyi), Scholz, M. (Markus), Sargurupremraj, M. (Muralidharan), Pitkanen, N. (Niina), Franzén, O. (Oscar), Joshi, P.K. (Peter), Noordam, R. (Raymond), Marioni, R.E. (Riccardo), Hwang, S.-J. (Shih-Jen), Musani, S.K. (Solomon K.), Schminke, U. (Ulf), Palmas, W. (Walter), Isaacs, A.J. (Aaron), Correa, D.D., Zonderman, A.B., Hofman, A. (Albert), Teumer, A. (Alexander), Cox, A.J. (Amanda J.), Uitterlinden, A.G. (André), Wong, A. (Andrew), Smit, A.J. (Andries), Newman, A.B. (Anne B.), Britton, A.R., Ruusalepp, A. (Arno), Sennblad, B. (Bengt), Hedblad, B. (Bo), Pasaniuc, B. (Bogdan), Penninx, B.W.J.H. (Brenda), Langefeld, C.D. (Carl D.), Wassel, C.L. (Christina), Tzourio, C. (Christophe), Fava, C. (Cristiano), Baldassarre, D. (Damiano), O’Leary, D.H. (Daniel H.), Teupser, D. (Daniel), Kuh, D. (Diana), Tremoli, E. (Elena), Mannarino, E. (Elmo), Grossi, E. (Enzo), Boerwinkle, E.A. (Eric), Schadt, E.E. (Eric E.), Ingelsson, E. (Erik), Veglia, F. (Fabrizio), Rivadeneira Ramirez, F. (Fernando), Beutner, F. (Frank), Chauhan, G. (Ganesh), Heiss, G. (Gerardo), Snieder, H. (Harold), Campbell, H. (Harry), Völzke, H. (Henry), Markus, H.S. (Hugh), Deary, I.J. (Ian), Jukema, J.W. (Jan Wouter), Graaf, J. (Jacqueline) de, Price, J. (Jacqueline), Pott, J. (Janne), Hopewell, J., Liang, J. (Jingjing), Thiery, J.P. (Joachim), Engmann, J. (Jorgen), Gertow, K. (Karl), Rice, K.M. (Kenneth), Taylor, K.D. (Kent), Dhana, K. (Klodian), Kiemeney, L.A.L.M. (Lambertus A. L. M.), Kao, W.H.L. (Wen), Raffield, L.M. (Laura M.), Launer, L.J. (Lenore), Holdt, L.M. (Lesca), Dörr, M. (Marcus), Kubisch, C. (Christian), Traylor, M. (Matthew), Sitzer, M. (Matthias), Kumari, M. (Meena), Kivimaki, M. (Mika), Nalls, M.A. (Michael), Melander, O. (Olle), Raitakari, O. (Olli), Franco, O.H. (Oscar), Rueda-Ochoa, O.L. (Oscar), Roussos, A. (Alexandra), Whincup, P.H. (Peter), Amouyel, P. (Philippe), Giral, P. (Philippe), Anugu, P. (Pramod), Wong, Q. (Quenna), Malik, R. (Rainer), Rauramaa, R. (Rainer), Burkhardt, R. (Ralph), Hardy, R. (Rebecca), Schmidt, R. (Reinhold), Mutsert, R. (Reneé) de, Strawbridge, R.J. (Rona), Wannamethee, S.G. (Goya), Hägg, S. (Sara), Shah, S. (Sonia), McLachlan, S. (Stela), Trompet, S. (Stella), Seshadri, S. (Sudha), Kurl, S. (Sudhir), Heckbert, S.R. (Susan), Ring, S.M. (Susan), Harris, T.B. (Tamara B.), Lehtimäki, T. (Terho), Galesloot, T.E. (Tessel), Shah, T. (Tina), Faire, U. (Ulf) de, Plagnol, V. (Vincent), Rosamond, W.D. (Wayne), Post, W.S. (Wendy S.), Zhu, X. (Xiaofeng), Zhang, X. (Xiaoling), Guo, X. (Xiuqing), Saba, Y. (Yasaman), Okada, Y. (Yukinori), Mishra, A. (Aniket), Rutten-Jacobs, L. (Loes), Giese, A.-K. (Anne-Katrin), van der Laan, S.W. (Sander W.), Gretarsdottir, S. (Solveig), Anderson, C.D. (Christopher D.), Chong, M. (Michael), Adams, H.H.H. (Hieab), Ago, T. (Tetsuro), Almgren, P. (Peter), Ay, H. (Hakan), Bartz, T.M. (Traci M.), Benavente, O.R. (Oscar R.), Bevan, S. (Steve), Boncoraglio, G. (Giorgio Battista), Brown, R.D. (Robert D.), Butterworth, A.S. (Adam S.), Carrera, C. (Caty), Carty, C.L. (Cara L.), Chasman, D.I. (Daniel), Chen, W-M., Cole, J.W. (John W.), Cotlarciuc, I. (Ioana), Cruchaga, C. (Carlos), Danesh, J. (John), Bakker, P.I.W. (Paul) de, DeStefano, A.L. (Anita), Hoed, M. (Marcel) den, Duan, Q. (Qing), Engelter, S.T. (Stefan), Falcone, G.J. (Guido J.), Gottesman, R.F. (Rebecca), Grewal, R.P. (Raji P.), Gustafsson, S. (Stefan), Haessler, J. (Jeff), Harris, T.B. (Tamara), Hassan, A. (Ahamad), Havulinna, A.S. (Aki), Holliday, E.G. (Elizabeth), Howard, G. (George), Hsu, F.-C. (Fang-Chi), Hyacinth, H.I. (Hyacinth I.), Ikram, M.A. (Arfan), Irvin, M.R. (Marguerite R.), Jian, X. (Xueqiu), Jimenez-Conde, J. (Jordi), Johnson, J.A. (Julie A.), Jukema, J.W. (J. Wouter), Kanai, M. (Masahiro), Keene, K.L. (Keith), Kissela, B.M. (Brett M.), Kleindorfer, D.O. (Dawn O.), Kooperberg, C. (Charles), Kubo, M. (Michiaki), Lange, L.A. (Leslie), Langefeld, C.D. (Carl), Langenberg, C. (Claudia), Lee, J.-M. (Jin-Moo), Lemmens, R. (Robin), Leys, D. (Didier), Lewis, C.M. (Cathryn), Lin, W.-Y. (Wei-Yu), Lindgren, A.G. (Arne G.), Lorentzen, E. (Erik), Magnusson, P.K. (Patrik), Maguire, J.M. (Jane), Manichaikul, A. (Ani), McArdle, P.F. (Patrick), Meschia, J.F. (James F.), Mosley, T.H. (Thomas H.), Ninomiya, T. (Toshiharu), O’Donnell, M.J. (Martin J.), Pulit, S.L. (Sara), Rannikmäe, K. (Kristiina), Reiner, A.P. (Alexander P.), Rexrode, K. (Kathryn), Rich, S.S. (Stephen), Ridker, P.M. (Paul), Rost, N.S. (Natalia), Rothwell, P.M. (Peter), Rundek, T. (Tatjana), Muir, K.W. (Keith), Sakaue, S. (Saori), Sale, M.M. (Michele M.), Salomaa, V. (Veikko), Sapkota, B.R. (Bishwa R.), Schmidt, C.O. (Carsten O.), Sharma, P. (Pankaj), Slowik, A. (Agnieszka), Sudlow, C. (Cathie), Tanislav, C. (Christian), Tatlisumak, T. (Turgut), Thijs, V. (Vincent), Thorleifsson, G. (Gudmar), Thorsteinsdottir, U. (Unnur), Tiedt, S. (Steffen), Walters, M. (Matthew), Wareham, N.J. (Nick), Wassertheil-Smoller, S. (Sylvia), Wiggins, K.L. (Kerri), Yang, Q. (Qiong Fang), Yusuf, S. (Salim), Pastinen, T. (Tomi), Schadt, E.E. (Eric), Koplev, S. (Simon), Codoni, V. (Veronica), Civelek, M. (Mete), Smith, N.L. (Nicholas), Tregouet, D.-A. (David-Alexandre), Christophersen, I.E. (Ingrid E.), Roselli, C. (Carolina), Lubitz, S.A. (Steven A.), Ellinor, P.T. (Patrick), Tai, E.S. (E. Shyong), Kooner, J.S. (Jaspal S.), Kato, N. (Norihiro), He, J. (Jiang), Harst, P. (Pim) van der, Elliott, P. (Paul), Chambers, J.C. (John C.), Takeuchi, F. (Fumihiko), Johnson, A.D. (Andrew), Sanghera, D.K. (Dharambir K.), Jern, C. (Christina), Strbian, D. (Daniel), Fernandez-Cadenas, I. (Israel), Longstreth Jr, W.T., Rolfs, A. (Arndt), Hata, J. (Jun), Woo, D. (Daniel), Rosand, J. (Jonathan), Pare, G. (Guillame), Saleheen, D. (Danish), Zwart, J-A. (John-Anker), Worrall, B.B. (Bradford B.), Kittner, T. (Thomas), Howson, J.M.M. (Joanna M. M.), Kamatani, Y. (Yoichiro), Dehghan, A. (Abbas), Seldenrijk, K.A. (Kees), Morrison, A.C. (Alanna), Hamsten, A. (Anders), Psaty, B.M. (Bruce), Duijn, C.M. (Cornelia) van, Lawlor, D.A. (Debbie), Mook-Kanamori, D.O. (Dennis O.), Bowden, D.W. (Donald), Schmidt, H. (Helena), Wilson, J.F. (James F.), Wilson, J.F. (James), Rotter, J.I. (Jerome I.), Wardlaw, J.M. (J.), Deanfield, J. (John), Halcox, J. (Julian), Lyytikäinen, L.-P. (Leo-Pekka), Loeffler, M. (Markus), Evans, M.K. (Michele), Debette, S. (Stéphanie), Humphries, S.E. (Steve), Völker, U. (Uwe), Gudnason, V. (Vilmundur), Hingorani, A. (Aroon), Björkegren, J.L.M. (Johan L.M.), Casas, J.P. (Juan), Ódonnell, C.J. (Christopher), Morris, R.W. (Richard), Franceschini, N. (Nora), Giambartolomei, C. (Claudia), Vries, P.S. (Paul) de, Finan, C. (Chris), Bis, J.C. (Joshua), Huntley, R.P. (Rachael P.), Lovering, R.C. (Ruth C.), Tajuddin, S.M. (Salman M.), Winkler, T.W. (Thomas W.), Graff, M. (Misa), Kavousi, M. (Maryam), Dale, C. (Caroline), Smith, A.V. (Albert), Hofer, E. (Edith), Leeuwen, E.M. (Elisa) van, Nolte, I.M. (Ilja), Lu, L. (Lingyi), Scholz, M. (Markus), Sargurupremraj, M. (Muralidharan), Pitkanen, N. (Niina), Franzén, O. (Oscar), Joshi, P.K. (Peter), Noordam, R. (Raymond), Marioni, R.E. (Riccardo), Hwang, S.-J. (Shih-Jen), Musani, S.K. (Solomon K.), Schminke, U. (Ulf), Palmas, W. (Walter), Isaacs, A.J. (Aaron), Correa, D.D., Zonderman, A.B., Hofman, A. (Albert), Teumer, A. (Alexander), Cox, A.J. (Amanda J.), Uitterlinden, A.G. (André), Wong, A. (Andrew), Smit, A.J. (Andries), Newman, A.B. (Anne B.), Britton, A.R., Ruusalepp, A. (Arno), Sennblad, B. (Bengt), Hedblad, B. (Bo), Pasaniuc, B. (Bogdan), Penninx, B.W.J.H. (Brenda), Langefeld, C.D. (Carl D.), Wassel, C.L. (Christina), Tzourio, C. (Christophe), Fava, C. (Cristiano), Baldassarre, D. (Damiano), O’Leary, D.H. (Daniel H.), Teupser, D. (Daniel), Kuh, D. (Diana), Tremoli, E. (Elena), Mannarino, E. (Elmo), Grossi, E. (Enzo), Boerwinkle, E.A. (Eric), Schadt, E.E. (Eric E.), Ingelsson, E. (Erik), Veglia, F. (Fabrizio), Rivadeneira Ramirez, F. (Fernando), Beutner, F. (Frank), Chauhan, G. (Ganesh), Heiss, G. (Gerardo), Snieder, H. (Harold), Campbell, H. (Harry), Völzke, H. (Henry), Markus, H.S. (Hugh), Deary, I.J. (Ian), Jukema, J.W. (Jan Wouter), Graaf, J. (Jacqueline) de, Price, J. (Jacqueline), Pott, J. (Janne), Hopewell, J., Liang, J. (Jingjing), Thiery, J.P. (Joachim), Engmann, J. (Jorgen), Gertow, K. (Karl), Rice, K.M. (Kenneth), Taylor, K.D. (Kent), Dhana, K. (Klodian), Kiemeney, L.A.L.M. (Lambertus A. L. M.), Kao, W.H.L. (Wen), Raffield, L.M. (Laura M.), Launer, L.J. (Lenore), Holdt, L.M. (Lesca), Dörr, M. (Marcus), Kubisch, C. (Christian), Traylor, M. (Matthew), Sitzer, M. (Matthias), Kumari, M. (Meena), Kivimaki, M. (Mika), Nalls, M.A. (Michael), Melander, O. (Olle), Raitakari, O. (Olli), Franco, O.H. (Oscar), Rueda-Ochoa, O.L. (Oscar), Roussos, A. (Alexandra), Whincup, P.H. (Peter), Amouyel, P. (Philippe), Giral, P. (Philippe), Anugu, P. (Pramod), Wong, Q. (Quenna), Malik, R. (Rainer), Rauramaa, R. (Rainer), Burkhardt, R. (Ralph), Hardy, R. (Rebecca), Schmidt, R. (Reinhold), Mutsert, R. (Reneé) de, Strawbridge, R.J. (Rona), Wannamethee, S.G. (Goya), Hägg, S. (Sara), Shah, S. (Sonia), McLachlan, S. (Stela), Trompet, S. (Stella), Seshadri, S. (Sudha), Kurl, S. (Sudhir), Heckbert, S.R. (Susan), Ring, S.M. (Susan), Harris, T.B. (Tamara B.), Lehtimäki, T. (Terho), Galesloot, T.E. (Tessel), Shah, T. (Tina), Faire, U. (Ulf) de, Plagnol, V. (Vincent), Rosamond, W.D. (Wayne), Post, W.S. (Wendy S.), Zhu, X. (Xiaofeng), Zhang, X. (Xiaoling), Guo, X. (Xiuqing), Saba, Y. (Yasaman), Okada, Y. (Yukinori), Mishra, A. (Aniket), Rutten-Jacobs, L. (Loes), Giese, A.-K. (Anne-Katrin), van der Laan, S.W. (Sander W.), Gretarsdottir, S. (Solveig), Anderson, C.D. (Christopher D.), Chong, M. (Michael), Adams, H.H.H. (Hieab), Ago, T. (Tetsuro), Almgren, P. (Peter), Ay, H. (Hakan), Bartz, T.M. (Traci M.), Benavente, O.R. (Oscar R.), Bevan, S. (Steve), Boncoraglio, G. (Giorgio Battista), Brown, R.D. (Robert D.), Butterworth, A.S. (Adam S.), Carrera, C. (Caty), Carty, C.L. (Cara L.), Chasman, D.I. (Daniel), Chen, W-M., Cole, J.W. (John W.), Cotlarciuc, I. (Ioana), Cruchaga, C. (Carlos), Danesh, J. (John), Bakker, P.I.W. (Paul) de, DeStefano, A.L. (Anita), Hoed, M. (Marcel) den, Duan, Q. (Qing), Engelter, S.T. (Stefan), Falcone, G.J. (Guido J.), Gottesman, R.F. (Rebecca), Grewal, R.P. (Raji P.), Gustafsson, S. (Stefan), Haessler, J. (Jeff), Harris, T.B. (Tamara), Hassan, A. (Ahamad), Havulinna, A.S. (Aki), Holliday, E.G. (Elizabeth), Howard, G. (George), Hsu, F.-C. (Fang-Chi), Hyacinth, H.I. (Hyacinth I.), Ikram, M.A. (Arfan), Irvin, M.R. (Marguerite R.), Jian, X. (Xueqiu), Jimenez-Conde, J. (Jordi), Johnson, J.A. (Julie A.), Jukema, J.W. (J. Wouter), Kanai, M. (Masahiro), Keene, K.L. (Keith), Kissela, B.M. (Brett M.), Kleindorfer, D.O. (Dawn O.), Kooperberg, C. (Charles), Kubo, M. (Michiaki), Lange, L.A. (Leslie), Langefeld, C.D. (Carl), Langenberg, C. (Claudia), Lee, J.-M. (Jin-Moo), Lemmens, R. (Robin), Leys, D. (Didier), Lewis, C.M. (Cathryn), Lin, W.-Y. (Wei-Yu), Lindgren, A.G. (Arne G.), Lorentzen, E. (Erik), Magnusson, P.K. (Patrik), Maguire, J.M. (Jane), Manichaikul, A. (Ani), McArdle, P.F. (Patrick), Meschia, J.F. (James F.), Mosley, T.H. (Thomas H.), Ninomiya, T. (Toshiharu), O’Donnell, M.J. (Martin J.), Pulit, S.L. (Sara), Rannikmäe, K. (Kristiina), Reiner, A.P. (Alexander P.), Rexrode, K. (Kathryn), Rich, S.S. (Stephen), Ridker, P.M. (Paul), Rost, N.S. (Natalia), Rothwell, P.M. (Peter), Rundek, T. (Tatjana), Muir, K.W. (Keith), Sakaue, S. (Saori), Sale, M.M. (Michele M.), Salomaa, V. (Veikko), Sapkota, B.R. (Bishwa R.), Schmidt, C.O. (Carsten O.), Sharma, P. (Pankaj), Slowik, A. (Agnieszka), Sudlow, C. (Cathie), Tanislav, C. (Christian), Tatlisumak, T. (Turgut), Thijs, V. (Vincent), Thorleifsson, G. (Gudmar), Thorsteinsdottir, U. (Unnur), Tiedt, S. (Steffen), Walters, M. (Matthew), Wareham, N.J. (Nick), Wassertheil-Smoller, S. (Sylvia), Wiggins, K.L. (Kerri), Yang, Q. (Qiong Fang), Yusuf, S. (Salim), Pastinen, T. (Tomi), Schadt, E.E. (Eric), Koplev, S. (Simon), Codoni, V. (Veronica), Civelek, M. (Mete), Smith, N.L. (Nicholas), Tregouet, D.-A. (David-Alexandre), Christophersen, I.E. (Ingrid E.), Roselli, C. (Carolina), Lubitz, S.A. (Steven A.), Ellinor, P.T. (Patrick), Tai, E.S. (E. Shyong), Kooner, J.S. (Jaspal S.), Kato, N. (Norihiro), He, J. (Jiang), Harst, P. (Pim) van der, Elliott, P. (Paul), Chambers, J.C. (John C.), Takeuchi, F. (Fumihiko), Johnson, A.D. (Andrew), Sanghera, D.K. (Dharambir K.), Jern, C. (Christina), Strbian, D. (Daniel), Fernandez-Cadenas, I. (Israel), Longstreth Jr, W.T., Rolfs, A. (Arndt), Hata, J. (Jun), Woo, D. (Daniel), Rosand, J. (Jonathan), Pare, G. (Guillame), Saleheen, D. (Danish), Zwart, J-A. (John-Anker), Worrall, B.B. (Bradford B.), Kittner, T. (Thomas), Howson, J.M.M. (Joanna M. M.), Kamatani, Y. (Yoichiro), Dehghan, A. (Abbas), Seldenrijk, K.A. (Kees), Morrison, A.C. (Alanna), Hamsten, A. (Anders), Psaty, B.M. (Bruce), Duijn, C.M. (Cornelia) van, Lawlor, D.A. (Debbie), Mook-Kanamori, D.O. (Dennis O.), Bowden, D.W. (Donald), Schmidt, H. (Helena), Wilson, J.F. (James F.), Wilson, J.F. (James), Rotter, J.I. (Jerome I.), Wardlaw, J.M. (J.), Deanfield, J. (John), Halcox, J. (Julian), Lyytikäinen, L.-P. (Leo-Pekka), Loeffler, M. (Markus), Evans, M.K. (Michele), Debette, S. (Stéphanie), Humphries, S.E. (Steve), Völker, U. (Uwe), Gudnason, V. (Vilmundur), Hingorani, A. (Aroon), Björkegren, J.L.M. (Johan L.M.), Casas, J.P. (Juan), Ódonnell, C.J. (Christopher), and Morris, R.W. (Richard)
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.
Published: 2018
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111. Whole exome sequencing study identifies novel rare and common Alzheimer’s-Associated variants involved in immune response and transcriptional regulation

Author: Bis, J.C. (Joshua), Jian, X. (Xueqiu), Kunkle, B.W. (Brian W.), Chen, Y. (Yuning), Hamilton-Nelson, K.L. (Kara L.), Bush, W.S. (William S.), Salerno, W.J. (William J.), Lancour, D. (Daniel), Ma, Y. (Yiyi), Renton, A. (Alan), Marcora, E. (Edoardo), Farrell, J.J. (John J.), Zhao, Y. (Yi), Qu, L. (Liming), Ahmad, S. (Shahzad), Amin, N. (Najaf), Amouyel, P. (Philippe), Beecham, G.W., Below, J.E. (Jennifer E.), Campion, D. (Dominique), Charbonnier, C. (Camille), Chung, J. (Jaeyoon), Crane, L.M.A., Cruchaga, C. (Carlos), Cupples, L.A. (L. Adrienne), Dartigues, J.-F., Debette, S. (Stéphanie), Deleuze, J.-F. (Jean-François), Fulton, L. (Lucinda), Gabriel, S.B. (Stacey), Genin, E. (Emmanuelle), Gibbs, R.A. (Richard A.), Goate, A.M. (Alison), Grenier-Boley, B. (Benjamin), Gupta, N. (Namrata), Haines, J.L. (Jonathan), Havulinna, A.S. (Aki), Helisalmi, S. (Seppo), Hiltunen, M. (Mikko), Howrigan, D.P. (Daniel P.), Ikram, M.A. (Arfan), Kaprio, J. (Jaakko), Konrad, J. (Jan), Kuzma, A. (Amanda), Lander, E.S. (Eric), Lathrop, M. (Mark), Lehtimäki, T. (Terho), Lin, H. (Honghuang), Mattila, K. (Kari), Mayeux, R. (Richard), Muzny, D. (Donna), Nasser, W. (Waleed), Neale, B.M. (Benjamin), Nho, K. (Kwangsik), Nicolas, G. (Gaël), Patel, D. (Devanshi), Pericak-Vance, M.A. (Margaret), Perola, M. (Markus), Psaty, B.M. (Bruce M.), Quenez, O. (Olivier), Rajabli, F. (Farid), Redon, R. (Richard), Reitz, C. (Christiane), Remes, A. (Anne), Salomaa, V. (Veikko), Sarnowski, C., Schmidt, H. (Helena), Schmidt, M. (Michael), Schmidt, R. (Reinhold), Soininen, H. (H.), Thornton, T.A. (Timothy A.), Tosto, G. (G.), Tzourio, C. (Christophe), Lee, S.J. (Sven) van der, Duijn, C.M. (Cornelia) van, Vardarajan, B.N. (Badri), Wang, W. (Weixin), Wijsman, E.M. (Ellen), Wilson, R.K. (Richard K.), Witten, D. (Daniela), Worley, K.C. (Kim C.), Zhang, X. (Xiaoling), Bellenguez, C. (Céline), Lambert, J.-C. (J.), Kurki, M.I. (Mitja I.), Palotie, A. (Aarno), Daly, M. (Mark), Boerwinkle, E. (Eric), Lunetta, K.L. (Kathryn), DeStefano, A.L. (Anita), Dupuis, J. (Josée), Martin, E.R. (Eden R.), Schellenberg, G.D. (Gerard), Seshadri, S. (Sudha), Naj, A.C. (Adam C.), Fornage, M. (Myriam), Farrer, L.A. (Lindsay), Bis, J.C. (Joshua), Jian, X. (Xueqiu), Kunkle, B.W. (Brian W.), Chen, Y. (Yuning), Hamilton-Nelson, K.L. (Kara L.), Bush, W.S. (William S.), Salerno, W.J. (William J.), Lancour, D. (Daniel), Ma, Y. (Yiyi), Renton, A. (Alan), Marcora, E. (Edoardo), Farrell, J.J. (John J.), Zhao, Y. (Yi), Qu, L. (Liming), Ahmad, S. (Shahzad), Amin, N. (Najaf), Amouyel, P. (Philippe), Beecham, G.W., Below, J.E. (Jennifer E.), Campion, D. (Dominique), Charbonnier, C. (Camille), Chung, J. (Jaeyoon), Crane, L.M.A., Cruchaga, C. (Carlos), Cupples, L.A. (L. Adrienne), Dartigues, J.-F., Debette, S. (Stéphanie), Deleuze, J.-F. (Jean-François), Fulton, L. (Lucinda), Gabriel, S.B. (Stacey), Genin, E. (Emmanuelle), Gibbs, R.A. (Richard A.), Goate, A.M. (Alison), Grenier-Boley, B. (Benjamin), Gupta, N. (Namrata), Haines, J.L. (Jonathan), Havulinna, A.S. (Aki), Helisalmi, S. (Seppo), Hiltunen, M. (Mikko), Howrigan, D.P. (Daniel P.), Ikram, M.A. (Arfan), Kaprio, J. (Jaakko), Konrad, J. (Jan), Kuzma, A. (Amanda), Lander, E.S. (Eric), Lathrop, M. (Mark), Lehtimäki, T. (Terho), Lin, H. (Honghuang), Mattila, K. (Kari), Mayeux, R. (Richard), Muzny, D. (Donna), Nasser, W. (Waleed), Neale, B.M. (Benjamin), Nho, K. (Kwangsik), Nicolas, G. (Gaël), Patel, D. (Devanshi), Pericak-Vance, M.A. (Margaret), Perola, M. (Markus), Psaty, B.M. (Bruce M.), Quenez, O. (Olivier), Rajabli, F. (Farid), Redon, R. (Richard), Reitz, C. (Christiane), Remes, A. (Anne), Salomaa, V. (Veikko), Sarnowski, C., Schmidt, H. (Helena), Schmidt, M. (Michael), Schmidt, R. (Reinhold), Soininen, H. (H.), Thornton, T.A. (Timothy A.), Tosto, G. (G.), Tzourio, C. (Christophe), Lee, S.J. (Sven) van der, Duijn, C.M. (Cornelia) van, Vardarajan, B.N. (Badri), Wang, W. (Weixin), Wijsman, E.M. (Ellen), Wilson, R.K. (Richard K.), Witten, D. (Daniela), Worley, K.C. (Kim C.), Zhang, X. (Xiaoling), Bellenguez, C. (Céline), Lambert, J.-C. (J.), Kurki, M.I. (Mitja I.), Palotie, A. (Aarno), Daly, M. (Mark), Boerwinkle, E. (Eric), Lunetta, K.L. (Kathryn), DeStefano, A.L. (Anita), Dupuis, J. (Josée), Martin, E.R. (Eden R.), Schellenberg, G.D. (Gerard), Seshadri, S. (Sudha), Naj, A.C. (Adam C.), Fornage, M. (Myriam), and Farrer, L.A. (Lindsay)
Abstract: The Alzheimer’s Disease Sequencing Project (ADSP) undertook whole exome sequencing in 5,740 late-onset Alzheimer disease (AD) cases and 5,096 cognitively normal controls primarily of European ancestry (EA), among whom 218 cases and 177 controls were Caribbean Hispanic (CH). An age-, sex- and APOE based risk score and family history were used to select cases most likely to harbor novel AD risk variants and controls least likely to develop AD by age 85 years. We tested ~1.5 million single nucleotide variants (SNVs) and 50,000 insertion-deletion polymorphisms (indels) for association to AD, using multiple models considering individual variants as well as gene-based tests aggregating rare, predicted functional, and loss of function variants. Sixteen single variants and 19 genes that met criteria for significant or suggestive associations after multiple-testing correction were evaluated for replication in four independent samples; three with whole exome sequencing (2,778 cases, 7,262 contro
Published: 2018
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112. Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function

Author: Davies, G. (Gail), Lam, M. (Max), Harris, S.E. (Sarah), Trampush, J.W. (Joey W.), Luciano, M. (Michelle), Hill, W.D. (W. David), Hagenaars, S. (Saskia), Ritchie, S.J. (Stuart J.), Marioni, R.E. (Riccardo), Fawns-Ritchie, C., Liewald, D.C.M. (David C. M.), Okely, J.A. (Judith A.), Ahola-Olli, A.V. (Ari V.), Barnes, C.L.K. (Catriona L. K.), Bertram, L. (Lars), Bis, J.C. (Joshua), Burdick, K.E. (Katherine E.), Christoforou, A. (Andrea), Derosse, P. (Pamela), Djurovic, S. (Srdjan), Espeseth, T. (Thomas), Giakoumaki, S. (Stella), Giddaluru, S. (Sudheer), Gustavson, D.E. (Daniel E.), Hayward, C. (Caroline), Hofer, E. (Edith), Ikram, M.A. (Arfan), Karlsson, R. (Robert), Knowles, E. (Emma), Lahti, J. (Jari), Leber, I. (Isabelle), Li, S. (Shuo), Mather, R., Melle, I. (Ingrid), Morris, D. (Derek), Oldmeadow, C. (Christopher), Palviainen, T. (Teemu), Payton, A. (Antony), Pazoki, R. (Raha), Petrovic, K. (Katja), Reynolds, C.A. (C.), Sargurupremraj, M. (Muralidharan), Scholz, M. (Markus), Smith, J.A. (Jennifer A), Smith, A.V. (Albert), Terzikhan, N. (Natalie), Thalamuthu, A. (Anbupalam), Trompet, S. (Stella), Lee, S.J. (Sven) van der, Ware, E.B. (Erin B.), Windham, B.G. (Gwen), Wright, M.J. (Margaret J.), Yang, J. (Jingyun), Yu, J. (Jin), Ames, D.J. (David), Amin, N. (Najaf), Amouyel, P. (Philippe), Andreassen, O.A. (Ole), Armstrong, N.J. (Nicola J.), Assareh, A.A., Attia, J. (John), Attix, D. (Deborah), Avramopoulos, D. (Dimitrios), Bennett, D.A. (David), Böhmer, M.R. (Marcel), Boyle, P.A. (Patricia A.), Brodaty, H. (Henry), Campbell, H. (Harry), Cannon, T.D. (Tyrone D.), Cirulli, E.T. (Elizabeth T.), Congdon, E. (Eliza), Conley, E.D. (Emily Drabant), Corley, J. (Janie), Cox, S.R. (Simon R.), Dale, A.M. (Anders), Dehghan, A. (Abbas), Dick, D. (Danielle), Dickinson, D. (Dwight), Hagen, K. (Knut), Evangelou, E. (Evangelos), Faul, J.D. (Jessica D.), Ford, I. (Ian), Freimer, N.A. (Nelson A.), Gao, H. (He), Giegling, I. (Ina), Gillespie, N.A. (Nathan A.), Gordon, S.D. (Scott D.), Gottesman, R.F. (Rebecca), Griswold, M.D. (Michael), Gudnason, V. (Vilmundur), Harris, T.B. (Tamara), Hartmann, A.M. (Annette M), Hatzimanolis, A. (Alex), Heiss, G. (Gerardo), Holliday, E.G. (Elizabeth), Joshi, P.K. (Peter), Kähönen, M. (Mika), Kardia, S.L.R. (Sharon L. R.), Karlsson, I. (Ida), Kleineidam, L. (Luca), Knopman, D.S. (David), Kochan, N.A. (Nicole A.), Konte, B. (Bettina), Kwok, J.B.J. (John), Le Hellard, S. (Stephanie), Lee, T. (Teresa), Lehtimäki, T. (Terho), Li, S.-C. (Shu-Chen), Liu, T. (Tian), Koini, M. (Marisa), London, E. (Edythe), Longstreth Jr, W.T., Lopez, O.L. (Oscar), Loukola, A. (Anu), Luck, T. (Tobias), Lundervold, A.J. (Astri), Lundquist, A. (Anders), Lyytikäinen, L.-P. (Leo-Pekka), Martin, N.G. (Nicholas), Montgomery, G.W. (Grant W.), Murray, A.D. (Alison D.), Need, A.C. (Anna C.), Noordam, R. (Raymond), Nyberg, L. (Lisa), Ollier, W.E.R. (William), Papenberg, G., Pattie, A. (Alison), Polasek, O. (Ozren), Poldrack, R.A. (Russell A.), Psaty, B.M. (Bruce M.), Reppermund, S., Riedel-Heller, S. (Steffi), Rose, R.J. (Richard), Rotter, J.I. (Jerome I.), Roussos, A. (Alexandra), Rovio, S.P. (Suvi P.), Saba, Y. (Yasaman), Sabb, F.W. (Fred W.), Sachdev, P.S. (Perminder), Satizabal, C.L. (Claudia), Schmid, M. (Matthias), Scott, R.J. (Rodney J.), Scult, M.A. (Matthew A.), Simino, J. (Jeannette), Slagboom, P.E. (Eline), Smyrnis, N. (Nikolaos), Soumaré, A. (Aicha), Stefanis, N.C. (Nikos C.), Stott, D.J. (David. J.), Straub, R.E. (Richard), Sundet, K. (Kjetil), Taylor, A.M. (Adele M.), Taylor, K.D. (Kent), Tzoulaki, I., Tzourio, C. (Christophe), Uitterlinden, A.G. (André), Vitart, V. (Veronique), Voineskos, A.N. (Aristotle N.), Kaprio, J. (Jaakko), Wagner, M. (Michael), Wagner, H. (Hermann), Weinhold, L. (Leonie), Wen, K.H. (K. Hoyan), Widen, E., Yang, Q. (Qiong Fang), Zhao, W. (Wei), Adams, H.H.H. (Hieab), Arking, D.E. (Dan), Bilder, R.M. (Robert M.), Bitsios, P. (Panos), Boerwinkle, E. (Eric), Chiba-Falek, O. (Ornit), Corvin, A. (Aiden), Jager, P.L. (Philip) de, Debette, S. (Stéphanie), Donohoe, D.J. (Dennis), Elliott, P. (Paul), Fitzpatrick, A.L. (Annette), Gill, M. (Michael), Glahn, D.C. (David), Hägg, S. (Sara), Hansell, N.K. (Narelle), Hariri, A.R. (Ahmad), Ikram, M.K. (Kamran), Jukema, J.W. (Jan Wouter), Vuoksimaa, E. (Eero), Keller, M.C. (Matthew C), Kremen, W.S. (William S.), Launer, L.J. (Lenore), Lindenberger, U. (Ulman), Palotie, A. (Aarno), Pedersen, N.L. (Nancy), Pendleton, N. (Neil), Porteous, D.J. (David J.), Räikkönen, K. (Katri), Raitakari, O.T. (Olli T.), Ramirez, A. (Alfredo), Reinvang, I. (Ivar), Rudan, I. (Igor), Rujescu, D. (Dan), Schmidt, R. (Reinhold), Schmidt, H. (Helena), Schofield, P.W. (Peter W.), Schofield, C.J. (Christopher), Starr, J.M. (John), Steen, V.M. (Vidar), Trollor, J., Turner, S.T. (Steven T.), Duijn, C.M. (Cornelia) van, Villringer, A. (Arno), Weinberger, D.R. (Daniel), Weir, D.R. (David R.), Wilson, J.F. (James F.), Malhotra, A.K. (Anil K), McIntosh, A.M. (Andrew), Gale, C.R. (Catharine R.), Seshadri, S. (Sudha), Mosley, T.H. (Thomas H.), Bressler, J. (Jan), Lencz, T. (Todd), Deary, I.J. (Ian), Davies, G. (Gail), Lam, M. (Max), Harris, S.E. (Sarah), Trampush, J.W. (Joey W.), Luciano, M. (Michelle), Hill, W.D. (W. David), Hagenaars, S. (Saskia), Ritchie, S.J. (Stuart J.), Marioni, R.E. (Riccardo), Fawns-Ritchie, C., Liewald, D.C.M. (David C. M.), Okely, J.A. (Judith A.), Ahola-Olli, A.V. (Ari V.), Barnes, C.L.K. (Catriona L. K.), Bertram, L. (Lars), Bis, J.C. (Joshua), Burdick, K.E. (Katherine E.), Christoforou, A. (Andrea), Derosse, P. (Pamela), Djurovic, S. (Srdjan), Espeseth, T. (Thomas), Giakoumaki, S. (Stella), Giddaluru, S. (Sudheer), Gustavson, D.E. (Daniel E.), Hayward, C. (Caroline), Hofer, E. (Edith), Ikram, M.A. (Arfan), Karlsson, R. (Robert), Knowles, E. (Emma), Lahti, J. (Jari), Leber, I. (Isabelle), Li, S. (Shuo), Mather, R., Melle, I. (Ingrid), Morris, D. (Derek), Oldmeadow, C. (Christopher), Palviainen, T. (Teemu), Payton, A. (Antony), Pazoki, R. (Raha), Petrovic, K. (Katja), Reynolds, C.A. (C.), Sargurupremraj, M. (Muralidharan), Scholz, M. (Markus), Smith, J.A. (Jennifer A), Smith, A.V. (Albert), Terzikhan, N. (Natalie), Thalamuthu, A. (Anbupalam), Trompet, S. (Stella), Lee, S.J. (Sven) van der, Ware, E.B. (Erin B.), Windham, B.G. (Gwen), Wright, M.J. (Margaret J.), Yang, J. (Jingyun), Yu, J. (Jin), Ames, D.J. (David), Amin, N. (Najaf), Amouyel, P. (Philippe), Andreassen, O.A. (Ole), Armstrong, N.J. (Nicola J.), Assareh, A.A., Attia, J. (John), Attix, D. (Deborah), Avramopoulos, D. (Dimitrios), Bennett, D.A. (David), Böhmer, M.R. (Marcel), Boyle, P.A. (Patricia A.), Brodaty, H. (Henry), Campbell, H. (Harry), Cannon, T.D. (Tyrone D.), Cirulli, E.T. (Elizabeth T.), Congdon, E. (Eliza), Conley, E.D. (Emily Drabant), Corley, J. (Janie), Cox, S.R. (Simon R.), Dale, A.M. (Anders), Dehghan, A. (Abbas), Dick, D. (Danielle), Dickinson, D. (Dwight), Hagen, K. (Knut), Evangelou, E. (Evangelos), Faul, J.D. (Jessica D.), Ford, I. (Ian), Freimer, N.A. (Nelson A.), Gao, H. (He), Giegling, I. (Ina), Gillespie, N.A. (Nathan A.), Gordon, S.D. (Scott D.), Gottesman, R.F. (Rebecca), Griswold, M.D. (Michael), Gudnason, V. (Vilmundur), Harris, T.B. (Tamara), Hartmann, A.M. (Annette M), Hatzimanolis, A. (Alex), Heiss, G. (Gerardo), Holliday, E.G. (Elizabeth), Joshi, P.K. (Peter), Kähönen, M. (Mika), Kardia, S.L.R. (Sharon L. R.), Karlsson, I. (Ida), Kleineidam, L. (Luca), Knopman, D.S. (David), Kochan, N.A. (Nicole A.), Konte, B. (Bettina), Kwok, J.B.J. (John), Le Hellard, S. (Stephanie), Lee, T. (Teresa), Lehtimäki, T. (Terho), Li, S.-C. (Shu-Chen), Liu, T. (Tian), Koini, M. (Marisa), London, E. (Edythe), Longstreth Jr, W.T., Lopez, O.L. (Oscar), Loukola, A. (Anu), Luck, T. (Tobias), Lundervold, A.J. (Astri), Lundquist, A. (Anders), Lyytikäinen, L.-P. (Leo-Pekka), Martin, N.G. (Nicholas), Montgomery, G.W. (Grant W.), Murray, A.D. (Alison D.), Need, A.C. (Anna C.), Noordam, R. (Raymond), Nyberg, L. (Lisa), Ollier, W.E.R. (William), Papenberg, G., Pattie, A. (Alison), Polasek, O. (Ozren), Poldrack, R.A. (Russell A.), Psaty, B.M. (Bruce M.), Reppermund, S., Riedel-Heller, S. (Steffi), Rose, R.J. (Richard), Rotter, J.I. (Jerome I.), Roussos, A. (Alexandra), Rovio, S.P. (Suvi P.), Saba, Y. (Yasaman), Sabb, F.W. (Fred W.), Sachdev, P.S. (Perminder), Satizabal, C.L. (Claudia), Schmid, M. (Matthias), Scott, R.J. (Rodney J.), Scult, M.A. (Matthew A.), Simino, J. (Jeannette), Slagboom, P.E. (Eline), Smyrnis, N. (Nikolaos), Soumaré, A. (Aicha), Stefanis, N.C. (Nikos C.), Stott, D.J. (David. J.), Straub, R.E. (Richard), Sundet, K. (Kjetil), Taylor, A.M. (Adele M.), Taylor, K.D. (Kent), Tzoulaki, I., Tzourio, C. (Christophe), Uitterlinden, A.G. (André), Vitart, V. (Veronique), Voineskos, A.N. (Aristotle N.), Kaprio, J. (Jaakko), Wagner, M. (Michael), Wagner, H. (Hermann), Weinhold, L. (Leonie), Wen, K.H. (K. Hoyan), Widen, E., Yang, Q. (Qiong Fang), Zhao, W. (Wei), Adams, H.H.H. (Hieab), Arking, D.E. (Dan), Bilder, R.M. (Robert M.), Bitsios, P. (Panos), Boerwinkle, E. (Eric), Chiba-Falek, O. (Ornit), Corvin, A. (Aiden), Jager, P.L. (Philip) de, Debette, S. (Stéphanie), Donohoe, D.J. (Dennis), Elliott, P. (Paul), Fitzpatrick, A.L. (Annette), Gill, M. (Michael), Glahn, D.C. (David), Hägg, S. (Sara), Hansell, N.K. (Narelle), Hariri, A.R. (Ahmad), Ikram, M.K. (Kamran), Jukema, J.W. (Jan Wouter), Vuoksimaa, E. (Eero), Keller, M.C. (Matthew C), Kremen, W.S. (William S.), Launer, L.J. (Lenore), Lindenberger, U. (Ulman), Palotie, A. (Aarno), Pedersen, N.L. (Nancy), Pendleton, N. (Neil), Porteous, D.J. (David J.), Räikkönen, K. (Katri), Raitakari, O.T. (Olli T.), Ramirez, A. (Alfredo), Reinvang, I. (Ivar), Rudan, I. (Igor), Rujescu, D. (Dan), Schmidt, R. (Reinhold), Schmidt, H. (Helena), Schofield, P.W. (Peter W.), Schofield, C.J. (Christopher), Starr, J.M. (John), Steen, V.M. (Vidar), Trollor, J., Turner, S.T. (Steven T.), Duijn, C.M. (Cornelia) van, Villringer, A. (Arno), Weinberger, D.R. (Daniel), Weir, D.R. (David R.), Wilson, J.F. (James F.), Malhotra, A.K. (Anil K), McIntosh, A.M. (Andrew), Gale, C.R. (Catharine R.), Seshadri, S. (Sudha), Mosley, T.H. (Thomas H.), Bressler, J. (Jan), Lencz, T. (Todd), and Deary, I.J. (Ian)
Abstract: General cognitive function is a prominent and relatively stable human trait that is associated with many important life outcomes. We combine cognitive and genetic data from the CHARGE and COGENT consortia, and UK Biobank (total N = 300,486; age 16-102) and find 148 genome-wide significant independent loci (P < 5 × 10-8) associated with general cognitive function. Within the novel genetic loci are variants associated with neurodegenerative and neurodevelopmental disorders, physical and psychiatric illnesses, and brain structure. Gene-based analyses find 709 genes associated with general cognitive function. Expression levels across the c
Published: 2018
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113. Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function

Author: Davies, G., Lam, M., Harris, S.E., Trampush, J.W., Luciano, M., Hill, W.D., Hagenaars, S.P., Ritchie, S.J., Marioni, R.E., Fawns-Ritchie, C., Liewald, D.C.M., Okely, J.A., Ahola-Olli, A.V., Barnes, C.L.K., Bertram, L., Bis, J.C., Burdick, K.E., Christoforou, A., DeRosse, P., Djurovic, S., Espeseth, T., Giakoumaki, S., Giddaluru, S., Gustavson, D.E., Hayward, C., Hofer, E., Ikram, M.A., Karlsson, R., Knowles, E., Lahti, J., Leber, M., Li, S., Mather, K.A., Melle, I., Morris, D., Oldmeadow, C., Palviainen, T., Payton, A., Pazoki, R., Petrovic, K., Reynolds, C.A., Sargurupremraj, M., Scholz, M., Smith, J.A., Smith, A.V., Terzikhan, N., Thalamuthu, A., Trompet, S., van der Lee, S.J., Ware, E.B., Windham, B.G., Wright, M.J., Yang, J., Yu, J., Ames, D., Amin, N., Amouyel, P., Andreassen, O.A., Armstrong, N.J., Assareh, A.A., Attia, J.R., Attix, D., Avramopoulos, D., Bennett, D.A., Böhmer, A.C., Boyle, P.A., Brodaty, H., Campbell, H., Cannon, T.D., Cirulli, E.T., Congdon, E., Conley, E.D., Corley, J., Cox, S.R., Dale, A.M., Dehghan, A., Dick, D., Dickinson, D., Eriksson, J.G., Evangelou, E., Faul, J.D., Ford, I., Freimer, N.A., Gao, H., Giegling, I., Gillespie, N.A., Gordon, S.D., Gottesman, R.F., Griswold, M.E., Gudnason, V., Harris, T.B., Hartmann, A.M., Hatzimanolis, A., Heiss, G., Holliday, E.G., Joshi, P.K., Kähönen, M., Kardia, S.L.R., Karlsson, I., Kleineidam, L., Knopman, D.S., Kochan, N.A., Konte, B., Kwok, J.B., Le Hellard, S., Lee, T., Lehtimäki, T., Li, S-C, Liu, T., Koini, M., London, E., Longstreth, W.T., Lopez, O.L., Loukola, A., Luck, T., Lundervold, A.J., Lundquist, A., Lyytikäinen, L-P, Martin, N.G., Montgomery, G.W., Murray, A.D., Need, A.C., Noordam, R., Nyberg, L., Ollier, W., Papenberg, G., Pattie, A., Polasek, O., Poldrack, R.A., Psaty, B.M., Reppermund, S., Riedel-Heller, S.G., Rose, R.J., Rotter, J.I., Roussos, P., Rovio, S.P., Saba, Y., Sabb, F.W., Sachdev, P.S., Satizabal, C.L., Schmid, M., Scott, R.J., Scult, M.A., Simino, J., Slagboom, P.E., Smyrnis, N., Soumaré, A., Stefanis, N.C., Stott, D.J., Straub, R.E., Sundet, K., Taylor, A.M., Taylor, K.D., Tzoulaki, I., Tzourio, C., Uitterlinden, A., Vitart, V., Voineskos, A.N., Kaprio, J., Wagner, M., Wagner, H., Weinhold, L., Wen, K.H., Widen, E., Yang, Q., Zhao, W., Adams, H.H.H., Arking, D.E., Bilder, R.M., Bitsios, P., Boerwinkle, E., Chiba-Falek, O., Corvin, A., De Jager, P.L., Debette, S., Donohoe, G., Elliott, P., Fitzpatrick, A.L., Gill, M., Glahn, D.C., Hägg, S., Hansell, N.K., Hariri, A.R., Ikram, M.K., Jukema, J.W., Vuoksimaa, E., Keller, M.C., Kremen, W.S., Launer, L., Lindenberger, U., Palotie, A., Pedersen, N.L., Pendleton, N., Porteous, D.J., Räikkönen, K., Raitakari, O.T., Ramirez, A., Reinvang, I., Rudan, I., Rujescu, D., Schmidt, R., Schmidt, H., Schofield, P.W., Schofield, P.R., Starr, J.M., Steen, V.M., Trollor, J.N., Turner, S.T., van Duijn, C.M., Villringer, Arno, Weinberger, D.R., Weir, D.R., Wilson, J.F., Malhotra, A., McIntosh, A.M., Gale, C.R., Seshadri, S., Mosley, T.H., Bressler, J., Lencz, T., Deary, I.J., Davies, G., Lam, M., Harris, S.E., Trampush, J.W., Luciano, M., Hill, W.D., Hagenaars, S.P., Ritchie, S.J., Marioni, R.E., Fawns-Ritchie, C., Liewald, D.C.M., Okely, J.A., Ahola-Olli, A.V., Barnes, C.L.K., Bertram, L., Bis, J.C., Burdick, K.E., Christoforou, A., DeRosse, P., Djurovic, S., Espeseth, T., Giakoumaki, S., Giddaluru, S., Gustavson, D.E., Hayward, C., Hofer, E., Ikram, M.A., Karlsson, R., Knowles, E., Lahti, J., Leber, M., Li, S., Mather, K.A., Melle, I., Morris, D., Oldmeadow, C., Palviainen, T., Payton, A., Pazoki, R., Petrovic, K., Reynolds, C.A., Sargurupremraj, M., Scholz, M., Smith, J.A., Smith, A.V., Terzikhan, N., Thalamuthu, A., Trompet, S., van der Lee, S.J., Ware, E.B., Windham, B.G., Wright, M.J., Yang, J., Yu, J., Ames, D., Amin, N., Amouyel, P., Andreassen, O.A., Armstrong, N.J., Assareh, A.A., Attia, J.R., Attix, D., Avramopoulos, D., Bennett, D.A., Böhmer, A.C., Boyle, P.A., Brodaty, H., Campbell, H., Cannon, T.D., Cirulli, E.T., Congdon, E., Conley, E.D., Corley, J., Cox, S.R., Dale, A.M., Dehghan, A., Dick, D., Dickinson, D., Eriksson, J.G., Evangelou, E., Faul, J.D., Ford, I., Freimer, N.A., Gao, H., Giegling, I., Gillespie, N.A., Gordon, S.D., Gottesman, R.F., Griswold, M.E., Gudnason, V., Harris, T.B., Hartmann, A.M., Hatzimanolis, A., Heiss, G., Holliday, E.G., Joshi, P.K., Kähönen, M., Kardia, S.L.R., Karlsson, I., Kleineidam, L., Knopman, D.S., Kochan, N.A., Konte, B., Kwok, J.B., Le Hellard, S., Lee, T., Lehtimäki, T., Li, S-C, Liu, T., Koini, M., London, E., Longstreth, W.T., Lopez, O.L., Loukola, A., Luck, T., Lundervold, A.J., Lundquist, A., Lyytikäinen, L-P, Martin, N.G., Montgomery, G.W., Murray, A.D., Need, A.C., Noordam, R., Nyberg, L., Ollier, W., Papenberg, G., Pattie, A., Polasek, O., Poldrack, R.A., Psaty, B.M., Reppermund, S., Riedel-Heller, S.G., Rose, R.J., Rotter, J.I., Roussos, P., Rovio, S.P., Saba, Y., Sabb, F.W., Sachdev, P.S., Satizabal, C.L., Schmid, M., Scott, R.J., Scult, M.A., Simino, J., Slagboom, P.E., Smyrnis, N., Soumaré, A., Stefanis, N.C., Stott, D.J., Straub, R.E., Sundet, K., Taylor, A.M., Taylor, K.D., Tzoulaki, I., Tzourio, C., Uitterlinden, A., Vitart, V., Voineskos, A.N., Kaprio, J., Wagner, M., Wagner, H., Weinhold, L., Wen, K.H., Widen, E., Yang, Q., Zhao, W., Adams, H.H.H., Arking, D.E., Bilder, R.M., Bitsios, P., Boerwinkle, E., Chiba-Falek, O., Corvin, A., De Jager, P.L., Debette, S., Donohoe, G., Elliott, P., Fitzpatrick, A.L., Gill, M., Glahn, D.C., Hägg, S., Hansell, N.K., Hariri, A.R., Ikram, M.K., Jukema, J.W., Vuoksimaa, E., Keller, M.C., Kremen, W.S., Launer, L., Lindenberger, U., Palotie, A., Pedersen, N.L., Pendleton, N., Porteous, D.J., Räikkönen, K., Raitakari, O.T., Ramirez, A., Reinvang, I., Rudan, I., Rujescu, D., Schmidt, R., Schmidt, H., Schofield, P.W., Schofield, P.R., Starr, J.M., Steen, V.M., Trollor, J.N., Turner, S.T., van Duijn, C.M., Villringer, Arno, Weinberger, D.R., Weir, D.R., Wilson, J.F., Malhotra, A., McIntosh, A.M., Gale, C.R., Seshadri, S., Mosley, T.H., Bressler, J., Lencz, T., and Deary, I.J.
Abstract: General cognitive function is a prominent and relatively stable human trait that is associated with many important life outcomes. We combine cognitive and genetic data from the CHARGE and COGENT consortia, and UK Biobank (total N = 300,486; age 16–102) and find 148 genome-wide significant independent loci (P < 5 × 10−8) associated with general cognitive function. Within the novel genetic loci are variants associated with neurodegenerative and neurodevelopmental disorders, physical and psychiatric illnesses, and brain structure. Gene-based analyses find 709 genes associated with general cognitive function. Expression levels across the cortex are associated with general cognitive function. Using polygenic scores, up to 4.3% of variance in general cognitive function is predicted in independent samples. We detect significant genetic overlap between general cognitive function, reaction time, and many health variables including eyesight, hypertension, and longevity. In conclusion we identify novel genetic loci and pathways contributing to the heritability of general cognitive function.
Published: 2018

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

Author: 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, Pitkanen, N, Franzen, 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, Voelzke, 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, Doer, 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, Hagg, S, Shah, S, McLachlan, S, Trompet, S, Seshadri, S, Kurl, S, Heckbert, SR, Ring, S, Harris, TB, Lehtimaki, 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, Lyytikainen, L-P, Loeffler, M, Evans, MK, Debette, S, Humphries, SE, Voelker, U, Gudnason, V, Hingorani, AD, Bjorkegren, JLM, Casas, JP, O'Donnell, CJ, 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, Pitkanen, N, Franzen, 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, Voelzke, 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, Doer, 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, Hagg, S, Shah, S, McLachlan, S, Trompet, S, Seshadri, S, Kurl, S, Heckbert, SR, Ring, S, Harris, TB, Lehtimaki, 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, Lyytikainen, L-P, Loeffler, M, Evans, MK, Debette, S, Humphries, SE, Voelker, U, Gudnason, V, Hingorani, AD, Bjorkegren, JLM, Casas, JP, and O'Donnell, CJ
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.
Published: 2018

115. Genetics of the thrombomodulin-endothelial cell protein C receptor system and the risk of early-onset ischemic stroke

Author: Ko, S-B, Cole, JW, Xu, H, Ryan, K, Jaworek, T, Dueker, N, McArdle, P, Gaynor, B, Cheng, Y-C, O'Connell, J, Bevan, S, Malik, R, Ahmed, NU, Amouyel, P, Anjum, S, Bis, JC, Crosslin, D, Danesh, J, Engelter, ST, Fornage, M, Frossard, P, Gieger, C, Giese, A-K, Grond-Ginsbach, C, Ho, WK, Holliday, E, Hopewell, J, Hussain, M, Iqbal, W, Jabeen, S, Jannes, J, Kamal, A, Kamatani, Y, Kanse, S, Kloss, M, Lathrop, M, Leys, D, Lindgren, A, Longstreth, WT, Mahmood, K, Meisinger, C, Metso, TM, Mosley, T, Mueller-Nurasyid, M, Norrving, B, Parati, E, Peters, A, Pezzini, A, Quereshi, I, Rasheed, A, Rauf, A, Salam, T, Shen, J, Slowik, A, Stanne, T, Strauch, K, Tatlisumak, T, Thijs, VN, Tiedt, S, Traylor, M, Waldenberger, M, Walters, M, Zhao, W, Boncoraglio, G, Debette, S, Jern, C, Levi, C, Markus, H, Meschia, J, Rolfs, A, Rothwell, P, Saleheen, D, Seshadri, S, Sharma, P, Sudlow, C, Worrall, B, Stine, OC, Kittner, SJ, Mitchell, BD, Ko, S-B, Cole, JW, Xu, H, Ryan, K, Jaworek, T, Dueker, N, McArdle, P, Gaynor, B, Cheng, Y-C, O'Connell, J, Bevan, S, Malik, R, Ahmed, NU, Amouyel, P, Anjum, S, Bis, JC, Crosslin, D, Danesh, J, Engelter, ST, Fornage, M, Frossard, P, Gieger, C, Giese, A-K, Grond-Ginsbach, C, Ho, WK, Holliday, E, Hopewell, J, Hussain, M, Iqbal, W, Jabeen, S, Jannes, J, Kamal, A, Kamatani, Y, Kanse, S, Kloss, M, Lathrop, M, Leys, D, Lindgren, A, Longstreth, WT, Mahmood, K, Meisinger, C, Metso, TM, Mosley, T, Mueller-Nurasyid, M, Norrving, B, Parati, E, Peters, A, Pezzini, A, Quereshi, I, Rasheed, A, Rauf, A, Salam, T, Shen, J, Slowik, A, Stanne, T, Strauch, K, Tatlisumak, T, Thijs, VN, Tiedt, S, Traylor, M, Waldenberger, M, Walters, M, Zhao, W, Boncoraglio, G, Debette, S, Jern, C, Levi, C, Markus, H, Meschia, J, Rolfs, A, Rothwell, P, Saleheen, D, Seshadri, S, Sharma, P, Sudlow, C, Worrall, B, Stine, OC, Kittner, SJ, and Mitchell, BD
Abstract: BACKGROUND AND PURPOSE: Polymorphisms in coagulation genes have been associated with early-onset ischemic stroke. Here we pursue an a priori hypothesis that genetic variation in the endothelial-based receptors of the thrombomodulin-protein C system (THBD and PROCR) may similarly be associated with early-onset ischemic stroke. We explored this hypothesis utilizing a multi-stage design of discovery and replication. METHODS: Discovery was performed in the Genetics-of-Early-Onset Stroke (GEOS) Study, a biracial population-based case-control study of ischemic stroke among men and women aged 15-49 including 829 cases of first ischemic stroke (42.2% African-American) and 850 age-comparable stroke-free controls (38.1% African-American). Twenty-four single-nucleotide-polymorphisms (SNPs) in THBD and 22 SNPs in PROCR were evaluated. Following LD pruning (r2≥0.8), we advanced uncorrelated SNPs forward for association analyses. Associated SNPs were evaluated for replication in an early-onset ischemic stroke population (onset-age<60 years) consisting of 3676 cases and 21118 non-stroke controls from 6 case-control studies. Lastly, we determined if the replicated SNPs also associated with older-onset ischemic stroke in the METASTROKE data-base. RESULTS: Among GEOS Caucasians, PROCR rs9574, which was in strong LD with 8 other SNPs, and one additional independent SNP rs2069951, were significantly associated with ischemic stroke (rs9574, OR = 1.33, p = 0.003; rs2069951, OR = 1.80, p = 0.006) using an additive-model adjusting for age, gender and population-structure. Adjusting for risk factors did not change the associations; however, associations were strengthened among those without risk factors. PROCR rs9574 also associated with early-onset ischemic stroke in the replication sample (OR = 1.08, p = 0.015), but not older-onset stroke. There were no PROCR associations in African-Americans, nor were there any THBD associations in either ethnicity. CONCLUSION: PROCR polymorphisms are as
Published: 2018

116. Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function

Author: Davies, G, Lam, M, Harris, SE, Trampush, JW, Luciano, M, Hill, WD, Hagenaars, SP, Ritchie, SJ, Marioni, RE, Fawns-Ritchie, C, Liewald, DCM, Okely, JA, Ahola-Olli, AV, Barnes, CLK, Bertram, L, Bis, JC, Burdick, KE, Christoforou, A, DeRosse, P, Djurovic, S, Espeseth, T, Giakoumaki, S, Giddaluru, S, Gustavson, DE, Hayward, C, Hofer, E, Ikram, MA, Karlsson, R, Knowles, E, Lahti, J, Leber, M, Li, S, Mather, KA, Melle, I, Morris, D, Oldmeadow, C, Palviainen, T, Payton, A, Pazoki, R, Petrovic, K, Reynolds, CA, Sargurupremraj, M, Scholz, M, Smith, JA, Smith, AV, Terzikhan, N, Thalamuthu, A, Trompet, S, van der Lee, SJ, Ware, EB, Windham, BG, Wright, MJ, Yang, J, Yu, J, Ames, D, Amin, N, Amouyel, P, Andreassen, OA, Armstrong, NJ, Assareh, AA, Attia, JR, Attix, D, Avramopoulos, D, Bennett, DA, Boehmer, AC, Boyle, PA, Brodaty, H, Campbell, H, Cannon, TD, Cirulli, ET, Congdon, E, Conley, ED, Corley, J, Cox, SR, Dale, AM, Dehghan, A, Dick, D, Dickinson, D, Eriksson, JG, Evangelou, E, Faul, JD, Ford, I, Freimer, NA, Gao, H, Giegling, I, Gillespie, NA, Gordon, SD, Gottesman, RF, Griswold, ME, Gudnason, V, Harris, TB, Hartmann, AM, Hatzimanolis, A, Heiss, G, Holliday, EG, Joshi, PK, Kahonen, M, Kardia, SLR, Karlsson, I, Kleineidam, L, Knopman, DS, Kochan, NA, Konte, B, Kwok, JB, Le Hellard, S, Lee, T, Lehtimaki, T, Li, S-C, Liu, T, Koini, M, London, E, Longstreth, WT, Lopez, OL, Loukola, A, Luck, T, Lundervold, AJ, Lundquist, A, Lyytikainen, L-P, Martin, NG, Montgomery, GW, Murray, AD, Need, AC, Noordam, R, Nyberg, L, Ollier, W, Papenberg, G, Pattie, A, Polasek, O, Poldrack, RA, Psaty, BM, Reppermund, S, Riedel-Heller, SG, Rose, RJ, Rotter, JI, Roussos, P, Rovio, SP, Saba, Y, Sabb, FW, Sachdev, PS, Satizabal, CL, Schmid, M, Scott, RJ, Scult, MA, Simino, J, Slagboom, PE, Smyrnis, N, Soumare, A, Stefanis, NC, Stott, DJ, Straub, RE, Sundet, K, Taylor, AM, Taylor, KD, Tzoulaki, I, Tzourio, C, Uitterlinden, A, Vitart, V, Voineskos, AN, Kaprio, J, Wagner, M, Wagner, H, Weinhold, L, Wen, KH, Widen, E, Yang, Q, Zhao, W, Adams, HHH, Arking, DE, Bilder, RM, Bitsios, P, Boerwinkle, E, Chiba-Falek, O, Corvin, A, De Jager, PL, Debette, S, Donohoe, G, Elliott, P, Fitzpatrick, AL, Gill, M, Glahn, DC, Hagg, S, Hansell, NK, Hariri, AR, Ikram, MK, Jukema, JW, Vuoksimaa, E, Keller, MC, Kremen, WS, Launer, L, Lindenberger, U, Palotie, A, Pedersen, NL, Pendleton, N, Porteous, DJ, Raikkonen, K, Raitakari, OT, Ramirez, A, Reinvang, I, Rudan, I, Rujescu, D, Schmidt, R, Schmidt, H, Schofield, PW, Schofield, PR, Starr, JM, Steen, VM, Trollor, JN, Turner, ST, Van Duijn, CM, Villringer, A, Weinberger, DR, Weir, DR, Wilson, JF, Malhotra, A, McIntosh, AM, Gale, CR, Seshadri, S, Mosley, TH, Bressler, J, Lencz, T, Deary, IJ, Davies, G, Lam, M, Harris, SE, Trampush, JW, Luciano, M, Hill, WD, Hagenaars, SP, Ritchie, SJ, Marioni, RE, Fawns-Ritchie, C, Liewald, DCM, Okely, JA, Ahola-Olli, AV, Barnes, CLK, Bertram, L, Bis, JC, Burdick, KE, Christoforou, A, DeRosse, P, Djurovic, S, Espeseth, T, Giakoumaki, S, Giddaluru, S, Gustavson, DE, Hayward, C, Hofer, E, Ikram, MA, Karlsson, R, Knowles, E, Lahti, J, Leber, M, Li, S, Mather, KA, Melle, I, Morris, D, Oldmeadow, C, Palviainen, T, Payton, A, Pazoki, R, Petrovic, K, Reynolds, CA, Sargurupremraj, M, Scholz, M, Smith, JA, Smith, AV, Terzikhan, N, Thalamuthu, A, Trompet, S, van der Lee, SJ, Ware, EB, Windham, BG, Wright, MJ, Yang, J, Yu, J, Ames, D, Amin, N, Amouyel, P, Andreassen, OA, Armstrong, NJ, Assareh, AA, Attia, JR, Attix, D, Avramopoulos, D, Bennett, DA, Boehmer, AC, Boyle, PA, Brodaty, H, Campbell, H, Cannon, TD, Cirulli, ET, Congdon, E, Conley, ED, Corley, J, Cox, SR, Dale, AM, Dehghan, A, Dick, D, Dickinson, D, Eriksson, JG, Evangelou, E, Faul, JD, Ford, I, Freimer, NA, Gao, H, Giegling, I, Gillespie, NA, Gordon, SD, Gottesman, RF, Griswold, ME, Gudnason, V, Harris, TB, Hartmann, AM, Hatzimanolis, A, Heiss, G, Holliday, EG, Joshi, PK, Kahonen, M, Kardia, SLR, Karlsson, I, Kleineidam, L, Knopman, DS, Kochan, NA, Konte, B, Kwok, JB, Le Hellard, S, Lee, T, Lehtimaki, T, Li, S-C, Liu, T, Koini, M, London, E, Longstreth, WT, Lopez, OL, Loukola, A, Luck, T, Lundervold, AJ, Lundquist, A, Lyytikainen, L-P, Martin, NG, Montgomery, GW, Murray, AD, Need, AC, Noordam, R, Nyberg, L, Ollier, W, Papenberg, G, Pattie, A, Polasek, O, Poldrack, RA, Psaty, BM, Reppermund, S, Riedel-Heller, SG, Rose, RJ, Rotter, JI, Roussos, P, Rovio, SP, Saba, Y, Sabb, FW, Sachdev, PS, Satizabal, CL, Schmid, M, Scott, RJ, Scult, MA, Simino, J, Slagboom, PE, Smyrnis, N, Soumare, A, Stefanis, NC, Stott, DJ, Straub, RE, Sundet, K, Taylor, AM, Taylor, KD, Tzoulaki, I, Tzourio, C, Uitterlinden, A, Vitart, V, Voineskos, AN, Kaprio, J, Wagner, M, Wagner, H, Weinhold, L, Wen, KH, Widen, E, Yang, Q, Zhao, W, Adams, HHH, Arking, DE, Bilder, RM, Bitsios, P, Boerwinkle, E, Chiba-Falek, O, Corvin, A, De Jager, PL, Debette, S, Donohoe, G, Elliott, P, Fitzpatrick, AL, Gill, M, Glahn, DC, Hagg, S, Hansell, NK, Hariri, AR, Ikram, MK, Jukema, JW, Vuoksimaa, E, Keller, MC, Kremen, WS, Launer, L, Lindenberger, U, Palotie, A, Pedersen, NL, Pendleton, N, Porteous, DJ, Raikkonen, K, Raitakari, OT, Ramirez, A, Reinvang, I, Rudan, I, Rujescu, D, Schmidt, R, Schmidt, H, Schofield, PW, Schofield, PR, Starr, JM, Steen, VM, Trollor, JN, Turner, ST, Van Duijn, CM, Villringer, A, Weinberger, DR, Weir, DR, Wilson, JF, Malhotra, A, McIntosh, AM, Gale, CR, Seshadri, S, Mosley, TH, Bressler, J, Lencz, T, and Deary, IJ
Abstract: General cognitive function is a prominent and relatively stable human trait that is associated with many important life outcomes. We combine cognitive and genetic data from the CHARGE and COGENT consortia, and UK Biobank (total N = 300,486; age 16-102) and find 148 genome-wide significant independent loci (P < 5 × 10-8) associated with general cognitive function. Within the novel genetic loci are variants associated with neurodegenerative and neurodevelopmental disorders, physical and psychiatric illnesses, and brain structure. Gene-based analyses find 709 genes associated with general cognitive function. Expression levels across the cortex are associated with general cognitive function. Using polygenic scores, up to 4.3% of variance in general cognitive function is predicted in independent samples. We detect significant genetic overlap between general cognitive function, reaction time, and many health variables including eyesight, hypertension, and longevity. In conclusion we identify novel genetic loci and pathways contributing to the heritability of general cognitive function.
Published: 2018

117. Atrial fibrillation genetic risk differentiates cardioembolic stroke from other stroke subtypes

Author: Pulit, SL, Weng, L-C, McArdle, PF, Trinquart, L, Choi, SH, Mitchell, BD, Rosand, J, de Bakker, PIW, Benjamin, EJ, Ellinor, PT, Kittner, SJ, Lubitz, SA, Anderson, CD, Christophersen, IE, Rienstra, M, Roselli, C, Yin, X, Geelhoed, B, Barnard, J, Lin, H, Arking, DE, Smith, A, Albert, CM, Chaffin, M, Tucker, NR, Li, M, Klarin, D, Bihlmeyer, NA, Low, S-K, Weeke, PE, Mueller-Nurasyid, M, Smith, JG, Brody, JA, Niemeijer, MN, Doerr, M, Trompet, S, Huffman, J, Gustafsson, S, Schurmann, C, Kleber, ME, Lyytikainen, L-P, Seppala, I, Malik, R, Horimoto, ARVR, Perez, M, Sinisalo, J, Aeschbacher, S, Theriault, S, Yao, J, Radmanesh, F, Weiss, S, Teumer, A, Clauss, S, Deo, R, Rader, DJ, Shah, S, Sun, A, Hopewell, JC, Debette, S, Chauhan, G, Yang, Q, Worrall, BB, Pare, G, Kamatani, Y, Hagemeijer, YP, Verweij, N, Siland, JE, Kubo, M, Smith, JD, Van Wagoner, DR, Bis, JC, Perz, S, Psaty, BM, Ridker, PM, Magnani, JW, Harris, TB, Launer, LJ, Shoemaker, MB, Padmanabhan, S, Haessler, J, Bartz, TM, Waldenberger, M, Lichtner, P, Arendt, M, Krieger, JE, Kahonen, M, Risch, L, Mansur, AJ, Peters, A, Smith, BH, Lind, L, Scott, SA, Lu, Y, Bottinger, EB, Hernesniemi, J, Lindgren, CM, Wong, JA, Huang, J, Eskola, M, Morris, AP, Ford, I, Reiner, AP, Delgado, G, Chen, LY, Chen, Y-DI, Sandhu, RK, Boerwinkle, E, Eisele, L, Lannfelt, L, Rost, N, Taylor, KD, Campbell, A, Magnusson, PK, Porteous, D, Hocking, LJ, Vlachopoulou, E, Pedersen, NL, Nikus, K, Orho-Melander, M, Hamsten, A, Heeringa, J, Denny, JC, Kriebel, J, Darbar, D, Newton-Cheh, C, Shaffer, C, Macfarlane, PW, Heilmann, S, Almgren, P, Huang, PL, Sotoodehnia, N, Soliman, EZ, Uitterlinden, AG, Hofman, A, Franco, OH, Voelker, U, Joeckel, K-H, Sinner, MF, Lin, HJ, Guo, X, Dichgans, M, Ingelsson, E, Kooperberg, C, Melander, O, Loos, RJF, Laurikka, J, Conen, D, van der Harst, P, Lokki, M-L, Kathiresan, S, Pereira, A, Jukema, JW, Hayward, C, Rotter, J, Maerz, W, Lehtimaki, T, Stricker, BH, Chung, MK, Felix, SB, Gudnason, V, Alonso, A, Roden, DM, Kaeaeb, S, Chasman, D, Heckbert, SR, Tanaka, T, Lunetta, KL, Smoller, S, Sorkin, J, Wang, X, Selim, M, Pikula, A, Wolf, P, Seshadri, S, de Bakker, P, Rexrode, K, Chen, I, Luke, M, Sale, M, Lee, T-H, Chang, K-C, Elkind, M, Goldstein, L, James, ML, Breteler, M, O'Donnell, C, Leys, D, Carty, C, Kidwell, C, Olesen, J, Sharma, P, Rich, S, Tatlisumak, T, Happola, O, Bijlenga, P, Soriano, C, Giralt, E, Roquer, J, Jimenez-Conde, J, Cotlarcius, I, Hardy, J, Korostynski, M, Boncoraglio, G, Ballabio, E, Parati, E, Mateusz, A, Urbanik, A, Dziedzic, T, Jagiella, J, Gasowski, J, Wnuk, M, Olszanecki, R, Pera, J, Slowik, A, Juchniewicz, KJ, Levi, C, Nyquist, P, Cendes, I, Cabral, N, Franca, P, Goncalves, A, Keller, L, Crisby, M, Kostulas, K, Lemmens, R, Ahmadi, K, Opherk, C, Duering, M, Gonik, M, Staals, J, Burri, P, Sadr-Nabavi, A, Romero, J, Biffi, A, Anderson, C, Falcone, G, Brouwers, B, Du, R, Kourkoulis, C, Battey, T, Lubitz, S, Mueller-Myhsok, B, Meschia, J, Brott, T, Pichler, A, Enzinger, C, Schmidt, H, Schmidt, R, Seiler, S, Blanton, S, Yamada, Y, Bersano, A, Rundek, T, Sacco, R, Chan, Y-FY, Gschwendtner, A, Deng, Z, Barr, T, Gwinn, K, Corriveau, R, Singleton, A, Waddy, S, Launer, L, Chen, C, Le, KE, Lee, WL, Tan, EK, Olugbodi, A, Rothwell, P, Schilling, S, Mok, V, Lebedeva, E, Jern, C, Jood, K, Olsson, S, Kim, H, Lee, C, Kilarski, L, Markus, H, Peycke, J, Bevan, S, Sheu, W, Chiou, HY, Chern, J, Giraldo, E, Taqi, M, Jain, V, Lam, O, Howard, G, Woo, D, Kittner, S, Mitchell, B, Cole, J, O'Connell, J, Milewicz, D, Illoh, K, Worrall, B, Stine, C, Karaszewski, B, Werring, D, Sofat, R, Smalley, J, Lindgren, A, Hansen, B, Norrving, B, Smith, G, Jose Martin, J, Thijs, V, Klijn, K, van't Hof, F, Algra, A, Macleod, M, Perry, R, Arnett, D, Pezzini, A, Padovani, A, Cramer, S, Fisher, M, Saleheen, D, Broderick, J, Kissela, B, Doney, A, Sudlow, C, Rannikmae, K, Silliman, S, McDonough, C, Walters, M, Pedersen, A, Nakagawa, K, Chang, C, Dobbins, M, McArdle, P, Chang, Y-C, Brown, R, Brown, D, Holliday, E, Kalaria, R, Maguire, J, Attia, J, Farrall, M, Giese, A-K, Fornage, M, Majersik, J, Cushman, M, Keene, K, Bennett, S, Tirschwell, D, Psaty, B, Reiner, A, Longstreth, W, Spence, D, Montaner, J, Fernandez-Cadenas, I, Langefeld, C, Bushnell, C, Heitsch, L, Lee, J-M, Sheth, K, Pulit, SL, Weng, L-C, McArdle, PF, Trinquart, L, Choi, SH, Mitchell, BD, Rosand, J, de Bakker, PIW, Benjamin, EJ, Ellinor, PT, Kittner, SJ, Lubitz, SA, Anderson, CD, Christophersen, IE, Rienstra, M, Roselli, C, Yin, X, Geelhoed, B, Barnard, J, Lin, H, Arking, DE, Smith, A, Albert, CM, Chaffin, M, Tucker, NR, Li, M, Klarin, D, Bihlmeyer, NA, Low, S-K, Weeke, PE, Mueller-Nurasyid, M, Smith, JG, Brody, JA, Niemeijer, MN, Doerr, M, Trompet, S, Huffman, J, Gustafsson, S, Schurmann, C, Kleber, ME, Lyytikainen, L-P, Seppala, I, Malik, R, Horimoto, ARVR, Perez, M, Sinisalo, J, Aeschbacher, S, Theriault, S, Yao, J, Radmanesh, F, Weiss, S, Teumer, A, Clauss, S, Deo, R, Rader, DJ, Shah, S, Sun, A, Hopewell, JC, Debette, S, Chauhan, G, Yang, Q, Worrall, BB, Pare, G, Kamatani, Y, Hagemeijer, YP, Verweij, N, Siland, JE, Kubo, M, Smith, JD, Van Wagoner, DR, Bis, JC, Perz, S, Psaty, BM, Ridker, PM, Magnani, JW, Harris, TB, Launer, LJ, Shoemaker, MB, Padmanabhan, S, Haessler, J, Bartz, TM, Waldenberger, M, Lichtner, P, Arendt, M, Krieger, JE, Kahonen, M, Risch, L, Mansur, AJ, Peters, A, Smith, BH, Lind, L, Scott, SA, Lu, Y, Bottinger, EB, Hernesniemi, J, Lindgren, CM, Wong, JA, Huang, J, Eskola, M, Morris, AP, Ford, I, Reiner, AP, Delgado, G, Chen, LY, Chen, Y-DI, Sandhu, RK, Boerwinkle, E, Eisele, L, Lannfelt, L, Rost, N, Taylor, KD, Campbell, A, Magnusson, PK, Porteous, D, Hocking, LJ, Vlachopoulou, E, Pedersen, NL, Nikus, K, Orho-Melander, M, Hamsten, A, Heeringa, J, Denny, JC, Kriebel, J, Darbar, D, Newton-Cheh, C, Shaffer, C, Macfarlane, PW, Heilmann, S, Almgren, P, Huang, PL, Sotoodehnia, N, Soliman, EZ, Uitterlinden, AG, Hofman, A, Franco, OH, Voelker, U, Joeckel, K-H, Sinner, MF, Lin, HJ, Guo, X, Dichgans, M, Ingelsson, E, Kooperberg, C, Melander, O, Loos, RJF, Laurikka, J, Conen, D, van der Harst, P, Lokki, M-L, Kathiresan, S, Pereira, A, Jukema, JW, Hayward, C, Rotter, J, Maerz, W, Lehtimaki, T, Stricker, BH, Chung, MK, Felix, SB, Gudnason, V, Alonso, A, Roden, DM, Kaeaeb, S, Chasman, D, Heckbert, SR, Tanaka, T, Lunetta, KL, Smoller, S, Sorkin, J, Wang, X, Selim, M, Pikula, A, Wolf, P, Seshadri, S, de Bakker, P, Rexrode, K, Chen, I, Luke, M, Sale, M, Lee, T-H, Chang, K-C, Elkind, M, Goldstein, L, James, ML, Breteler, M, O'Donnell, C, Leys, D, Carty, C, Kidwell, C, Olesen, J, Sharma, P, Rich, S, Tatlisumak, T, Happola, O, Bijlenga, P, Soriano, C, Giralt, E, Roquer, J, Jimenez-Conde, J, Cotlarcius, I, Hardy, J, Korostynski, M, Boncoraglio, G, Ballabio, E, Parati, E, Mateusz, A, Urbanik, A, Dziedzic, T, Jagiella, J, Gasowski, J, Wnuk, M, Olszanecki, R, Pera, J, Slowik, A, Juchniewicz, KJ, Levi, C, Nyquist, P, Cendes, I, Cabral, N, Franca, P, Goncalves, A, Keller, L, Crisby, M, Kostulas, K, Lemmens, R, Ahmadi, K, Opherk, C, Duering, M, Gonik, M, Staals, J, Burri, P, Sadr-Nabavi, A, Romero, J, Biffi, A, Anderson, C, Falcone, G, Brouwers, B, Du, R, Kourkoulis, C, Battey, T, Lubitz, S, Mueller-Myhsok, B, Meschia, J, Brott, T, Pichler, A, Enzinger, C, Schmidt, H, Schmidt, R, Seiler, S, Blanton, S, Yamada, Y, Bersano, A, Rundek, T, Sacco, R, Chan, Y-FY, Gschwendtner, A, Deng, Z, Barr, T, Gwinn, K, Corriveau, R, Singleton, A, Waddy, S, Launer, L, Chen, C, Le, KE, Lee, WL, Tan, EK, Olugbodi, A, Rothwell, P, Schilling, S, Mok, V, Lebedeva, E, Jern, C, Jood, K, Olsson, S, Kim, H, Lee, C, Kilarski, L, Markus, H, Peycke, J, Bevan, S, Sheu, W, Chiou, HY, Chern, J, Giraldo, E, Taqi, M, Jain, V, Lam, O, Howard, G, Woo, D, Kittner, S, Mitchell, B, Cole, J, O'Connell, J, Milewicz, D, Illoh, K, Worrall, B, Stine, C, Karaszewski, B, Werring, D, Sofat, R, Smalley, J, Lindgren, A, Hansen, B, Norrving, B, Smith, G, Jose Martin, J, Thijs, V, Klijn, K, van't Hof, F, Algra, A, Macleod, M, Perry, R, Arnett, D, Pezzini, A, Padovani, A, Cramer, S, Fisher, M, Saleheen, D, Broderick, J, Kissela, B, Doney, A, Sudlow, C, Rannikmae, K, Silliman, S, McDonough, C, Walters, M, Pedersen, A, Nakagawa, K, Chang, C, Dobbins, M, McArdle, P, Chang, Y-C, Brown, R, Brown, D, Holliday, E, Kalaria, R, Maguire, J, Attia, J, Farrall, M, Giese, A-K, Fornage, M, Majersik, J, Cushman, M, Keene, K, Bennett, S, Tirschwell, D, Psaty, B, Reiner, A, Longstreth, W, Spence, D, Montaner, J, Fernandez-Cadenas, I, Langefeld, C, Bushnell, C, Heitsch, L, Lee, J-M, and Sheth, K
Abstract: OBJECTIVE: We sought to assess whether genetic risk factors for atrial fibrillation (AF) can explain cardioembolic stroke risk. METHODS: We evaluated genetic correlations between a previous genetic study of AF and AF in the presence of cardioembolic stroke using genome-wide genotypes from the Stroke Genetics Network (N = 3,190 AF cases, 3,000 cardioembolic stroke cases, and 28,026 referents). We tested whether a previously validated AF polygenic risk score (PRS) associated with cardioembolic and other stroke subtypes after accounting for AF clinical risk factors. RESULTS: We observed a strong correlation between previously reported genetic risk for AF, AF in the presence of stroke, and cardioembolic stroke (Pearson r = 0.77 and 0.76, respectively, across SNPs with p < 4.4 × 10-4 in the previous AF meta-analysis). An AF PRS, adjusted for clinical AF risk factors, was associated with cardioembolic stroke (odds ratio [OR] per SD = 1.40, p = 1.45 × 10-48), explaining ∼20% of the heritable component of cardioembolic stroke risk. The AF PRS was also associated with stroke of undetermined cause (OR per SD = 1.07, p = 0.004), but no other primary stroke subtypes (all p > 0.1). CONCLUSIONS: Genetic risk of AF is associated with cardioembolic stroke, independent of clinical risk factors. Studies are warranted to determine whether AF genetic risk can serve as a biomarker for strokes caused by AF.
Published: 2018

118. Fourth European stroke science workshop

Author: Debette, S., Strbian, D., Wardlaw, J. M., van der Worp, H. B., Rinkel, G. J.E., Caso, V., Dichgans, M., Tournier-Lasserve, E., Grefkes, C., Kelly, P. J., Muir, K., Berge, E., Trégouët, D. A., Roffe, C., Brainin, M., Beck, J., Steiner, T., de Lau, L. M., Jouvent, E., Veltkamp, R., Baron, J. C., Nedeltchev, K., Bath, P. M., Quinn, T. J., Richard, E., Ziemann, U., Liesz, A., Ntaios, G., Iadecola, C., Lees, K. R., Christensen, H. Krarup, van Veluw, S. J., Endres, M., Anderson, C. S., Molina, C. A., Düring, M., Dufouil, C., Ostergaard, L., Samani, N. J., Fischer, U., de Leeuw, F. E., Norrving, B., Biessels, G. J., Cordonnier, C., Mas, J. L., Mattle, H., Debette, S., Strbian, D., Wardlaw, J. M., van der Worp, H. B., Rinkel, G. J.E., Caso, V., Dichgans, M., Tournier-Lasserve, E., Grefkes, C., Kelly, P. J., Muir, K., Berge, E., Trégouët, D. A., Roffe, C., Brainin, M., Beck, J., Steiner, T., de Lau, L. M., Jouvent, E., Veltkamp, R., Baron, J. C., Nedeltchev, K., Bath, P. M., Quinn, T. J., Richard, E., Ziemann, U., Liesz, A., Ntaios, G., Iadecola, C., Lees, K. R., Christensen, H. Krarup, van Veluw, S. J., Endres, M., Anderson, C. S., Molina, C. A., Düring, M., Dufouil, C., Ostergaard, L., Samani, N. J., Fischer, U., de Leeuw, F. E., Norrving, B., Biessels, G. J., Cordonnier, C., Mas, J. L., and Mattle, H.
Abstract: Lake Eibsee, Garmisch-Partenkirchen, 16 to 18 November, 2017: The European Stroke Organisation convened >120 stroke experts from 21 countries to discuss latest results and hot topics in clinical, translational and basic stroke research. Since its inception in 2011, the European Stroke Science Workshop has become a cornerstone of European Stroke Organisation’s academic activities and a major highlight for researchers in the field. Participants include stroke researchers at all career stages and with different backgrounds, who convene for plenary lectures and discussions. The workshop was organised in seven scientific sessions focusing on the following topics: (1) acute stroke treatment and endovascular therapy; (2) small vessel disease; (3) opportunities for stroke research in the omics era; (4) vascular cognitive impairment; (5) intracerebral and subarachnoid haemorrhage; (6) alternative treatment concepts and (7) neural circuits, recovery and rehabilitation. All sessions started with a keynote lecture providing an overview on current developments, followed by focused talks on a timely topic with the most recent findings, including unpublished data. In the following, we summarise the key contents of the meeting. The program is provided in the online only Data Supplement. The workshop started with a key note lecture on how to improve the efficiency of clinical trial endpoints in stroke, which was delivered by Craig Anderson (Sydney, Australia) and set the scene for the following discussions.
Published: 2018

119. Determinants and outcome of multiple and early recurrent cervical artery dissections

Author: Compter, A, Schilling, S, Vaineau, C, Goeggel-Simonetti, B, Metso, T, Southerland, A, Pezzini, A, Kloss, M, Touzé, E, Worrall, B, Thijs, V, Bejot, Y, Reiner, P, Grond-Ginsbach, C, Bersano, A, Brandt, T, Caso, V, Lyrer, P, Traenka, C, Lichy, C, Martin, J, Leys, D, Sarikaya, H, Baumgartner, R, Jung, S, Fischer, U, Engelter, S, Dallongeville, J, Chabriat, H, Tatlisumak, T, Bousser, M, Arnold, M, Debette, S, Abboud, S, Pandolfo, M, Bodenant, M, Louillet, F, Mas, J, Leder, S, Léger, A, Deltour, S, Crozier, S, Méresse, I, Canaple, S, Godefroy, O, Giroud, M, Decavel, P, Medeiros, E, Montiel, P, Moulin, T, Vuillier, F, Amouyel, P, Metso, A, Werner, I, Santos, M, Dichgans, M, Thomas-Feles, C, Weber, R, De Giuli, V, Caria, F, Poli, L, Padovani, A, Lanfranconi, S, Beretta, S, Ferrarese, C, Giacolone, G, Paolucci, S, Fluri, F, Hatz, F, Gisler, D, Bonati, L, Gensicke, H, Amort, M, Altintas, A, Markus, H, Majersik, J, Cole, J, Kittner, S, Buffon, F, Heldner, M, Mattle, H, Kurmann, R, Gralla, J, Compter, Annette, Schilling, Sabrina, Vaineau, Cloé Juliette, Goeggel-Simonetti, Barbara, Metso, Tiina M., Southerland, Andrew, Pezzini, Alessandro, Kloss, Manja, Touzé, Emmanuel, Worrall, Bradford B., Thijs, Vincent, Bejot, Yannick, Reiner, Peggy, Grond-Ginsbach, Caspar, Bersano, Anna, Brandt, Tobias, Caso, Valeria, Lyrer, Philippe A., Traenka, Christopher, Lichy, Christoph, Martin, Juan José, Leys, Didier, Sarikaya, Hakan, Baumgartner, Ralph W., Jung, Simon, Fischer, Urs, Engelter, Stefan T., Dallongeville, Jean, Chabriat, Hugues, Tatlisumak, Turgut, Bousser, Marie-Germaine, Arnold, Marcel, Debette, Stéphanie, Abboud S, Pandolfo M, Bodenant M, Louillet F, Mas JL, Leder S, Léger A, Deltour S, Crozier S, Méresse I, Canaple S, Godefroy O, Giroud M, Decavel P, Medeiros E, Montiel P, Moulin T, Vuillier F, Amouyel P, Metso AJ, Werner I, Arnold ML, Santos MD, Dichgans M, Thomas-Feles C, Weber R, De Giuli V, Caria F, Poli L, Padovani A, Lanfranconi S, Beretta S, Ferrarese C, Giacolone G, Paolucci S, Fluri F, Hatz F, Gisler D, Bonati L, Gensicke H, Amort M, Altintas A, Markus H, Majersik J, Cole J, Kittner S, Buffon F, Heldner MR, Mattle HP, Kurmann R, Gralla J., Compter, A, Schilling, S, Vaineau, C, Goeggel-Simonetti, B, Metso, T, Southerland, A, Pezzini, A, Kloss, M, Touzé, E, Worrall, B, Thijs, V, Bejot, Y, Reiner, P, Grond-Ginsbach, C, Bersano, A, Brandt, T, Caso, V, Lyrer, P, Traenka, C, Lichy, C, Martin, J, Leys, D, Sarikaya, H, Baumgartner, R, Jung, S, Fischer, U, Engelter, S, Dallongeville, J, Chabriat, H, Tatlisumak, T, Bousser, M, Arnold, M, Debette, S, Abboud, S, Pandolfo, M, Bodenant, M, Louillet, F, Mas, J, Leder, S, Léger, A, Deltour, S, Crozier, S, Méresse, I, Canaple, S, Godefroy, O, Giroud, M, Decavel, P, Medeiros, E, Montiel, P, Moulin, T, Vuillier, F, Amouyel, P, Metso, A, Werner, I, Santos, M, Dichgans, M, Thomas-Feles, C, Weber, R, De Giuli, V, Caria, F, Poli, L, Padovani, A, Lanfranconi, S, Beretta, S, Ferrarese, C, Giacolone, G, Paolucci, S, Fluri, F, Hatz, F, Gisler, D, Bonati, L, Gensicke, H, Amort, M, Altintas, A, Markus, H, Majersik, J, Cole, J, Kittner, S, Buffon, F, Heldner, M, Mattle, H, Kurmann, R, Gralla, J, Compter, Annette, Schilling, Sabrina, Vaineau, Cloé Juliette, Goeggel-Simonetti, Barbara, Metso, Tiina M., Southerland, Andrew, Pezzini, Alessandro, Kloss, Manja, Touzé, Emmanuel, Worrall, Bradford B., Thijs, Vincent, Bejot, Yannick, Reiner, Peggy, Grond-Ginsbach, Caspar, Bersano, Anna, Brandt, Tobias, Caso, Valeria, Lyrer, Philippe A., Traenka, Christopher, Lichy, Christoph, Martin, Juan José, Leys, Didier, Sarikaya, Hakan, Baumgartner, Ralph W., Jung, Simon, Fischer, Urs, Engelter, Stefan T., Dallongeville, Jean, Chabriat, Hugues, Tatlisumak, Turgut, Bousser, Marie-Germaine, Arnold, Marcel, Debette, Stéphanie, Abboud S, Pandolfo M, Bodenant M, Louillet F, Mas JL, Leder S, Léger A, Deltour S, Crozier S, Méresse I, Canaple S, Godefroy O, Giroud M, Decavel P, Medeiros E, Montiel P, Moulin T, Vuillier F, Amouyel P, Metso AJ, Werner I, Arnold ML, Santos MD, Dichgans M, Thomas-Feles C, Weber R, De Giuli V, Caria F, Poli L, Padovani A, Lanfranconi S, Beretta S, Ferrarese C, Giacolone G, Paolucci S, Fluri F, Hatz F, Gisler D, Bonati L, Gensicke H, Amort M, Altintas A, Markus H, Majersik J, Cole J, Kittner S, Buffon F, Heldner MR, Mattle HP, Kurmann R, and Gralla J.
Abstract: Objective To assess putative risk factors and outcome of multiple and early recurrent cervical artery dissection (CeAD). Methods We combined data from 2 multicenter cohorts and compared patients with multiple CeAD at initial diagnosis, early recurrent CeAD within 3 to 6 months, and single nonrecurrent CeAD. Putative risk factors, clinical characteristics, functional outcome, and risk of recurrent ischemic events were assessed. Results Of 1,958 patients with CeAD (mean ± SD age 44.3 ± 10 years, 43.9% women), 1,588 (81.1%) had single nonrecurrent CeAD, 340 (17.4%) hadmultiple CeAD, and 30 (1.5%) presented with single CeAD at admission and had early recurrent CeAD. Patients with multiple or early recurrent CeAD did not significantly differ with respect to putative risk factors, clinical presentation, and outcome. In multivariable analyses, patients with multiple or early recurrent CeAD more often had recent infection (odds ratio [OR] 1.81, 95% confidence interval [CI] 1.29-2.53), vertebral artery dissection (OR 1.82, 95% CI 1.34-2.46), family history of stroke (OR 1.55, 95% CI 1.06-2.25), cervical pain (OR 1.36, 95% CI 1.01-1.84), and subarachnoid hemorrhage (OR 2.85, 95% CI 1.01-8.04) at initial presentation compared to patients with single nonrecurrent CeAD. Patients withmultiple or early recurrent CeAD also had a higher incidence of cerebral ischemia (hazard ratio 2.77, 95% CI 1.49-5.14) at 3 to 6 months but no difference in functional outcome compared to patients with single nonrecurrent CeAD. Conclusion Patients with multiple and early recurrent CeAD share similar risk factors, clinical characteristics, and functional outcome. Compared to patients with single nonrecurrent CeAD, they are more likely to have recurrent cerebral ischemia at 3 to 6 months, possibly reflecting an underlying transient vasculopathy.
Published: 2018

120. Predictors of delayed stroke in patients with cervical artery dissection

Author: Lichy, C, Metso, A, Pezzini, A, Leys, D, Metso, T, Lyrer, P, Debette, S, Thijs, V, Abboud, S, Kloss, M, Samson, Y, Caso, V, Sessa, M, Beretta, S, Lamy, C, Medeiros, E, Bersano, A, Touze, E, Tatlisumak, T, Grau, A, Brandt, T, Engelter, S, Grond-Ginsbach, C, Lichy C., Metso A., Pezzini A., Leys D., Metso T., Lyrer P., Debette S., Thijs V., Abboud S., Kloss M., Samson Y., Caso V., Sessa M., Beretta S., Lamy C., Medeiros E., Bersano A., Touze E., Tatlisumak T., Grau A., Brandt T., Engelter S., Grond-Ginsbach C., Lichy, C, Metso, A, Pezzini, A, Leys, D, Metso, T, Lyrer, P, Debette, S, Thijs, V, Abboud, S, Kloss, M, Samson, Y, Caso, V, Sessa, M, Beretta, S, Lamy, C, Medeiros, E, Bersano, A, Touze, E, Tatlisumak, T, Grau, A, Brandt, T, Engelter, S, Grond-Ginsbach, C, Lichy C., Metso A., Pezzini A., Leys D., Metso T., Lyrer P., Debette S., Thijs V., Abboud S., Kloss M., Samson Y., Caso V., Sessa M., Beretta S., Lamy C., Medeiros E., Bersano A., Touze E., Tatlisumak T., Grau A., Brandt T., Engelter S., and Grond-Ginsbach C.
Abstract: BackgroundStroke in patients with acute cervical artery dissection may be anticipated by initial transient ischemic or nonischemic symptoms.AimIdentifying risk factors for delayed stroke upon cervical artery dissection.MethodsCervical artery dissection patients from the multicenter Cervical Artery Dissection and Ischemic Stroke Patients study were classified as patients without stroke (n=339), with stroke preceded by nonstroke symptoms (delayed stroke, n=244), and with stroke at onset (n=382). Demographics, clinical, and vascular findings were compared between the three groups.ResultsPatients with delayed stroke were more likely to present with occlusive cervical artery dissection (P<0001), multiple cervical artery dissection (P=0031), and vertebral artery dissection (P<0001) than patients without stroke. No differences were observed in age, smoking, arterial hypertension, hypercholesterolemia, migraine, body mass index, infections during the last week, and trauma during the last month, but patients with delayed stroke had less often transient ischemic attack (P<0001) and local signs (Horner syndrome and cranial nerve palsy; P<0001).ConclusionsOcclusive cervical artery dissection, multiple cervical artery dissection, and vertebral artery dissection were associated with an increased risk for delayed stroke. No other risk factors for delayed stroke were identified. Immediate cervical imaging of cervical artery dissection patients without ischemic stroke is needed to identify patients at increased risk for delayed ischemia.
Published: 2015

121. Common coding variant in SERPINA1 increases the risk for large artery stroke

Author: Malik, R, Dau, T, Gonik, M, Sivakumar, A, Deredge, DJ, Edeleva, EV, Götzfried, J, Van Der Laan, SW, Pasterkamp, G, Beaufort, N, Seixas, S, Bevan, S, Lincz, LF, Holliday, EG, Burgess, AI, Rannikmäe, K, Minnerup, J, Kriebel, J, Waldenberger, M, Müller-Nurasyid, M, Lichtner, P, Saleheen, D, Woo, D, Debette, S, Maguire, J, Cole, JW, Majersik, J, Jimenez-Conde, J, Lee, JM, Rost, N, Pare, G, Jern, C, Lindgren, AG, Cardenas, IF, Rothwell, PM, Levi, C, Attia, J, Sudlow, CLM, Braun, D, Markus, HS, Wintrode, PL, Berger, K, Jenne, DE, and Dichgans, M
Subjects: Repressor Proteins, Stroke, alpha 1-Antitrypsin, Humans, Deuterium Exchange Measurement, Leukocyte Elastase, 3' Untranslated Regions, Polymorphism, Single Nucleotide, Histone Deacetylases, Mass Spectrometry, Genetic Association Studies, Plaque, Atherosclerotic
Abstract: Large artery atherosclerotic stroke (LAS) shows substantial heritability not explained by previous genome-wide association studies. Here, we explore the role of coding variation in LAS by analyzing variants on the HumanExome BeadChip in a total of 3,127 cases and 9,778 controls from Europe, Australia, and South Asia. We report on a nonsynonymous single-nucleotide variant in serpin family A member 1 (SERPINA1) encoding alpha-1 antitrypsin [AAT; p.V213A; P = 5.99E-9, odds ratio (OR) = 1.22] and confirm histone deacetylase 9 (HDAC9) as a major risk gene for LAS with an association in the 3?-UTR (rs2023938; P = 7.76E-7, OR = 1.28). Using quantitative microscale thermophoresis, we show that M1 (A213) exhibits an almost twofold lower dissociation constant with its primary target human neutrophil elastase (NE) in lipoprotein-containing plasma, but not in lipid-free plasma. Hydrogen/deuterium exchange combined with mass spectrometry further revealed a significant difference in the global flexibility of the two variants. The observed stronger interaction with lipoproteins in plasma and reduced global flexibility of the Val-213 variant most likely improve its local availability and reduce the extent of proteolytic inactivation by other proteases in atherosclerotic plaques. Our results indicate that the interplay between AAT, NE, and lipoprotein particles is modulated by the gate region around position 213 in AAT, far away from the unaltered reactive center loop (357-360). Collectively, our findings point to a functionally relevant balance between lipoproteins, proteases, and AAT in atherosclerosis.
Published: 2017

122. Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease

Author: Lambert, J. C., Ibrahim-Verbaas, C. A., Russo, G., Mayhaus, M., Lannefelt, L., Hakonarson, H., Pichler, S., Carrasquillo, M. M., Ingelsson, M., Beekly, D., Alvarez, V., Zou, F., Valladares, O., Thorton-Wells, T. A., Younkin, S. G., Coto, E., Hamilton-Nelson, K. L., Gu, W., Razquin, C., Pastor, P., Mateo, I., Owen, M. J., Faber, K. M., Jonsson, P. V., Jones, N., Combarros, O., O'Donovan, M. C., Cantwell, L. B., Soininen, H., Blacker, D., Mead, S., Mosley, T. H., Bennett, D. A., Harris, T. B., Fratiglioni, L., Smith, A. V., Holmes, C., de Bruijn, R. F., Passmore, P., Montine, T. J., Bettens, K., Rotter, J. I., Brice, A., Morgan, K., Foroud, T. M., Kukull, W. A., Chouraki, V., Hannequin, D., Powell, J. F., Nalls, M. A., Ritchie, K., Lunetta, K. L., Kauwe, J. S., Boerwinkle, E., Riemenschneider, M., Boada, M., Hiltuenen, M., Thomas, C., Martin, E. R., Schmidt, R., Rujescu, D., Wang, L. S., Dartigues, J. F., Mayeux, R., Tzourio, C., Hofman, A., Nöthen, M. M., Graff, C., Ikram, M. A., Psaty, B. M., Jones, L., Haines, J. L., Holmans, P. A., Lathrop, M., Pericak-Vance, M. A., Launer, L. J., Farrer, L. A., van Duijn, C. M., Van Broeckhoven, C., Zelenika, D., Moskvina, V., Seshadri, S., Williams, J., Schellenberg, G. D., Amouyel, P., Alpérovitch, A., Boland, A., Delépoine, M., Dubois, B., Duron, E., Vardarajan, B. N., Epelbaum, J., Van Cauwenberghe, C., Engelborghs, S., Vandenberghe, R., De Deyn, P. P., Ferri, R., Romano, C., Caltagirone, C., Orfei, M. D., Ciaramella, A., Kamatani, Y., Scarpini, E., Fenoglio, C., Siciliano, G., Bonuccelli, U., Bagnoli, S., Bracco, L., Bessi, V., Cecchetti, R., Bastgiani, P., Squassina, A., Harold, D., Lin, C. F., Seripa, D., Frank-García, A., Sastre, I., Blesa, R., Alcolea, D., Suárez-Clavet, M., Sánchez-Juan, P., Muñoz Fernandez, C., Aladro Benito, Y., Thonberg, H., Gerrish, A., Forshell, C., Lilus, L., Kinhult-Ståhlbom, A., Giedraitis, V., Kilander, L., Brundin, R. M., Concari, L., Helisalmi, S., Koivisto, A. M., Haapasalo, A., Schmidt, H., Solfrizzi, V., Frisardi, V., Ott, J., Carney, R. M., Mash, D. C., Albert, M. S., Albin, R. L., Apostolova, L. G., Arnold, S. E., Barmada, M. M., Kunkle, B., Barnes, L. L., Beach, T. G., Bigio, E. H., Bird, T. D., Boeve, B. F., Bowen, J. D., Boxer, A., Burk, J. R., Cairns, N. J., Cao, C., Dunstan, M. L., Carlson, C. S., Carroll, S. L., Chibnik, L. B., Chui, H. C., Clark, D. G., Corneveaux, J., Cribbs, D. G., DeCarli, C., DeKosky, S. T., Demirci, F. Y., Ruiz, A., Dick, M., Dickson, D. W., Duara, R., Ertekin-Taner, N., Fallon, K. B., Farlow, M. R., Ferris, S., Frosch, M. P., Galasko, G. R., Ganguli, M., Bihoreau, M. T., Gearing, M., Geschwind, D. H., Ghetti, B., Gilman, S., Glass, J. D., Growdon, J. H., Hamilton, R. L., Harrell, L. E., Head, E., Honig, L. S., Choi, S. H., Hulette, C. M., Hyman, B. T., Jarvik, G. P., Jicha, G. A., Jin, L. W., Karydas, A., Kaye, J. A., Kim, R., Koo, E. H., Reitz, C., Kowall, N. W., Kramer, J. H., Kramer, P., LaFerla, F. M., Lah, J. J., Levernez, J. B., Levey, A. I., Li, G., Lieberman, A. P., Lyketsos, C. G., Pasquier, F., Mack, W. J., Marson, D. C., Martiniuk, F., Masliah, E., McCormick, W. C., McCurry, S. M., McDavid, A. N., McKee, A. C., Mesulam, M., Miller, B. L., Naj, A. C., Cruchaga, C., Miller, C. A., Miller, J. W., Morris, J. C., Murrell, J. R., Olichney, J. M., Pankratz, V. S., Parasi, J. E., Peskind, E., Peterson, R. C., Pierce, A., Craig, D., Poon, W. W., Potter, H., Quinn, J. F., Raj, A., Raskind, M., Raiman, E. M., Reisberg, B., Ringman, J. M., Roberson, E. D., Rosen, H. J., Amin, N., Rosenberg, R. N., Sano, M., Saykin, A. J., Schneider, J. A., Schneider, L. S., Seely, W. W., Smith, A. G., Sonnen, J. A., Spina, S., Stern, R. A., Berr, C., Tanzi, R. E., Trojanowski, J. Q., Troncoso, J. C., Van Deerlin, V. M., Van Eldik, L. J., Vinters, H. V., Vonsattel, J. P., Weintraub, S., Welsh-Bohmer, K. A., Williamson, J., Lopez, O. L., Woltjer, R. L., Yu, C. E., Barber, R., Au, R., Wolf, P. A., Beiser, A., Debette, S., Yang, Q., Weinstein, G., Johnson, A. D., De Jager, P. L., Wang, J., Uitterlinden, A. G., Rivadeneira, F., Koudstgaal, P. J., Longstreth, W. T., Becker, J. T., Kuller, L. H., Lumley, T., Rice, K., Garcia, M., Deramecourt, V., Aspelund, T., Marksteiner, J. J., Dal-Bianco, P., Töglhofer, A. M., Freudenberger, P., Ransmayr, G., Benke, T., Toeglhofer, A. M., Bressler, J., Breteler, M. M., Johnston, J. A., Fornage, M., Hernández, I., Rosende Roca, M., Ana Mauleón, M., Alegrat, M., RamÍrez-Lorca, R., González-Perez, A., Chapman, J., Stretton, A., Morgan, A., Evans, D., Kehoe, P. G., Medway, C., Lord, J., Turton, J., Hooper, N. M., Vardy, E., Warren, J. D., Schott, J. M., Uphill, J., Ryan, N., Lovestone, S., Rossor, M., Ben-Shlomo, Y., Makrina, D., Gkatzima, O., Lupton, M., Koutroumani, M., Avramidou, D., Germanou, A., Jessen, F., Riedel-Heller, S., Sims, R., Letenneur, L., Dichgans, M., Heun, R., Kölsch, H., Schürmann, B., Herold, C., Lacour, A., Drichel, D., Hoffman, P., Kornhuber, J., Morón, F. J., Feulner, T., van den Bussche, H., Lawlor, B., Lynch, A., Mann, D., Smith, A. D., Warden, D., Wilcock, G., Heuser, I., Wiltgang, J., Rubinsztein, D. C., Frölich, L., Hüll, M., Mayo, K., Livingston, G., Bass, N. J., Gurling, H., McQuillen, A., Gwilliam, R., Deloukas, P., Al-Chalabi, A., Eiriksdottir, G., Shaw, C. E., Singleton, A. B., Guerreiro, R., Jöckel, K. H., Klopp, N., Wichmann, H. E., Graff-Radford, N. R., Ma, L., Bisceglio, G., Sleegers, K., Fisher, E., Warner, N., Pickering-Brown, S., Becker, Tim, Goate, A. M., Fiévet, N., Huentelman, M. W., Gill, M., Brown, K., Bellenguez, C., Kamboh, M. I., Keller, L., Barberger-Gateau, P., McGuiness, B., Larson, E. B., Green, R., Myers, A. J., Dufouil, C., Todd, S., Wallon, D., DeStafano, A. L., Love, S., Rogaeva, E., Gallacher, J., St George-Hyslop, P., Clarimon, J., Lleo, A., Bayer, A., Tsuang, D. W., Yu, L., Tsolaki, M., Bis, J. C., Bossù, P., Spalletta, G., Proitsi, P., Collinge, J., Sorbi, S., Sanchez-Garcia, F., Fox, N. C., Hardy, J., Deniz Naranjo, M. C., Bosco, P., Beecham, G. W., Clarke, R., Brayne, C., Galimberti, D., Mancuso, M., Matthews, F., Initiative, European Alzheimer's Disease, Disease, Genetic and Environmental Risk in Alzheimer's, Consortium, Alzheimer's Disease Genetic, Epidemiology, Cohorts for Heart and Aging Research in Genomic, Moebus, S., Grenier-Boley, B., Mecocci, P., Del Zompo, M., Maier, W., Hampel, H., Pilotto, A., Bullido, M., Panza, F., Caffarra, P., Nacmias, B., Gilbert, J. R., Neurology, Radiology & Nuclear Medicine, and Epidemiology
Subjects: Male, Apolipoprotein E, epidemiology [Alzheimer Disease], SORL1, Medizin, genetics [Alzheimer Disease], Genome-wide association study, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, Article, PICALM, Cohort Studies, Alzheimer Disease, ddc:570, PSEN2, Genetics, medicine, Humans, Genetic Predisposition to Disease, Age of Onset, Aged, Genetic association, Aged, 80 and over, Middle Aged, medicine.disease, Genetic Loci, Case-Control Studies, Female, Human medicine, Alzheimer's disease, statistics & numerical data [Genome-Wide Association Study], Genome-Wide Association Study
Abstract: Eleven susceptibility loci for late-onset Alzheimer's disease (LOAD) were identified by previous studies; however, a large portion of the genetic risk for this disease remains unexplained. We conducted a large, two-stage meta-analysis of genome-wide association studies (GWAS) in individuals of European ancestry. In stage 1, we used genotyped and imputed data (7,055,881 SNPs) to perform meta-analysis on 4 previously published GWAS data sets consisting of 17,008 Alzheimer's disease cases and 37,154 controls. In stage 2, 11,632 SNPs were genotyped and tested for association in an independent set of 8,572 Alzheimer's disease cases and 11,312 controls. In addition to the APOE locus (encoding apolipoprotein E), 19 loci reached genome-wide significance (P < 5 x 10(-8)) in the combined stage 1 and stage 2 analysis, of which 11 are newly associated with Alzheimer's disease.
Published: 2013
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123. Trends in the incidence of dementia: design and methods in the Alzheimer Cohorts Consortium

Author: Chibnik, L.B. (Lori), Wolters, F.J. (Frank), Bäckman, K. (Kristoffer), Beiser, A. (Alexa), Berr, C. (Claudine), Bis, J.C. (Joshua), Boerwinkle, E. (Eric), Bos, D. (Daniel), Brayne, C. (Carol), Dartigues, J.-F., Darweesh, S.K.L. (Sirwan), Debette, S. (Stéphanie), Davis-Plourde, K.L. (Kendra L.), Dufouil, C. (Carole), Fornage, M. (Myriam), Grasset, L. (Leslie), Gudnason, V. (Vilmundur), Hadjichrysanthou, C. (Christoforos), Helmer, C. (Catherine), Ikram, M.K. (Kamran), Kern, S. (Silke), Kuller, L.H. (Lewis), Launer, L.J. (Lenore), Lopez, O.L. (Oscar), Matthews, F. (Fiona), Meirelles, O., Mosley, T.H. (Thomas H.), Ower, A. (Alison), Psaty, B.M. (Bruce M.), Satizabal, C.L. (Claudia), Seshadri, S. (Sudha), Skoog, I., Stephan, B.C.M., Tzourio, C. (Christophe), Waziry, R. (Reem), Wong, M.M. (Mei Mei), Zettergren, A. (Anna), Hofman, A. (Albert), Chibnik, L.B. (Lori), Wolters, F.J. (Frank), Bäckman, K. (Kristoffer), Beiser, A. (Alexa), Berr, C. (Claudine), Bis, J.C. (Joshua), Boerwinkle, E. (Eric), Bos, D. (Daniel), Brayne, C. (Carol), Dartigues, J.-F., Darweesh, S.K.L. (Sirwan), Debette, S. (Stéphanie), Davis-Plourde, K.L. (Kendra L.), Dufouil, C. (Carole), Fornage, M. (Myriam), Grasset, L. (Leslie), Gudnason, V. (Vilmundur), Hadjichrysanthou, C. (Christoforos), Helmer, C. (Catherine), Ikram, M.K. (Kamran), Kern, S. (Silke), Kuller, L.H. (Lewis), Launer, L.J. (Lenore), Lopez, O.L. (Oscar), Matthews, F. (Fiona), Meirelles, O., Mosley, T.H. (Thomas H.), Ower, A. (Alison), Psaty, B.M. (Bruce M.), Satizabal, C.L. (Claudia), Seshadri, S. (Sudha), Skoog, I., Stephan, B.C.M., Tzourio, C. (Christophe), Waziry, R. (Reem), Wong, M.M. (Mei Mei), Zettergren, A. (Anna), and Hofman, A. (Albert)
Abstract: Several studies have reported a decline in incidence of dementia which may have large implications for the projected burden of disease, and provide important guidance to preventive efforts. However, reports are conflicting or inconclusive with regard to the impact of gender and education with underlying causes of a presumed declining trend remaining largely unidentified. The Alzheimer Cohorts Consortium aggregates data from nine international population-based cohorts to determine changes in the incidence of dementia since 1990. We will employ Poisson regression models to calculate incidence rates in each cohort and Cox proportional hazard regression to compare 5-year cumulative hazards across study-specific epochs. Finally, we will meta-analyse changes per decade across cohorts, and repeat all analysis stratified by sex, education and APOE genotype. In all cohorts combined, there are data on almost 69,000 people at risk of dementia with the range of follow-up years between 2 and 27. The average age at baseline is similar across cohorts ranging between 72 and 77. Uniting a wide range of disease-specific and methodological expertise in research teams, the first analyses within the Alzheimer Cohorts Consortium are underway to tackle outstanding challenges in the assessment of time-trends in dementia occurrence.
Published: 2017
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124. Genetic variation at 16q24.2 is associated with small vessel stroke

Author: Traylor, M. (Matthew), Malik, R. (Rainer), Nalls, M.A. (Michael), Cotlarciuc, I. (Ioana), Radmanesh, F. (Farid), Thorleifsson, G. (Gudmar), Hanscombe, K.B. (Ken B.), Langefeld, C.D. (Carl), Saleheen, D. (Danish), Rost, N.S. (Natalia), Yet, I. (Idil), Spector, T.D. (Timothy), Bell, J.T. (Jordana), Hannon, E. (Eilis), Mill, J. (Jonathan), Chauhan, G. (Ganesh), Debette, S. (Stéphanie), Bis, J.C. (Joshua), Longstreth Jr, W.T., Ikram, M.K. (Kamran), Launer, L.J. (Lenore), Seshadri, S. (Sudha), Hamilton-Bruce, M.A. (Monica Anne), Jimenez-Conde, J. (Jordi), Cole, J.W. (John W.), Schmidt, R. (Reinhold), Slowik, A. (Agnieszka), Lemmens, R. (Robin), Lindgren, A.G. (Arne G.), Melander, O. (Olle), Grewal, R.P. (Raji P.), Sacco, R.L. (Ralph), Rundek, T. (Tatjana), Rexrode, K. (Kathryn), Arnett, D.K. (Donna), Johnson, J.A. (Julie A.), Benavente, O.R. (Oscar R.), Wasssertheil-Smoller, S. (Sylvia), Lee, J.-M. (Jin-Moo), Pulit, S.L. (Sara), Wong, Q. (Quenna), Rich, S.S. (Stephen), Bakker, P.I.W. (Paul) de, McArdle, P.F. (Patrick), Woo, D. (Daniel), Anderson, C.D. (Christopher D.), Xu, H. (Huichun), Heitsch, L. (Laura), Fornage, M. (Myriam), Jern, C. (Christina), Zwart, J-A. (John-Anker), Thorsteinsdottir, U. (Unnur), Gretarsdottir, S. (Solveig), Lewis, C.M. (Cathryn), Sharma, P. (Pankaj), Sudlow, C. (Cathie), Rothwell, P.M. (Peter), Boncoraglio, G. (Giorgio Battista), Thijs, V. (Vincent), Levi, C. (Christopher), Meschia, J.F. (James F.), Rosand, J. (Jonathan), Kittner, T. (Thomas), Mitchell, B.D. (Braxton), Kubisch, C. (Christian), Worrall, B.B. (Bradford B.), Markus, H.S. (Hugh), Traylor, M. (Matthew), Malik, R. (Rainer), Nalls, M.A. (Michael), Cotlarciuc, I. (Ioana), Radmanesh, F. (Farid), Thorleifsson, G. (Gudmar), Hanscombe, K.B. (Ken B.), Langefeld, C.D. (Carl), Saleheen, D. (Danish), Rost, N.S. (Natalia), Yet, I. (Idil), Spector, T.D. (Timothy), Bell, J.T. (Jordana), Hannon, E. (Eilis), Mill, J. (Jonathan), Chauhan, G. (Ganesh), Debette, S. (Stéphanie), Bis, J.C. (Joshua), Longstreth Jr, W.T., Ikram, M.K. (Kamran), Launer, L.J. (Lenore), Seshadri, S. (Sudha), Hamilton-Bruce, M.A. (Monica Anne), Jimenez-Conde, J. (Jordi), Cole, J.W. (John W.), Schmidt, R. (Reinhold), Slowik, A. (Agnieszka), Lemmens, R. (Robin), Lindgren, A.G. (Arne G.), Melander, O. (Olle), Grewal, R.P. (Raji P.), Sacco, R.L. (Ralph), Rundek, T. (Tatjana), Rexrode, K. (Kathryn), Arnett, D.K. (Donna), Johnson, J.A. (Julie A.), Benavente, O.R. (Oscar R.), Wasssertheil-Smoller, S. (Sylvia), Lee, J.-M. (Jin-Moo), Pulit, S.L. (Sara), Wong, Q. (Quenna), Rich, S.S. (Stephen), Bakker, P.I.W. (Paul) de, McArdle, P.F. (Patrick), Woo, D. (Daniel), Anderson, C.D. (Christopher D.), Xu, H. (Huichun), Heitsch, L. (Laura), Fornage, M. (Myriam), Jern, C. (Christina), Zwart, J-A. (John-Anker), Thorsteinsdottir, U. (Unnur), Gretarsdottir, S. (Solveig), Lewis, C.M. (Cathryn), Sharma, P. (Pankaj), Sudlow, C. (Cathie), Rothwell, P.M. (Peter), Boncoraglio, G. (Giorgio Battista), Thijs, V. (Vincent), Levi, C. (Christopher), Meschia, J.F. (James F.), Rosand, J. (Jonathan), Kittner, T. (Thomas), Mitchell, B.D. (Braxton), Kubisch, C. (Christian), Worrall, B.B. (Bradford B.), and Markus, H.S. (Hugh)
Abstract: Objective: Genome-wide association studies (GWAS) have been successful at identifying associations with stroke and stroke subtypes, but have not yet identified any associations solely with small vessel stroke (SVS). SVS comprises one quarter of all ischemic stroke and is a major manifestation of cerebral small vessel disease, the primary cause of vascular cognitive impairment. Studies across neurological traits have shown that younger-onset cases have an increased genetic burden. We leveraged this increased genetic burden by performing an age-at-onset informed GWAS meta-analysis, including a large younger-onset SVS population, to identify novel associations with stroke. Methods: We used a three-stage age-at-onset informed GWAS to identify novel genetic variants associated with stroke. On identifying a novel locus associated with SVS, we assessed its influence on other small vessel disease phenotypes, as well as on messenger RNA (mRNA) expression of nearby genes, and on DNA methylation of nearby CpG sites in whole blood and in the fetal brain. Results: We identified an association with SVS in 4,203 cases and 50,728 controls on chromosome 16q24.2 (odds ratio [OR; 95% confidence interval {CI}] = 1.16 [1.10–1.22]; p = 3.2 × 10−9). The lead single-nucleotide polymorphism (rs12445022) was also associated with cerebral white matter hyperintensities (OR [95% CI] = 1.10 [1.05–1.16]; p = 5.3 × 10−5; N = 3,670), but not intracerebral hemorrhage (OR [95% CI] = 0.97 [0.84–1.12]; p = 0.71; 1,545 cases, 1,481 controls). rs12445022 is associated with mRNA expression of ZCCHC14 in arterial tissues (p = 9.4 × 10−7) and DNA methylation at probe cg16596957
Published: 2017
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125. Novel genetic loci associated with hippocampal volume

Author: Hibar, D.P. (Derrek), Adams, H.H.H. (Hieab), Jahanshad, N. (Neda), Chauhan, G. (Ganesh), Stein, J.L., Hofer, E. (Edith), Rentería, M.E. (Miguel), Bis, J.C. (Joshua), Arias-Vásquez, A. (Alejandro), Ikram, M.K. (M. Kamran), Desrivières, S. (Sylvane), Vernooij, M.W. (Meike), Abramovic, L. (Lucija), Alhusaini, S. (Saud), Amin, N. (Najaf), Andersson, M. (Micael), Arfanakis, K. (Konstantinos), Aribisala, B. (Benjamin), Armstrong, N.J. (Nicola J.), Athanasiu, L. (Lavinia), Axelsson, T. (Tomas), Beecham, A.H. (Ashley), Beiser, A. (Alexa), Bernard, M. (Manon), Blanton, S.H. (Susan H.), Bohlken, M.M. (Marc M.), Boks, M.P.M. (Marco), Bralten, L.B.C. (Linda), Brickman, A.M. (Adam M.), Carmichael, O. (Owen), Chakravarty, M.M. (M. Mallar), Chen, Q. (Qiang), Ching, C.R.K. (Christopher), Chouraki, V. (Vincent), Cuellar-Partida, G. (Gabriel), Crivello, F. (Fabrice), Braber, A. (Anouk) den, Doan, N.T. (Nhat Trung), Ehrlich, S.M. (Stefan), Giddaluru, S. (Sudheer), Goldman, A.L. (Aaron L.), Gottesman, R.F. (Rebecca), Grimm, O. (Oliver), Griswold, M.D. (Michael), Guadalupe, T. (Tulio), Gutman, B.A. (Boris A.), Hass, J. (Johanna), Haukvik, U.K. (Unn), Hoehn, D. (David), Holmes, A.J. (Avram), Hoogman, M. (Martine), Janowitz, D. (Deborah), Jia, T. (Tianye), Jørgensen, K.N. (Kjetil N.), Karbalai, N. (Nazanin), Kasperaviciute, D. (Dalia), Kim, S. (Shinseog), Klein, M. (Marieke), Kraemer, B. (Bernd), Lee, P.H. (Phil), Liewald, D.C.M. (David), Lopez, L.M. (Lorna), Luciano, M. (Michelle), MacAre, C. (Christine), Marquand, A.F. (Andre F.), Matarin, M. (Mar), Mather, R., Mattheisen, M. (Manuel), McKay, D.R. (David R.), Milaneschi, Y. (Yuri), Muñoz Maniega, S. (Susana), Nho, K. (Kwangsik), Nugent, A.C. (Allison), Nyquist, P. (Paul), Loohuis, L.M.O. (Loes M. Olde), Oosterlaan, J. (Jaap), Papmeyer, M. (Martina), Pirpamer, L. (Lukas), Pütz, B. (Benno), Ramasamy, A. (Adaikalavan), Richards, J.S. (Jennifer S.), Risacher, S.L. (Shannon), Roiz-Santiañez, R. (Roberto), Rommelse, N. (Nanda), Ropele, S. (Stefan), Rose, E.J. (Emma), Royle, N.A. (Natalie), Rundek, T. (Tatjana), Sämann, P.G. (Philipp), Saremi, A. (Arvin), Satizabal, C.L. (Claudia), Schmaal, L. (Lianne), Schork, N.J. (Nicholas), Shen, L. (Li), Shin, J. (Jean), Shumskaya, E. (Elena), Smith, A.V. (Albert Vernon), Sprooten, R. (Roy), Strike, L.T. (Lachlan), Teumer, A. (Alexander), Tordesillas-Gutierrez, D. (Diana), Toro, R. (Roberto), Trabzuni, D. (Danyah), Trompet, S. (Stella), Vaidya, D. (Dhananjay), van der Grond, J. (Jeroen), Lee, S.J. (Sven) van der, Van Der Meer, D. (Dennis), Van Donkelaar, M.M.J. (Marjolein M. J.), Eijk, K.R. (Kristel) van, Erp, T.G.M. (Theo G.) van, Van Rooij, D. (Daan), Walton, E. (Esther), Westlye, L.T. (Lars), Whelan, C.D. (Christopher), Windham, B.G. (Gwen), Winkler, A.M. (Anderson), Wittfeld, K. (Katharina), Woldehawariat, G. (Girma), Björnsson, A. (Asgeir), Wolfers, T. (Thomas), Yanek, L.R. (Lisa), Yang, J. (Jingyun), Zijdenbos, A.P., Zwiers, M.P. (Marcel), Agartz, I. (Ingrid), Almasy, L. (Laura), Ames, D.J. (David), Amouyel, P. (Philippe), Andreassen, O.A. (Ole), Arepalli, S. (Sampath), Assareh, A.A., Barral, S. (Sandra), Bastin, M.E. (Mark), Becker, D.M. (Diane M.), Becker, J.T. (James), Bennett, D.A. (David A.), Blangero, J. (John), Bokhoven, H. (Hans) van, Boomsma, D.I. (Dorret), Brodaty, H. (Henry), Brouwer, R.M. (Rachel), Brunner, H.G., Buckner, M., Buitelaar, J.K. (Jan), Bulayeva, K. (Kazima), Cahn, W. (Wiepke), Calhoun, V.D. (Vince), Cannon, D.M. (Dara), Cavalleri, G. (Gianpiero), Cheng, C.-Y. (Ching-Yu), Cichon, S. (Sven), Cookson, M.R. (Mark), Corvin, A. (Aiden), Crespo-Facorro, B. (Benedicto), Curran, J.E. (Joanne), Czisch, M. (Michael), Dale, A.M. (Anders), Davies, G.E. (Gareth), Craen, A.J. (Anton) de, Geus, E.J.C. (Eco) de, Jager, P.L. (Philip) de, Zubicaray, G.I. (Greig) de, Deary, I.J. (Ian), Debette, S. (Stéphanie), DeCarli, C. (Charles), Delanty, N., Depondt, C. (Chantal), DeStefano, A.L. (Anita), Dillman, A. (Allissa), Djurovic, S. (Srdjan), Donohoe, D.J. (Dennis), Drevets, D.A. (Douglas), Duggirala, R. (Ravi), Dyer, M.D. (Matthew), Enzinger, C. (Christian), Erk, S., Espeseth, T. (Thomas), Fedko, I.O. (Iryna O.), Fernández, G. (Guillén), Ferrucci, L. (Luigi), Fisher, S.E. (Simon), Fleischman, D. (Debra), Ford, I. (Ian), Fornage, M. (Myriam), Foroud, T. (Tatiana), Fox, P.T. (Peter), Francks, C. (Clyde), Fukunaga, M. (Masaki), Gibbs, J.R. (J. Raphael), Glahn, D.C. (David), Gollub, R.L. (Randy), Göring, H.H.H. (Harald H.), Green, R.C. (Robert C.), Gruber, O. (Oliver), Gudnason, V. (Vilmundur), Guelfi, S. (Sebastian), Håberg, A.K. (Asta K.), Hansell, N.K. (Narelle), Hardy, J. (John), Hartman, C.A. (C.), Hashimoto, R. (Ryota), Hegenscheid, K. (Katrin), Heinz, J. (Judith), Le Hellard, S. (Stephanie), Hernandez, D.G. (Dena), Heslenfeld, D.J. (Dirk), Ho, B.-C. (Beng-Choon), Hoekstra, P.J. (Pieter), Hoffmann, W. (Wolfgang), Hofman, A. (Albert), Holsboer, F. (Florian), Homuth, G. (Georg), Hosten, N. (Norbert), Hottenga, J.J. (Jouke Jan), Huentelman, M.J. (Matthew), Pol, H.H., Ikeda, M. (Masashi), Jack, C.R. (Clifford R.), Jenkinson, S. (Sarah), Johnson, R. (Robert), Jönsson, E.G. (Erik G.), Jukema, J.W., Kahn, R. (René), Kanai, R. (Ryota), Kloszewska, I. (Iwona), Knopman, D.S. (David S.), Kochunov, P. (Peter), Kwok, J.B. (John B.), Lawrie, S. (Stephen), Lemaître, H. (Herve), Liu, X. (Xinmin), Longo, D.L. (Dan L.), Lopez, O.L. (Oscar L.), Lovestone, S. (Simon), Martinez, O. (Oliver), Martinot, J.-L. (Jean-Luc), Mattay, V.S. (Venkata S.), McDonald, C. (Colm), McIntosh, A.M. (Andrew), McMahon, F.J. (Francis J.), McMahon, K.L. (Katie L.), Mecocci, P. (Patrizia), Melle, I. (Ingrid), Meyer-Lindenberg, A. (Andreas), Mohnke, S. (Sebastian), Montgomery, G.W. (Grant W.), Morris, D.W. (Derek W), Mosley, T.H. (Thomas H.), Mühleisen, T.W. (Thomas), Müller-Myhsok, B. (B.), Nalls, M.A. (Michael), Nauck, M. (Matthias), Nichols, T.E. (Thomas), Niessen, W.J. (Wiro), Nöthen, M.M. (Markus), Nyberg, L. (Lars), Ohi, K. (Kazutaka), Olvera, R.L. (Rene), Ophoff, R.A. (Roel), Pandolfo, M. (Massimo), Paus, T. (Tomas), Pausova, Z. (Zdenka), Penninx, B.W.J.H. (Brenda), Pike, G.B. (G. Bruce), Potkin, S.G. (Steven), Psaty, B.M. (Bruce), Reppermund, S., Rietschel, M. (Marcella), Roffman, J.L. (Joshua), Seiferth, N. (Nina), Rotter, J.I. (Jerome I.), Ryten, M. (Mina), Sacco, R.L. (Ralph L.), Sachdev, P.S. (Perminder), Saykin, A.J. (Andrew), Schmidt, R. (Reinhold), Schmidt, H. (Helena), Schofield, C.J. (Christopher), Sigursson, S. (Sigurdur), Simmons, A. (Andrew), Singleton, A. (Andrew), Sisodiya, S.M. (Sanjay), Smith, C. (Colin), Smoller, J.W., Soininen, H. (H.), Steen, V.M. (Vidar), Stott, D.J. (David J.), Sussmann, J. (Jessika), Thalamuthu, A. (Anbupalam), Toga, A.W. (Arthur W.), Traynor, B. (Bryan), Troncoso, J.C. (Juan), Tsolaki, M. (Magda), Tzourio, C. (Christophe), Uitterlinden, A.G. (André), Hernández, M.C.V. (Maria C. Valdés), Brug, M.P. (Marcel) van der, Lugt, A. (Aad) van der, Wee, N.J. (Nic) van der, Haren, N.E.M. (Neeltje E.) van, Ent, D. (Dennis) van 't, Tol, M.J.D. (Marie-José) van, Vardarajan, B.N. (Badri), Vellas, B. (Bruno), Veltman, D.J. (Dick), Völzke, H. (Henry), Walter, H.J. (Henrik), Wardlaw, J. (Joanna), Wassink, A.M.J. (Annemarie), Weale, M.E. (Michael), Weinberger, D.R. (Daniel R.), Weiner, M.W. (Michael W.), Wen, W. (Wei), Westman, E. (Eric), White, T.J.H. (Tonya), Wong, T.Y. (Tien Y.), Wright, C.B. (Clinton B.), Zielke, R.H. (Ronald H.), Zonderman, A.B., Martin, N.G. (Nicholas), Duijn, C.M. (Cornelia) van, Wright, M.J. (Margaret), Longstreth Jr, W.T., Schumann, G. (Gunter), Grabe, H.J. (Hans Jörgen), Franke, B. (Barbara), Launer, L.J. (Lenore), Medland, S.E. (Sarah), Seshadri, S. (Sudha), Thompson, P.M. (Paul), Ikram, M.K. (Kamran), Hibar, D.P. (Derrek), Adams, H.H.H. (Hieab), Jahanshad, N. (Neda), Chauhan, G. (Ganesh), Stein, J.L., Hofer, E. (Edith), Rentería, M.E. (Miguel), Bis, J.C. (Joshua), Arias-Vásquez, A. (Alejandro), Ikram, M.K. (M. Kamran), Desrivières, S. (Sylvane), Vernooij, M.W. (Meike), Abramovic, L. (Lucija), Alhusaini, S. (Saud), Amin, N. (Najaf), Andersson, M. (Micael), Arfanakis, K. (Konstantinos), Aribisala, B. (Benjamin), Armstrong, N.J. (Nicola J.), Athanasiu, L. (Lavinia), Axelsson, T. (Tomas), Beecham, A.H. (Ashley), Beiser, A. (Alexa), Bernard, M. (Manon), Blanton, S.H. (Susan H.), Bohlken, M.M. (Marc M.), Boks, M.P.M. (Marco), Bralten, L.B.C. (Linda), Brickman, A.M. (Adam M.), Carmichael, O. (Owen), Chakravarty, M.M. (M. Mallar), Chen, Q. (Qiang), Ching, C.R.K. (Christopher), Chouraki, V. (Vincent), Cuellar-Partida, G. (Gabriel), Crivello, F. (Fabrice), Braber, A. (Anouk) den, Doan, N.T. (Nhat Trung), Ehrlich, S.M. (Stefan), Giddaluru, S. (Sudheer), Goldman, A.L. (Aaron L.), Gottesman, R.F. (Rebecca), Grimm, O. (Oliver), Griswold, M.D. (Michael), Guadalupe, T. (Tulio), Gutman, B.A. (Boris A.), Hass, J. (Johanna), Haukvik, U.K. (Unn), Hoehn, D. (David), Holmes, A.J. (Avram), Hoogman, M. (Martine), Janowitz, D. (Deborah), Jia, T. (Tianye), Jørgensen, K.N. (Kjetil N.), Karbalai, N. (Nazanin), Kasperaviciute, D. (Dalia), Kim, S. (Shinseog), Klein, M. (Marieke), Kraemer, B. (Bernd), Lee, P.H. (Phil), Liewald, D.C.M. (David), Lopez, L.M. (Lorna), Luciano, M. (Michelle), MacAre, C. (Christine), Marquand, A.F. (Andre F.), Matarin, M. (Mar), Mather, R., Mattheisen, M. (Manuel), McKay, D.R. (David R.), Milaneschi, Y. (Yuri), Muñoz Maniega, S. (Susana), Nho, K. (Kwangsik), Nugent, A.C. (Allison), Nyquist, P. (Paul), Loohuis, L.M.O. (Loes M. Olde), Oosterlaan, J. (Jaap), Papmeyer, M. (Martina), Pirpamer, L. (Lukas), Pütz, B. (Benno), Ramasamy, A. (Adaikalavan), Richards, J.S. (Jennifer S.), Risacher, S.L. (Shannon), Roiz-Santiañez, R. (Roberto), Rommelse, N. (Nanda), Ropele, S. (Stefan), Rose, E.J. (Emma), Royle, N.A. (Natalie), Rundek, T. (Tatjana), Sämann, P.G. (Philipp), Saremi, A. (Arvin), Satizabal, C.L. (Claudia), Schmaal, L. (Lianne), Schork, N.J. (Nicholas), Shen, L. (Li), Shin, J. (Jean), Shumskaya, E. (Elena), Smith, A.V. (Albert Vernon), Sprooten, R. (Roy), Strike, L.T. (Lachlan), Teumer, A. (Alexander), Tordesillas-Gutierrez, D. (Diana), Toro, R. (Roberto), Trabzuni, D. (Danyah), Trompet, S. (Stella), Vaidya, D. (Dhananjay), van der Grond, J. (Jeroen), Lee, S.J. (Sven) van der, Van Der Meer, D. (Dennis), Van Donkelaar, M.M.J. (Marjolein M. J.), Eijk, K.R. (Kristel) van, Erp, T.G.M. (Theo G.) van, Van Rooij, D. (Daan), Walton, E. (Esther), Westlye, L.T. (Lars), Whelan, C.D. (Christopher), Windham, B.G. (Gwen), Winkler, A.M. (Anderson), Wittfeld, K. (Katharina), Woldehawariat, G. (Girma), Björnsson, A. (Asgeir), Wolfers, T. (Thomas), Yanek, L.R. (Lisa), Yang, J. (Jingyun), Zijdenbos, A.P., Zwiers, M.P. (Marcel), Agartz, I. (Ingrid), Almasy, L. (Laura), Ames, D.J. (David), Amouyel, P. (Philippe), Andreassen, O.A. (Ole), Arepalli, S. (Sampath), Assareh, A.A., Barral, S. (Sandra), Bastin, M.E. (Mark), Becker, D.M. (Diane M.), Becker, J.T. (James), Bennett, D.A. (David A.), Blangero, J. (John), Bokhoven, H. (Hans) van, Boomsma, D.I. (Dorret), Brodaty, H. (Henry), Brouwer, R.M. (Rachel), Brunner, H.G., Buckner, M., Buitelaar, J.K. (Jan), Bulayeva, K. (Kazima), Cahn, W. (Wiepke), Calhoun, V.D. (Vince), Cannon, D.M. (Dara), Cavalleri, G. (Gianpiero), Cheng, C.-Y. (Ching-Yu), Cichon, S. (Sven), Cookson, M.R. (Mark), Corvin, A. (Aiden), Crespo-Facorro, B. (Benedicto), Curran, J.E. (Joanne), Czisch, M. (Michael), Dale, A.M. (Anders), Davies, G.E. (Gareth), Craen, A.J. (Anton) de, Geus, E.J.C. (Eco) de, Jager, P.L. (Philip) de, Zubicaray, G.I. (Greig) de, Deary, I.J. (Ian), Debette, S. (Stéphanie), DeCarli, C. (Charles), Delanty, N., Depondt, C. (Chantal), DeStefano, A.L. (Anita), Dillman, A. (Allissa), Djurovic, S. (Srdjan), Donohoe, D.J. (Dennis), Drevets, D.A. (Douglas), Duggirala, R. (Ravi), Dyer, M.D. (Matthew), Enzinger, C. (Christian), Erk, S., Espeseth, T. (Thomas), Fedko, I.O. (Iryna O.), Fernández, G. (Guillén), Ferrucci, L. (Luigi), Fisher, S.E. (Simon), Fleischman, D. (Debra), Ford, I. (Ian), Fornage, M. (Myriam), Foroud, T. (Tatiana), Fox, P.T. (Peter), Francks, C. (Clyde), Fukunaga, M. (Masaki), Gibbs, J.R. (J. Raphael), Glahn, D.C. (David), Gollub, R.L. (Randy), Göring, H.H.H. (Harald H.), Green, R.C. (Robert C.), Gruber, O. (Oliver), Gudnason, V. (Vilmundur), Guelfi, S. (Sebastian), Håberg, A.K. (Asta K.), Hansell, N.K. (Narelle), Hardy, J. (John), Hartman, C.A. (C.), Hashimoto, R. (Ryota), Hegenscheid, K. (Katrin), Heinz, J. (Judith), Le Hellard, S. (Stephanie), Hernandez, D.G. (Dena), Heslenfeld, D.J. (Dirk), Ho, B.-C. (Beng-Choon), Hoekstra, P.J. (Pieter), Hoffmann, W. (Wolfgang), Hofman, A. (Albert), Holsboer, F. (Florian), Homuth, G. (Georg), Hosten, N. (Norbert), Hottenga, J.J. (Jouke Jan), Huentelman, M.J. (Matthew), Pol, H.H., Ikeda, M. (Masashi), Jack, C.R. (Clifford R.), Jenkinson, S. (Sarah), Johnson, R. (Robert), Jönsson, E.G. (Erik G.), Jukema, J.W., Kahn, R. (René), Kanai, R. (Ryota), Kloszewska, I. (Iwona), Knopman, D.S. (David S.), Kochunov, P. (Peter), Kwok, J.B. (John B.), Lawrie, S. (Stephen), Lemaître, H. (Herve), Liu, X. (Xinmin), Longo, D.L. (Dan L.), Lopez, O.L. (Oscar L.), Lovestone, S. (Simon), Martinez, O. (Oliver), Martinot, J.-L. (Jean-Luc), Mattay, V.S. (Venkata S.), McDonald, C. (Colm), McIntosh, A.M. (Andrew), McMahon, F.J. (Francis J.), McMahon, K.L. (Katie L.), Mecocci, P. (Patrizia), Melle, I. (Ingrid), Meyer-Lindenberg, A. (Andreas), Mohnke, S. (Sebastian), Montgomery, G.W. (Grant W.), Morris, D.W. (Derek W), Mosley, T.H. (Thomas H.), Mühleisen, T.W. (Thomas), Müller-Myhsok, B. (B.), Nalls, M.A. (Michael), Nauck, M. (Matthias), Nichols, T.E. (Thomas), Niessen, W.J. (Wiro), Nöthen, M.M. (Markus), Nyberg, L. (Lars), Ohi, K. (Kazutaka), Olvera, R.L. (Rene), Ophoff, R.A. (Roel), Pandolfo, M. (Massimo), Paus, T. (Tomas), Pausova, Z. (Zdenka), Penninx, B.W.J.H. (Brenda), Pike, G.B. (G. Bruce), Potkin, S.G. (Steven), Psaty, B.M. (Bruce), Reppermund, S., Rietschel, M. (Marcella), Roffman, J.L. (Joshua), Seiferth, N. (Nina), Rotter, J.I. (Jerome I.), Ryten, M. (Mina), Sacco, R.L. (Ralph L.), Sachdev, P.S. (Perminder), Saykin, A.J. (Andrew), Schmidt, R. (Reinhold), Schmidt, H. (Helena), Schofield, C.J. (Christopher), Sigursson, S. (Sigurdur), Simmons, A. (Andrew), Singleton, A. (Andrew), Sisodiya, S.M. (Sanjay), Smith, C. (Colin), Smoller, J.W., Soininen, H. (H.), Steen, V.M. (Vidar), Stott, D.J. (David J.), Sussmann, J. (Jessika), Thalamuthu, A. (Anbupalam), Toga, A.W. (Arthur W.), Traynor, B. (Bryan), Troncoso, J.C. (Juan), Tsolaki, M. (Magda), Tzourio, C. (Christophe), Uitterlinden, A.G. (André), Hernández, M.C.V. (Maria C. Valdés), Brug, M.P. (Marcel) van der, Lugt, A. (Aad) van der, Wee, N.J. (Nic) van der, Haren, N.E.M. (Neeltje E.) van, Ent, D. (Dennis) van 't, Tol, M.J.D. (Marie-José) van, Vardarajan, B.N. (Badri), Vellas, B. (Bruno), Veltman, D.J. (Dick), Völzke, H. (Henry), Walter, H.J. (Henrik), Wardlaw, J. (Joanna), Wassink, A.M.J. (Annemarie), Weale, M.E. (Michael), Weinberger, D.R. (Daniel R.), Weiner, M.W. (Michael W.), Wen, W. (Wei), Westman, E. (Eric), White, T.J.H. (Tonya), Wong, T.Y. (Tien Y.), Wright, C.B. (Clinton B.), Zielke, R.H. (Ronald H.), Zonderman, A.B., Martin, N.G. (Nicholas), Duijn, C.M. (Cornelia) van, Wright, M.J. (Margaret), Longstreth Jr, W.T., Schumann, G. (Gunter), Grabe, H.J. (Hans Jörgen), Franke, B. (Barbara), Launer, L.J. (Lenore), Medland, S.E. (Sarah), Seshadri, S. (Sudha), Thompson, P.M. (Paul), and Ikram, M.K. (Kamran)
Abstract: The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (rg =-0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness.
Published: 2017
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126. Novel genetic loci associated with hippocampal volume

Author: Hibar, D.P., Adams, H.H.H., Jahanshad, N., Chauhan, G., Stein, J.L., Hofer, E., Renteria, M.E., Bis, J.C., Arias-Vasquez, A., Ikram, M.K., Desrivières, S., Vernooij, M.W., Abramovic, L., Alhusaini, S., Amin, N., Andersson, M., Arfanakis, K., Aribisala, B.S., Armstrong, N.J., Athanasiu, L., Axelsson, T., Beecham, A.H., Beiser, A., Bernard, M., Blanton, S.H., Bohlken, M.M., Boks, M.P., Bralten, J., Brickman, A.M., Carmichael, O., Chakravarty, M.M., Chen, Q., Ching, C.R.K., Chouraki, V., Cuellar-Partida, G., Crivello, F., den Braber, A., Doan, N.T., Ehrlich, S., Giddaluru, S., Goldman, A.L., Gottesman, R.F., Grimm, O., Griswold, M.E., Guadalupe, T., Gutman, B.A., Hass, J., Haukvik, U.K., Hoehn, D., Holmes, A.J., Hoogman, M., Janowitz, D., Jia, T., Jørgensen, K.N., Karbalai, N., Kasperaviciute, D., Kim, S., Klein, M., Kraemer, B., Lee, P.H., Liewald, D.C.M., Lopez, L.M., Luciano, M., Macare, C., Marquand, A.F., Matarin, M., Mather, K.A., Mattheisen, M., McKay, D.R., Milaneschi, Y., Munoz Maniega, S., Nho, K., Nugent, A.C., Nyquist, P., Loohuis, L.M.O., Oosterlaan, J., Papmeyer, M., Pirpamer, L., Putz, B., Ramasamy, A., Richards, J.S., Risacher, S.L., Roiz-Santiañez, R., Rommelse, N., Ropele, S., Rose, E.J., Royle, N.A., Rundek, T., Sämann, P.G., Saremi, A., Satizabal, C.L., Schmaal, L., Schork, A.J., Shen, L., Shin, J., Shumskaya, E., Smith, A.V., Sprooten, E., Strike, L.T., Teumer, A., Tordesillas-Gutierrez, D., Toro, R., Trabzuni, D., Trompet, S., Vaidya, D., Van der Grond, J., van der Lee, S.J., van der Meer, D., van Donkelaar, M.M.J., van Eijk, K.R., Van Erp, T.G.M., Van Rooij, D., Walton, E., Westlye, L.T., Whelan, C.D., Windham, B.G., Winkler, A.M., Wittfeld, K., Woldehawariat, G., Wolf, C., Wolfers, T., Yanek, L.R., Yang, J., Zijdenbos, A., Zwiers, M.P., Agartz, I., Almasy, L., Ames, D., Amouyel, P., Andreassen, O.A., Arepalli, S., Assareh, A.A., Barral, S., Bastin, M.E., Becker, D.M., Becker, J.T., Bennett, D.A., Blangero, J., van Bokhoven, H., Boomsma, D.I., Brodaty, H., Brouwer, R.M., Brunner, H.G., Buckner, R.L., Buitelaar, J.K., Bulayeva, K.B., Cahn, W., Calhoun, V.D., Cannon, D.M., Cavalleri, G.L., Cheng, C-Y, Cichon, S., Cookson, M.R., Corvin, A., Crespo-Facorro, B., Curran, J.E., Czisch, M., Dale, A.M., Davies, G.E., de Craen, A.J.M., de Geus, E.J.C., De Jager, P.L., de Zubicaray, G.I., Deary, I.J., Debette, S., DeCarli, C., Delanty, N., Depondt, C., DeStefano, A.L., Dillman, A., Djurovic, S., Donohoe, G., Drevets, W.C., Duggirala, R., Dyer, T.D., Enzinger, C., Erk, S., Espeseth, T., Fedko, I.O., Fernández, G., Ferrucci, L., Fisher, S.E., Fleischman, D.A., Ford, I., Fornage, M., Foroud, T.M., Fox, P.T., Francks, C., Fukunaga, M., Gibbs, J.R., Glahn, D.C., Gollub, R.L., Göring, H.H.H., Green, R.C., Gruber, O., Gudnason, V., Guelfi, S., Håberg, A.K., Hansell, N.K., Hardy, J., Hartman, C.A., Hashimoto, R., Hegenscheid, K., Heinz, A., Le Hellard, S., Hernandez, D.G., Heslenfeld, D.J., Ho, B-C., Hoekstra, P.J., Hoffmann, W., Hofman, A., Holsboer, F., Homuth, G., Hosten, N., Hottenga, J-J, Huentelman, M., Pol, H.E.H., Ikeda, M., Jack Jr, C.R., Jenkinson, M., Johnson, R., Jönsson, E.G., Jukema, J.W., Kahn, R.S., Kanai, R., Kloszewska, I., Knopman, D.S., Kochunov, P., Kwok, J.B., Lawrie, S.M., Lemaitre, H., Liu, X., Longo, D.L., Lopez, O.L., Lovestone, S., Martinez, O.P., Martinot, J-L, Mattay, V.S., McDonald, C., McIntosh, A.M., McMahon, F.J., McMahon, K.L., Mecocci, P., Melle, I., Meyer-Lindenberg, A., Mohnke, S., Montgomery, G.W., Morris, D.W., Mosley, T.H., Mühleisen, T.W., Müller-Myhsok, B., Nalls, M.A., Nauck, M., Nichols, T.E., Niessen, W.J., Nöthen, M.M., Nyberg, L., Ohi, K., Olvera, R.L., Ophoff, R.A., Pandolfo, M., Paus, T., Pausova, Z., Penninx, B.W.J.H., Pike, G.B., Potkin, S.G., Psaty, B.M., Reppermund, S., Rietschel, M., Roffman, J.L., Romanczuk-Seiferth, N., Rotter, J.I., Ryten, M., Sacco, R.L., Sachdev, P.S., Saykin, A.J., Schmidt, R., Schmidt, H., Schofield, P.R., Sigursson, S., Simmons, A., Singleton, A., Sisodiya, S.M., Smith, C., Smoller, J.W., Soininen, H., Steen, V.M., Stott, D.J., Sussmann, J.E., Thalamuthu, A., Toga, A.W., Traynor, B.J., Troncoso, J., Tsolaki, M., Tzourio, C., Uitterlinden, A.G., Hernández, M.C.V., van der Brug, M., van der Lugt, A., van der Wee, N.J.A., van Haren, N.E.M., van ’t Ent, D., van Tol, M-J, Vardarajan, B.N., Vellas, B., Veltman, D.J., Volzke, H., Walter, H., Wardlaw, J.M., Wassink, T.H., Weale, M.E., Weinberger, D.R., Weiner, M.W., Wen, W., Westman, E., White, T., Wong, T.Y., Wright, C.B., Zielke, R.H., Zonderman, A.B., Martin, N.G., van Duijn, C.M., Wright, M.J., Longstreth, W.T., Schumann, G., Grabe, H.J., Franke, B., Launer, L.J., Medland, S.E., Seshadri, S., Thompson, P.M., Ikram, M.A., Hibar, D.P., Adams, H.H.H., Jahanshad, N., Chauhan, G., Stein, J.L., Hofer, E., Renteria, M.E., Bis, J.C., Arias-Vasquez, A., Ikram, M.K., Desrivières, S., Vernooij, M.W., Abramovic, L., Alhusaini, S., Amin, N., Andersson, M., Arfanakis, K., Aribisala, B.S., Armstrong, N.J., Athanasiu, L., Axelsson, T., Beecham, A.H., Beiser, A., Bernard, M., Blanton, S.H., Bohlken, M.M., Boks, M.P., Bralten, J., Brickman, A.M., Carmichael, O., Chakravarty, M.M., Chen, Q., Ching, C.R.K., Chouraki, V., Cuellar-Partida, G., Crivello, F., den Braber, A., Doan, N.T., Ehrlich, S., Giddaluru, S., Goldman, A.L., Gottesman, R.F., Grimm, O., Griswold, M.E., Guadalupe, T., Gutman, B.A., Hass, J., Haukvik, U.K., Hoehn, D., Holmes, A.J., Hoogman, M., Janowitz, D., Jia, T., Jørgensen, K.N., Karbalai, N., Kasperaviciute, D., Kim, S., Klein, M., Kraemer, B., Lee, P.H., Liewald, D.C.M., Lopez, L.M., Luciano, M., Macare, C., Marquand, A.F., Matarin, M., Mather, K.A., Mattheisen, M., McKay, D.R., Milaneschi, Y., Munoz Maniega, S., Nho, K., Nugent, A.C., Nyquist, P., Loohuis, L.M.O., Oosterlaan, J., Papmeyer, M., Pirpamer, L., Putz, B., Ramasamy, A., Richards, J.S., Risacher, S.L., Roiz-Santiañez, R., Rommelse, N., Ropele, S., Rose, E.J., Royle, N.A., Rundek, T., Sämann, P.G., Saremi, A., Satizabal, C.L., Schmaal, L., Schork, A.J., Shen, L., Shin, J., Shumskaya, E., Smith, A.V., Sprooten, E., Strike, L.T., Teumer, A., Tordesillas-Gutierrez, D., Toro, R., Trabzuni, D., Trompet, S., Vaidya, D., Van der Grond, J., van der Lee, S.J., van der Meer, D., van Donkelaar, M.M.J., van Eijk, K.R., Van Erp, T.G.M., Van Rooij, D., Walton, E., Westlye, L.T., Whelan, C.D., Windham, B.G., Winkler, A.M., Wittfeld, K., Woldehawariat, G., Wolf, C., Wolfers, T., Yanek, L.R., Yang, J., Zijdenbos, A., Zwiers, M.P., Agartz, I., Almasy, L., Ames, D., Amouyel, P., Andreassen, O.A., Arepalli, S., Assareh, A.A., Barral, S., Bastin, M.E., Becker, D.M., Becker, J.T., Bennett, D.A., Blangero, J., van Bokhoven, H., Boomsma, D.I., Brodaty, H., Brouwer, R.M., Brunner, H.G., Buckner, R.L., Buitelaar, J.K., Bulayeva, K.B., Cahn, W., Calhoun, V.D., Cannon, D.M., Cavalleri, G.L., Cheng, C-Y, Cichon, S., Cookson, M.R., Corvin, A., Crespo-Facorro, B., Curran, J.E., Czisch, M., Dale, A.M., Davies, G.E., de Craen, A.J.M., de Geus, E.J.C., De Jager, P.L., de Zubicaray, G.I., Deary, I.J., Debette, S., DeCarli, C., Delanty, N., Depondt, C., DeStefano, A.L., Dillman, A., Djurovic, S., Donohoe, G., Drevets, W.C., Duggirala, R., Dyer, T.D., Enzinger, C., Erk, S., Espeseth, T., Fedko, I.O., Fernández, G., Ferrucci, L., Fisher, S.E., Fleischman, D.A., Ford, I., Fornage, M., Foroud, T.M., Fox, P.T., Francks, C., Fukunaga, M., Gibbs, J.R., Glahn, D.C., Gollub, R.L., Göring, H.H.H., Green, R.C., Gruber, O., Gudnason, V., Guelfi, S., Håberg, A.K., Hansell, N.K., Hardy, J., Hartman, C.A., Hashimoto, R., Hegenscheid, K., Heinz, A., Le Hellard, S., Hernandez, D.G., Heslenfeld, D.J., Ho, B-C., Hoekstra, P.J., Hoffmann, W., Hofman, A., Holsboer, F., Homuth, G., Hosten, N., Hottenga, J-J, Huentelman, M., Pol, H.E.H., Ikeda, M., Jack Jr, C.R., Jenkinson, M., Johnson, R., Jönsson, E.G., Jukema, J.W., Kahn, R.S., Kanai, R., Kloszewska, I., Knopman, D.S., Kochunov, P., Kwok, J.B., Lawrie, S.M., Lemaitre, H., Liu, X., Longo, D.L., Lopez, O.L., Lovestone, S., Martinez, O.P., Martinot, J-L, Mattay, V.S., McDonald, C., McIntosh, A.M., McMahon, F.J., McMahon, K.L., Mecocci, P., Melle, I., Meyer-Lindenberg, A., Mohnke, S., Montgomery, G.W., Morris, D.W., Mosley, T.H., Mühleisen, T.W., Müller-Myhsok, B., Nalls, M.A., Nauck, M., Nichols, T.E., Niessen, W.J., Nöthen, M.M., Nyberg, L., Ohi, K., Olvera, R.L., Ophoff, R.A., Pandolfo, M., Paus, T., Pausova, Z., Penninx, B.W.J.H., Pike, G.B., Potkin, S.G., Psaty, B.M., Reppermund, S., Rietschel, M., Roffman, J.L., Romanczuk-Seiferth, N., Rotter, J.I., Ryten, M., Sacco, R.L., Sachdev, P.S., Saykin, A.J., Schmidt, R., Schmidt, H., Schofield, P.R., Sigursson, S., Simmons, A., Singleton, A., Sisodiya, S.M., Smith, C., Smoller, J.W., Soininen, H., Steen, V.M., Stott, D.J., Sussmann, J.E., Thalamuthu, A., Toga, A.W., Traynor, B.J., Troncoso, J., Tsolaki, M., Tzourio, C., Uitterlinden, A.G., Hernández, M.C.V., van der Brug, M., van der Lugt, A., van der Wee, N.J.A., van Haren, N.E.M., van ’t Ent, D., van Tol, M-J, Vardarajan, B.N., Vellas, B., Veltman, D.J., Volzke, H., Walter, H., Wardlaw, J.M., Wassink, T.H., Weale, M.E., Weinberger, D.R., Weiner, M.W., Wen, W., Westman, E., White, T., Wong, T.Y., Wright, C.B., Zielke, R.H., Zonderman, A.B., Martin, N.G., van Duijn, C.M., Wright, M.J., Longstreth, W.T., Schumann, G., Grabe, H.J., Franke, B., Launer, L.J., Medland, S.E., Seshadri, S., Thompson, P.M., and Ikram, M.A.
Abstract: The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer’s disease (rg=−0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness.
Published: 2017

127. Genetic Imbalance in Patients with Cervical Artery Dissection

Author: Grond-Ginsbach, C, Chen, B, Krawczak, M, Pjontek, R, Ginsbach, P, Jiang, Y, Abboud, S, Arnold, M-L, Bersano, A, Brandt, T, Caso, V, Debette, S, Dichgans, M, Geschwendtner, A, Giacalone, G, Martin, J-J, Metso, AJ, Metso, TM, Grau, AJ, Kloss, M, Lichy, C, Pezzini, A, Traenka, C, Schreiber, S, Thijs, V, Touze, E, Del Zott, E, Tatlisumak, T, Leys, D, Lyrer, PA, Engelter, ST, Grond-Ginsbach, C, Chen, B, Krawczak, M, Pjontek, R, Ginsbach, P, Jiang, Y, Abboud, S, Arnold, M-L, Bersano, A, Brandt, T, Caso, V, Debette, S, Dichgans, M, Geschwendtner, A, Giacalone, G, Martin, J-J, Metso, AJ, Metso, TM, Grau, AJ, Kloss, M, Lichy, C, Pezzini, A, Traenka, C, Schreiber, S, Thijs, V, Touze, E, Del Zott, E, Tatlisumak, T, Leys, D, Lyrer, PA, and Engelter, ST
Abstract: BACKGROUND: Genetic and environmental risk factors are assumed to contribute to the susceptibility to cervical artery dissection (CeAD). To explore the role of genetic imbalance in the etiology of CeAD, copy number variants (CNVs) were identified in high-density microarrays samples from the multicenter CADISP (Cervical Artery Dissection and Ischemic Stroke Patients) study and from control subjects from the CADISP study and the German PopGen biobank. Microarray data from 833 CeAD patients and 2040 control subjects (565 subjects with ischemic stroke due to causes different from CeAD and 1475 disease-free individuals) were analyzed. Rare genic CNVs were equally frequent in CeAD-patients (16.4%; n=137) and in control subjects (17.0%; n=346) but differed with respect to their genetic content. Compared to control subjects, CNVs from CeAD patients were enriched for genes associated with muscle organ development and cell differentiation, which suggests a possible association with arterial development. CNVs affecting cardiovascular system development were more common in CeAD patients than in control subjects (p=0.003; odds ratio (OR) =2.5; 95% confidence interval (95% CI) =1.4-4.5) and more common in patients with a familial history of CeAD than in those with sporadic CeAD (p=0.036; OR=11.2; 95% CI=1.2-107). CONCLUSION: The findings suggest that rare genetic imbalance affecting cardiovascular system development may contribute to the risk of CeAD. Validation of these findings in independent study populations is warranted.
Published: 2017

128. Novel genetic loci associated with hippocampal volume

Author: Hibar, DP, Adams, HHH, Jahanshad, N, Chauhan, G, Stein, JL, Hofer, E, Renteria, ME, Bis, JC, Arias-Vasquez, A, Ikram, MK, Desrivieres, S, Vernooij, MW, Abramovic, L, Alhusaini, S, Amin, N, Andersson, M, Arfanakis, K, Aribisala, BS, Armstrong, NJ, Athanasiu, L, Axelsson, T, Beecham, AH, Beiser, A, Bernard, M, Blanton, SH, Bohlken, MM, Boks, MP, Bralten, J, Brickman, AM, Carmichael, O, Chakravarty, MM, Chen, Q, Ching, CRK, Chouraki, V, Cuellar-Partida, G, Crivello, F, Den Braber, A, Nhat, TD, Ehrlich, S, Giddaluru, S, Goldman, AL, Gottesman, RF, Grimm, O, Griswold, ME, Guadalupe, T, Gutman, BA, Hass, J, Haukvik, UK, Hoehn, D, Holmes, AJ, Hoogman, M, Janowitz, D, Jia, T, Jorgensen, KN, Karbalai, N, Kasperaviciute, D, Kim, S, Klein, M, Kraemer, B, Lee, PH, Liewald, DCM, Lopez, LM, Luciano, M, Macare, C, Marquand, AF, Matarin, M, Mather, KA, Mattheisen, M, McKay, DR, Milaneschi, Y, Maniega, SM, Nho, K, Nugent, AC, Nyquist, P, Loohuis, LMO, Oosterlaan, J, Papmeyer, M, Pirpamer, L, Puetz, B, Ramasamy, A, Richards, JS, Risacher, SL, Roiz-Santianez, R, Rommelse, N, Ropele, S, Rose, EJ, Royle, NA, Rundek, T, Saemann, PG, Saremi, A, Satizabal, CL, Schmaal, L, Schork, AJ, Shen, L, Shin, J, Shumskaya, E, Smith, AV, Sprooten, E, Strike, LT, Teumer, A, Tordesillas-Gutierrez, D, Toro, R, Trabzuni, D, Trompet, S, Vaidya, D, Van der Grond, J, Van der Lee, SJ, Van der Meer, D, Van Donkelaar, MMJ, Van Eijk, KR, Van Erp, TGM, Van Rooij, D, Walton, E, Westlye, LT, Whelan, CD, Windham, BG, Winkler, AM, Wittfeld, K, Woldehawariat, G, Wolf, C, Wolfers, T, Yanek, LR, Yang, J, Zijdenbos, A, Zwiers, MP, Agartz, I, Almasy, L, Ames, D, Amouyel, P, Andreassen, OA, Arepalli, S, Assareh, AA, Barral, S, Bastin, ME, Becker, DM, Becker, JT, Bennett, DA, Blangero, J, van Bokhoven, H, Boomsma, DI, Brodaty, H, Brouwer, RM, Brunner, HG, Buckner, RL, Buitelaar, JK, Bulayeva, KB, Cahn, W, Calhoun, VD, Cannon, DM, Cavalleri, GL, Cheng, C-Y, Cichon, S, Cookson, MR, Corvin, A, Crespo-Facorro, B, Curran, JE, Czisch, M, Dale, AM, Davies, GE, De Craen, AJM, De Geus, EJC, De Jager, PL, De Zubicaray, GI, Deary, IJ, Debette, S, DeCarli, C, Delanty, N, Depondt, C, DeStefano, A, Dillman, A, Djurovic, S, Donohoe, G, Drevets, WC, Duggirala, R, Dyer, TD, Enzinger, C, Erk, S, Espeseth, T, Fedko, IO, Fernandez, G, Ferrucci, L, Fisher, SE, Fleischman, DA, Ford, I, Fornage, M, Foroud, TM, Fox, PT, Francks, C, Fukunaga, M, Gibbs, JR, Glahn, DC, Gollub, RL, Goring, HHH, Green, RC, Gruber, O, Gudnason, V, Guelfi, S, Haberg, AK, Hansell, NK, Hardy, J, Hartman, CA, Hashimoto, R, Hegenscheid, K, Heinz, A, Le Hellard, S, Hernandez, DG, Heslenfeld, DJ, Ho, B-C, Hoekstra, PJ, Hoffmann, W, Hofman, A, Holsboer, F, Homuth, G, Hosten, N, Hottenga, J-J, Huentelman, M, Pol, HEH, Ikeda, M, Jack, CR, Jenkinson, M, Johnson, R, Joensson, EG, Jukema, JW, Kahn, RS, Kanai, R, Kloszewska, I, Knopman, DS, Kochunov, P, Kwok, JB, Lawrie, SM, Lemaitre, H, Liu, X, Longo, DL, Lopez, OL, Lovestone, S, Martinez, O, Martinot, J-L, Mattay, VS, McDonald, C, McIntosh, AM, McMahon, FJ, McMahon, KL, Mecocci, P, Melle, I, Meyer-Lindenberg, A, Mohnke, S, Montgomery, GW, Morris, DW, Mosley, TH, Muhleisen, TW, Mueller-Myhsok, B, Nalls, MA, Nauck, M, Nichols, TE, Niessen, WJ, Nothen, MM, Nyberg, L, Ohi, K, Olvera, RL, Ophoff, RA, Pandolfo, M, Paus, T, Pausova, Z, Penninx, BWJH, Pike, GB, Potkin, SG, Psaty, BM, Reppermund, S, Rietschel, M, Roffman, JL, Romanczuk-Seiferth, N, Rotter, JI, Ryten, M, Sacco, RL, Sachdev, PS, Saykin, AJ, Schmidt, R, Schmidt, H, Schofield, PR, Sigursson, S, Simmons, A, Singleton, A, Sisodiya, SM, Smith, C, Smoller, JW, Soininen, H, Steen, VM, Stott, DJ, Sussmann, JE, Thalamuthu, A, Toga, AW, Traynor, BJ, Troncoso, J, Tsolaki, M, Tzourio, C, Uitterlinden, AG, Hernandez, MCV, Van der Brug, M, van der Lugt, A, van der Wee, NJA, Van Haren, NEM, van't Ent, D, Van Tol, M-J, Vardarajan, BN, Vellas, B, Veltman, DJ, Voelzke, H, Walter, H, Wardlaw, JM, Wassink, TH, Weale, ME, Weinberger, DR, Weiner, MW, Wen, W, Westman, E, White, T, Wong, TY, Wright, CB, Zielke, RH, Zonderman, AB, Martin, NG, Van Duijn, CM, Wright, MJ, Longstreth, WT, Schumann, G, Grabe, HJ, Franke, B, Launer, LJ, Medland, SE, Seshadri, S, Thompson, PM, Ikram, MA, Hibar, DP, Adams, HHH, Jahanshad, N, Chauhan, G, Stein, JL, Hofer, E, Renteria, ME, Bis, JC, Arias-Vasquez, A, Ikram, MK, Desrivieres, S, Vernooij, MW, Abramovic, L, Alhusaini, S, Amin, N, Andersson, M, Arfanakis, K, Aribisala, BS, Armstrong, NJ, Athanasiu, L, Axelsson, T, Beecham, AH, Beiser, A, Bernard, M, Blanton, SH, Bohlken, MM, Boks, MP, Bralten, J, Brickman, AM, Carmichael, O, Chakravarty, MM, Chen, Q, Ching, CRK, Chouraki, V, Cuellar-Partida, G, Crivello, F, Den Braber, A, Nhat, TD, Ehrlich, S, Giddaluru, S, Goldman, AL, Gottesman, RF, Grimm, O, Griswold, ME, Guadalupe, T, Gutman, BA, Hass, J, Haukvik, UK, Hoehn, D, Holmes, AJ, Hoogman, M, Janowitz, D, Jia, T, Jorgensen, KN, Karbalai, N, Kasperaviciute, D, Kim, S, Klein, M, Kraemer, B, Lee, PH, Liewald, DCM, Lopez, LM, Luciano, M, Macare, C, Marquand, AF, Matarin, M, Mather, KA, Mattheisen, M, McKay, DR, Milaneschi, Y, Maniega, SM, Nho, K, Nugent, AC, Nyquist, P, Loohuis, LMO, Oosterlaan, J, Papmeyer, M, Pirpamer, L, Puetz, B, Ramasamy, A, Richards, JS, Risacher, SL, Roiz-Santianez, R, Rommelse, N, Ropele, S, Rose, EJ, Royle, NA, Rundek, T, Saemann, PG, Saremi, A, Satizabal, CL, Schmaal, L, Schork, AJ, Shen, L, Shin, J, Shumskaya, E, Smith, AV, Sprooten, E, Strike, LT, Teumer, A, Tordesillas-Gutierrez, D, Toro, R, Trabzuni, D, Trompet, S, Vaidya, D, Van der Grond, J, Van der Lee, SJ, Van der Meer, D, Van Donkelaar, MMJ, Van Eijk, KR, Van Erp, TGM, Van Rooij, D, Walton, E, Westlye, LT, Whelan, CD, Windham, BG, Winkler, AM, Wittfeld, K, Woldehawariat, G, Wolf, C, Wolfers, T, Yanek, LR, Yang, J, Zijdenbos, A, Zwiers, MP, Agartz, I, Almasy, L, Ames, D, Amouyel, P, Andreassen, OA, Arepalli, S, Assareh, AA, Barral, S, Bastin, ME, Becker, DM, Becker, JT, Bennett, DA, Blangero, J, van Bokhoven, H, Boomsma, DI, Brodaty, H, Brouwer, RM, Brunner, HG, Buckner, RL, Buitelaar, JK, Bulayeva, KB, Cahn, W, Calhoun, VD, Cannon, DM, Cavalleri, GL, Cheng, C-Y, Cichon, S, Cookson, MR, Corvin, A, Crespo-Facorro, B, Curran, JE, Czisch, M, Dale, AM, Davies, GE, De Craen, AJM, De Geus, EJC, De Jager, PL, De Zubicaray, GI, Deary, IJ, Debette, S, DeCarli, C, Delanty, N, Depondt, C, DeStefano, A, Dillman, A, Djurovic, S, Donohoe, G, Drevets, WC, Duggirala, R, Dyer, TD, Enzinger, C, Erk, S, Espeseth, T, Fedko, IO, Fernandez, G, Ferrucci, L, Fisher, SE, Fleischman, DA, Ford, I, Fornage, M, Foroud, TM, Fox, PT, Francks, C, Fukunaga, M, Gibbs, JR, Glahn, DC, Gollub, RL, Goring, HHH, Green, RC, Gruber, O, Gudnason, V, Guelfi, S, Haberg, AK, Hansell, NK, Hardy, J, Hartman, CA, Hashimoto, R, Hegenscheid, K, Heinz, A, Le Hellard, S, Hernandez, DG, Heslenfeld, DJ, Ho, B-C, Hoekstra, PJ, Hoffmann, W, Hofman, A, Holsboer, F, Homuth, G, Hosten, N, Hottenga, J-J, Huentelman, M, Pol, HEH, Ikeda, M, Jack, CR, Jenkinson, M, Johnson, R, Joensson, EG, Jukema, JW, Kahn, RS, Kanai, R, Kloszewska, I, Knopman, DS, Kochunov, P, Kwok, JB, Lawrie, SM, Lemaitre, H, Liu, X, Longo, DL, Lopez, OL, Lovestone, S, Martinez, O, Martinot, J-L, Mattay, VS, McDonald, C, McIntosh, AM, McMahon, FJ, McMahon, KL, Mecocci, P, Melle, I, Meyer-Lindenberg, A, Mohnke, S, Montgomery, GW, Morris, DW, Mosley, TH, Muhleisen, TW, Mueller-Myhsok, B, Nalls, MA, Nauck, M, Nichols, TE, Niessen, WJ, Nothen, MM, Nyberg, L, Ohi, K, Olvera, RL, Ophoff, RA, Pandolfo, M, Paus, T, Pausova, Z, Penninx, BWJH, Pike, GB, Potkin, SG, Psaty, BM, Reppermund, S, Rietschel, M, Roffman, JL, Romanczuk-Seiferth, N, Rotter, JI, Ryten, M, Sacco, RL, Sachdev, PS, Saykin, AJ, Schmidt, R, Schmidt, H, Schofield, PR, Sigursson, S, Simmons, A, Singleton, A, Sisodiya, SM, Smith, C, Smoller, JW, Soininen, H, Steen, VM, Stott, DJ, Sussmann, JE, Thalamuthu, A, Toga, AW, Traynor, BJ, Troncoso, J, Tsolaki, M, Tzourio, C, Uitterlinden, AG, Hernandez, MCV, Van der Brug, M, van der Lugt, A, van der Wee, NJA, Van Haren, NEM, van't Ent, D, Van Tol, M-J, Vardarajan, BN, Vellas, B, Veltman, DJ, Voelzke, H, Walter, H, Wardlaw, JM, Wassink, TH, Weale, ME, Weinberger, DR, Weiner, MW, Wen, W, Westman, E, White, T, Wong, TY, Wright, CB, Zielke, RH, Zonderman, AB, Martin, NG, Van Duijn, CM, Wright, MJ, Longstreth, WT, Schumann, G, Grabe, HJ, Franke, B, Launer, LJ, Medland, SE, Seshadri, S, Thompson, PM, and Ikram, MA
Abstract: The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (rg=-0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness.
Published: 2017

129. Genetic Variation at 16q24.2 Is Associated With Small Vessel Stroke

Author: Traylor, M, Malik, R, Nalls, MA, Cotlarciuc, I, Radmanesh, F, Thorleifsson, G, Hanscombe, KB, Langefeld, C, Saleheen, D, Rost, NS, Yet, I, Spector, TD, Bell, JT, Hannon, E, Mill, J, Chauhan, G, Debette, S, Bis, JC, Longstreth, WT, Ikram, MA, Launer, LJ, Seshadri, S, Hamilton-Bruce, MA, Jimenez-Conde, J, Cole, JW, Schmidt, R, Slowik, A, Lemmens, R, Lindgren, A, Melander, O, Grewal, RP, Sacco, RL, Rundek, T, Rexrode, K, Arnett, DK, Johnson, JA, Benavente, OR, Wasssertheil-Smoller, S, Lee, J-M, Pulit, SL, Wong, Q, Rich, SS, de Bakker, PIW, McArdle, PF, Woo, D, Anderson, CD, Xu, H, Heitsch, L, Fornage, M, Jern, C, Stefansson, K, Thorsteinsdottir, U, Gretarsdottir, S, Lewis, CM, Sharma, P, Sudlow, CLM, Rothwell, PM, Boncoraglio, GB, Thijs, V, Levi, C, Meschia, JF, Rosand, J, Kittner, SJ, Mitchell, BD, Dichgans, M, Worrall, BB, Markus, HS, Traylor, M, Malik, R, Nalls, MA, Cotlarciuc, I, Radmanesh, F, Thorleifsson, G, Hanscombe, KB, Langefeld, C, Saleheen, D, Rost, NS, Yet, I, Spector, TD, Bell, JT, Hannon, E, Mill, J, Chauhan, G, Debette, S, Bis, JC, Longstreth, WT, Ikram, MA, Launer, LJ, Seshadri, S, Hamilton-Bruce, MA, Jimenez-Conde, J, Cole, JW, Schmidt, R, Slowik, A, Lemmens, R, Lindgren, A, Melander, O, Grewal, RP, Sacco, RL, Rundek, T, Rexrode, K, Arnett, DK, Johnson, JA, Benavente, OR, Wasssertheil-Smoller, S, Lee, J-M, Pulit, SL, Wong, Q, Rich, SS, de Bakker, PIW, McArdle, PF, Woo, D, Anderson, CD, Xu, H, Heitsch, L, Fornage, M, Jern, C, Stefansson, K, Thorsteinsdottir, U, Gretarsdottir, S, Lewis, CM, Sharma, P, Sudlow, CLM, Rothwell, PM, Boncoraglio, GB, Thijs, V, Levi, C, Meschia, JF, Rosand, J, Kittner, SJ, Mitchell, BD, Dichgans, M, Worrall, BB, and Markus, HS
Abstract: OBJECTIVE: Genome-wide association studies (GWAS) have been successful at identifying associations with stroke and stroke subtypes, but have not yet identified any associations solely with small vessel stroke (SVS). SVS comprises one quarter of all ischemic stroke and is a major manifestation of cerebral small vessel disease, the primary cause of vascular cognitive impairment. Studies across neurological traits have shown that younger-onset cases have an increased genetic burden. We leveraged this increased genetic burden by performing an age-at-onset informed GWAS meta-analysis, including a large younger-onset SVS population, to identify novel associations with stroke. METHODS: We used a three-stage age-at-onset informed GWAS to identify novel genetic variants associated with stroke. On identifying a novel locus associated with SVS, we assessed its influence on other small vessel disease phenotypes, as well as on messenger RNA (mRNA) expression of nearby genes, and on DNA methylation of nearby CpG sites in whole blood and in the fetal brain. RESULTS: We identified an association with SVS in 4,203 cases and 50,728 controls on chromosome 16q24.2 (odds ratio [OR; 95% confidence interval {CI}] = 1.16 [1.10-1.22]; p = 3.2 × 10-9 ). The lead single-nucleotide polymorphism (rs12445022) was also associated with cerebral white matter hyperintensities (OR [95% CI] = 1.10 [1.05-1.16]; p = 5.3 × 10-5 ; N = 3,670), but not intracerebral hemorrhage (OR [95% CI] = 0.97 [0.84-1.12]; p = 0.71; 1,545 cases, 1,481 controls). rs12445022 is associated with mRNA expression of ZCCHC14 in arterial tissues (p = 9.4 × 10-7 ) and DNA methylation at probe cg16596957 in whole blood (p = 5.3 × 10-6 ). INTERPRETATION: 16q24.2 is associated with SVS. Associations of the locus with expression of ZCCHC14 and DNA methylation suggest the locus acts through changes to regulatory elements. Ann Neurol 2017;81:383-394.
Published: 2017

130. Trends in the incidence of dementia: design and methods in the Alzheimer Cohorts Consortium

Author: Chibnik, LB, Wolters, Frank, Backman, K, Beiser, A, Berr, C, Bis, JC, Boerwinkle, E, Bos, Daniel, Brayne, C, Dartigues, JF, Darweesh, Sirwan, Debette, S, Davis-Plourde, KL, Dufouil, C, Fornage, M, Grasset, L, Gudnason, V, Hadjichrysanthou, C, Helmer, C, Ikram, Arfan, Ikram, Kamran, Kern, S, Kuller, LH, Launer, L, Lopez, OL, Matthews, F, Meirelles, O, Mosley, T, Ower, A, Psaty, BM, Satizabal, CL, Seshadri, S, Skoog, I, Stephan, BCM, Tzourio, C, Waziry, R, Wong, MM, Zettergren, A, Hofman, Bert, Chibnik, LB, Wolters, Frank, Backman, K, Beiser, A, Berr, C, Bis, JC, Boerwinkle, E, Bos, Daniel, Brayne, C, Dartigues, JF, Darweesh, Sirwan, Debette, S, Davis-Plourde, KL, Dufouil, C, Fornage, M, Grasset, L, Gudnason, V, Hadjichrysanthou, C, Helmer, C, Ikram, Arfan, Ikram, Kamran, Kern, S, Kuller, LH, Launer, L, Lopez, OL, Matthews, F, Meirelles, O, Mosley, T, Ower, A, Psaty, BM, Satizabal, CL, Seshadri, S, Skoog, I, Stephan, BCM, Tzourio, C, Waziry, R, Wong, MM, Zettergren, A, and Hofman, Bert
Published: 2017

131. Stroke in first-degree relatives of patients with cervical artery dissection

Author: Kloss, M, Grond Ginsbach, C, Pezzini, A, Metso, T, Metso, A, Debette, S, Leys, D, Dallongeville, J, Caso, V, Thijs, V, Bersano, A, Touzé, E, Bonati, L, Tatlisumak, T, Arnold, M, Lyrer, P, Engelter, S, Pandolfo, M, Bodenant, M, Louillet, F, Mas, J, Deltour, S, Anne Léger, N, Canaple, S, Godefroy, O, Yannick Béjot, N, Moulin, T, Vuillier, F, Santos, M, Malik, R, Hausser, I, Brandt, T, Thomas Feles, C, Weber, R, Giossi, A, Volonghi, I, Padovani, A, Lanfranconi, S, Baron, P, Giacolone, G, Paolucci, S, Fluri, F, Hatz, F, Gisler, D, Amort, M, Bevan, S, Altintas, A., FERRARESE, CARLO, Kloss, M, Grond Ginsbach, C, Pezzini, A, Metso, T, Metso, A, Debette, S, Leys, D, Dallongeville, J, Caso, V, Thijs, V, Bersano, A, Touzé, E, Bonati, L, Tatlisumak, T, Arnold, M, Lyrer, P, Engelter, S, Pandolfo, M, Bodenant, M, Louillet, F, Mas, J, Deltour, S, Anne Léger, N, Canaple, S, Godefroy, O, Yannick Béjot, N, Moulin, T, Vuillier, F, Santos, M, Malik, R, Hausser, I, Brandt, T, Thomas Feles, C, Weber, R, Giossi, A, Volonghi, I, Padovani, A, Lanfranconi, S, Baron, P, Ferrarese, C, Giacolone, G, Paolucci, S, Fluri, F, Hatz, F, Gisler, D, Amort, M, Bevan, S, and Altintas, A
Subjects: Adult, Male, medicine.medical_specialty, Vertebral artery dissection, Young stroke, Brain Ischemia, Nuclear Family, Family history of stroke (FHS), Risk Factors, Internal medicine, medicine, Humans, First-degree relatives, Family history, Young adult, Stroke, Vertebral Artery Dissection, business.industry, Risk Factor, Odds ratio, Middle Aged, medicine.disease, Confidence interval, Surgery, Neurology, Female, Neurology (clinical), business, Cervical artery dissection (CeAD), Body mass index, Human
Abstract: Background and purpose Patients with ischaemic stroke (IS) caused by a spontaneous cervical artery dissection (CeAD) worry about an increased risk for stroke in their families. The occurrence of stroke in relatives of patients with CeAD and in those with ischaemic stroke attributable to other (non-CeAD) causes were compared. Methods The frequency of stroke in first-degree relatives (family history of stroke, FHS) was studied in IS patients (CeAD patients and age- and sex-matched non-CeAD patients) from the Cervical Artery Dissection and Ischemic Stroke Patients (CADISP) database. FHS ≤ 50 and FHS > 50 were defined as having relatives who suffered stroke at the age of ≤50 or >50 years. FHS ≤ 50 and FHS > 50 were studied in CeAD and non-CeAD IS patients and related to age, sex, number of siblings, hypertension, hypercholesterolemia, smoking and body mass index (BMI). Results In all, 1225 patients were analyzed. FHS ≤ 50 was less frequent in CeAD patients (15/598 = 2.5%) than in non-CeAD IS patients (38/627 = 6.1%) (P = 0.003; odds ratio 0.40, 95% confidence interval 0.22–0.73), also after adjustment for age, sex and number of siblings (P = 0.005; odds ratio 0.42, 95% confidence interval 0.23–0.77). The frequency of FHS > 50 was similar in both study groups. Vascular risk factors did not differ between patients with positive or negative FHS ≤ 50. However, patients with FHS > 50 were more likely to have hypertension and higher BMI. Conclusion Relatives of CeAD patients had fewer strokes at a young age than relatives of non-CeAD IS stroke patients.
Published: 2014

132. Genome-wide meta-analysis of cerebral white matter hyperintensities in patients with stroke

Author: Traylor, M, Zhang, Cr, Adib Samii, P, Devan, Wj, Parsons, Oe, Lanfranconi, S, Gregory, S, Cloonan, L, Falcone, Gj, Radmanesh, F, Fitzpatrick, K, Kanakis, A, Barrick, Tr, Moynihan, B, Lewis, Cm, Boncoraglio, Gb, Lemmens, R, Thijs, V, Sudlow, C, Wardlaw, J, Rothwell, Pm, Meschia, Jf, Worrall, Bb, Levi, C, Bevan, S, Furie, Kl, Dichgans, M, Rosand, J, Markus, Hs, Rost, N, Smoller, S, Sorkin, J, Wang, X, Selim, M, Pikula, A, Wolf, P, Debette, S, Seshadri, S, de Bakker, P, Chasman, D, Rexrode, K, Chen, I, Rotter, J, Luke, M, Sale, M, Lee, Th, Chang, Kc, Elkind, M, Goldstein, L, James, Ml, Breteler, M, O'Donnell, C, Leys, D, Carty, C, Kidwell, C, Olesen, J, Sharma, P, Rich, S, Tatlisumak, T, Happola, O, Bijlenga, P, Soriano, C, Giralt, E, Roquer, J, Jimenez Conde, J, Cotlarcius, I, Hardy, J, Korostynski, M, Boncoraglio, G, Ballabio, E, Parati, E, Mateusz, A, Urbanik, A, Dziedzic, T, Jagiella, J, Gasowski, J, Wnuk, M, Olszanecki, R, Pera, J, Slowik, A, Juchniewicz, Kj, Nyquist, P, Cendes, I, Cabral, N, Franca, P, Goncalves, A, Keller, L, Crisby, M, Kostulas, K, Ahmadi, K, Opherk, C, Duering, M, Malik, R, Gonik, M, Staals, J, Melander, O, Burri, P, Sadr Nabavi, A, Romero, J, Biffi, A, Anderson, C, Falcone, G, Brouwers, B, Du, R, Kourkoulis, C, Battey, T, Lubitz, S, Mueller Myhsok, B, Meschia, J, Brott, T, Pare, G, Pichler, A, Enzinger, C, Schmidt, H, Schmidt, R, Seiler, S, Blanton, S, Yamada, Y, Bersano, A, Rundek, T, Sacco, R, Yvonne Chan, Yf, Gschwendtner, A, Deng, Z, Barr, T, Gwinn, K, Corriveau, R, Singleton, A, Waddy, S, Launer, L, Chen, C, Ke, Le, Lee, Wl, Tan, Ek, Olugbodi, A, Rothwell, P, Schilling, S, Mok, V, Lebedeva, E, Jern, C, Jood, K, Olsson, S, Kim, H, Lee, C, Kilarski, L, Markus, H, Peycke, J, Sheu, W, Chiou, Hy, Chern, J, Giraldo, E, Taqi, M, Jain, V, Lam, O, Howard, G, Woo, D, Kittner, S, Mitchell, B, Cole, J, O'Connell, J, Milewicz, D, Illoh, K, Worrall, B, Stine, C, Karaszewski, B, Werring, D, Sofat, R, Smalley, J, Lindgren, A, Hansen, B, Norrving, B, Smith, G, Martín, Jj, Klijn, K, Van't Hof, F, Algra, A, Macleod, M, Perry, R, Arnett, D, Pezzini, Alessandro, Padovani, Alessandro, Cramer, S, Fisher, M, Saleheen, D, Broderick, J, Kissela, B, Doney, A, Rannikmae, K, Silliman, S, Mcdonough, C, Walters, M, Pedersen, A, Nakagawa, K, Chang, C, Dobbins, M, Mcardle, P, Chang, Yc, Brown, R, Brown, D, Holliday, E, Kalaria, R, Maguire, J, Attia, J, Farrall, M, Giese, Ak, Fornage, M, Majersik, J, Cushman, M, Keene, K, Bennett, S, Tirschwell, D, Psaty, B, Reiner, A, Longstreth, W, Spence, D, Montaner, J, Fernandez Cadenas, I, Langefeld, C, Bushnell, C, Heitsch, L, Lee, Jm, and Sheth, K.
Subjects: Cerebral Small Vessel Diseases, Genetic Predisposition to Disease, Genetic Testing, Humans, Polymorphism, Single Nucleotide, Risk Factors, Stroke, White Matter, Genome-Wide Association Study, Neurology (clinical), Single Nucleotide, C420 Human Genetics, Article, C431 Medical Genetics, C400 Genetics, Polymorphism, C440 Molecular Genetics
Abstract: Objective: For 3,670 stroke patients from the United Kingdom, United States, Australia, Belgium, and Italy, we performed a genome-wide meta-analysis of white matter hyperintensity volumes (WMHV) on data imputed to the 1000 Genomes reference dataset to provide insights into disease mechanisms. Methods: We first sought to identify genetic associations with white matter hyperintensities in a stroke population, and then examined whether genetic loci previously linked to WMHV in community populations are also associated in stroke patients. Having established that genetic associations are shared between the 2 populations, we performed a meta-analysis testing which associations with WMHV in stroke-free populations are associated overall when combined with stroke populations. Results: There were no associations at genome-wide significance with WMHV in stroke patients. All previously reported genome-wide significant associations with WMHV in community populations shared direction of effect in stroke patients. In a meta-analysis of the genome-wide significant and suggestive loci (p Conclusions: Genetic associations with WMHV are shared in otherwise healthy individuals and patients with stroke, indicating common genetic susceptibility in cerebral small vessel disease.
Published: 2016
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133. Low-frequency and common genetic variation in ischemic stroke : the METASTROKE collaboration

Author: Malik, R., Traylor, M., Pulit, S.L., Bevan, S., Hopewell, J.C., Holliday, E.G., Zhao, W., Abrantes, P., Amouyel, P., Attia, J.R., Battey, T.W., Berger, K., Boncoraglio, G.B., Chauhan, G., Cheng, Y.C., Chen, W.M., Clarke, R., Cotlarciuc, I., Debette, S., Falcone, G.J., Ferro, J.M., Gamble, D.M., Ilinca, A., Kittner, S.J., Kourkoulis, C.E., Lemmens, R., Levi, C.R., Lichtner, P., Lindgren, A., Liu, J., Meschia, J.F., Mitchell, B.D., Oliveira, S.A., Pera, J., Reiner, A.P., Rothwell, P.M., Sharma, P., Slowik, A., Sudlow, C.L., Tatlisumak, T., Thijs, V., Vicente, A.M., Woo, D., Seshadri, S., Saleheen, D., Rosand, J., Markus, H.S., Worrall, B.B., Dichgans, M., ISGC Analysis Group, METASTROKE collaboration, Wellcome Trust Case Control Consortium 2 (WTCCC2), and NINDS Stroke Genetics Network (SiGN)
Subjects: 0301 basic medicine, medicine.medical_specialty, Genome-wide association study, Polymorphism, Single Nucleotide, Gastroenterology, Article, Brain Ischemia, Doenças Cardio e Cérebro-vasculares, 03 medical and health sciences, 0302 clinical medicine, Missing heritability problem, Internal medicine, ABO blood group system, Genetic variation, Humans, Medicine, Cooperative Behavior, 1000 Genomes Project, Allele frequency, Stroke, Ischemic Stroke, Genetic association, Genetics, business.industry, Genetic Variation, Correction, medicine.disease, 030104 developmental biology, Case-Control Studies, Ischemic stroke, Cardiology, Neurology (clinical), business, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: Erratum in: Low-frequency and common genetic variation in ischemic stroke: The METASTROKE collaboration. [Neurology. 2016] Objective: To investigate the influence of common and low-frequency genetic variants on the risk of ischemic stroke (all IS) and etiologic stroke subtypes. Methods: We meta-analyzed 12 individual genome-wide association studies comprising 10,307 cases and 19,326 controls imputed to the 1000 Genomes (1 KG) phase I reference panel. We selected variants showing the highest degree of association (p , 1E-5) in the discovery phase for replication in Caucasian (13,435 cases and 29,269 controls) and South Asian (2,385 cases and 5,193 controls) samples followed by a transethnic meta-analysis. We further investigated the p value distribution for different bins of allele frequencies for all IS and stroke subtypes. Results: We showed genome-wide significance for 4 loci: ABO for all IS, HDAC9 for large vessel disease (LVD), and both PITX2 and ZFHX3 for cardioembolic stroke (CE). We further refined the association peaks for ABO and PITX2. Analyzing different allele frequency bins, we showed significant enrichment in low-frequency variants (allele frequency ,5%) for both LVD and small vessel disease, and an enrichment of higher frequency variants (allele frequency 10% and 30%) for CE (all p , 1E-5). Conclusions: Our findings suggest that the missing heritability in IS subtypes can in part be attributed to low-frequency and rare variants. Larger sample sizes are needed to identify the variants associated with all IS and stroke subtypes.
Published: 2016

134. The association between systolic blood pressure variability with depression, cognitive decline and white matter hyperintensities: the 3C Dijon MRI study

Author: Tully, P. J., primary, Debette, S., additional, and Tzourio, C., additional
Published: 2017
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135. White Matter Lesion Progression Genome-Wide Search for Genetic Influences

Author: Hofer, E., Cavalieri, M., Bis, J.C., DeCarli, C., Fornage, M., Sigurdsson, S., Srikanth, V., Trompet, S., Verhaaren, B.F.J., Wolf, C., Yang, Q., Adams, H.H.H., Amouyel, P., Beiser, A., Buckley, B.M., Callisaya, M., Chauhan, G., Craen, A.J.M. de, Dufouil, C., Duijn, C.M. van, Ford, I., Freudenberger, P., Gottesman, R.F., Gudnason, V., Heiss, G., Hofman, A., Lumley, T., Martinez, O., Mazoyer, B., Moran, C., Niessen, W.J., Phan, T., Psaty, B.M., Satizabal, C.L., Sattar, N., Schilling, S., Shibata, D.K., Slagboom, P.E., Smith, A., Stott, D.J., Taylor, K.D., Thomson, R., Toglhofer, A.M., Tzourio, C., Buchem, M. van, Wang, J., Westendorp, R.G.J., Windham, B.G., Vernooij, M.W., Zijdenbos, A., Beare, R., Debette, S., Ikram, M.A., Jukema, J.W., Launer, L.J., Longstreth, W.T., Mosley, T.H., Seshadri, S., Schmidt, H., Schmidt, R., and Cohorts Heart Aging Res Genomic Ep
Subjects: Adult, Male, Aging, Clinical Sciences, Cardiorespiratory Medicine and Haematology, Cardiovascular, Cohort Studies, Leukoencephalopathies, Clinical Research, Genetics, Humans, magnetic resonance imaging, 2.1 Biological and endogenous factors, Genetic Predisposition to Disease, Prospective Studies, Aetiology, Aged, Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium, Neurology & Neurosurgery, white matter lesions, Prevention, Human Genome, Neurosciences, Middle Aged, biological factors, White Matter, Disease Progression, Female, cerebral small vessel diseases, Genome-Wide Association Study
Abstract: Background and purposeWhite matter lesion (WML) progression on magnetic resonance imaging is related to cognitive decline and stroke, but its determinants besides baseline WML burden are largely unknown. Here, we estimated heritability of WML progression, and sought common genetic variants associated with WML progression in elderly participants from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium.MethodsHeritability of WML progression was calculated in the Framingham Heart Study. The genome-wide association study included 7773 elderly participants from 10 cohorts. To assess the relative contribution of genetic factors to progression of WML, we compared in 7 cohorts risk models including demographics, vascular risk factors plus single-nucleotide polymorphisms that have been shown to be associated cross-sectionally with WML in the current and previous association studies.ResultsA total of 1085 subjects showed WML progression. The heritability estimate for WML progression was low at 6.5%, and no single-nucleotide polymorphisms achieved genome-wide significance (P
Published: 2015

136. Multiethnic Genome-Wide Association Study of Cerebral White Matter Hyperintensities on MRI

Author: Verhaaren, BFJ, Debette, S, Bis, JC, Smith, JA, Ikram, MK, Adams, HH, Beecham, AH, Rajan, KB, Lopez, LM, Barral, S, Van Buchem, MA, Van Der Grond, J, Smith, AV, Hegenscheid, K, Aggarwal, NT, De Andrade, M, Atkinson, EJ, Beekman, M, Beiser, AS, Blanton, SH, Boerwinkle, E, Brickman, AM, Bryan, RN, Chauhan, G, Chen, CPLH, Chouraki, V, De Craen, AJM, Crivello, F, Deary, IJ, Deelen, J, De Jager, PL, Dufouil, C, Elkind, MSV, Evans, DA, Freudenberger, P, Gottesman, RF, Gunason, V, Habes, M, Heckbert, SR, Heiss, G, Hilal, S, Hofer, E, Hofman, A, Ibrahim-Verbaas, CA, Knopman, DS, Lewis, CE, Liao, J, Liewald, DCM, Luciano, M, Van Der Lugt, A, Martinez, OO, Mayeux, R, Mazoyer, B, Nalls, M, Nauck, M, Niessen, WJ, Oostra, BA, Psaty, BM, Rice, KM, Rotter, JI, Von Sarnowski, B, Schmidt, H, Schreiner, PJ, Schuur, M, Sidney, SS, Sigurdsson, S, Slagboom, PE, Stott, DJM, Van Swieten, JC, Teumer, A, Töglhofer, AM, Traylor, M, Trompet, S, Turner, ST, Tzourio, C, Uh, HW, Uitterlinden, AG, Vernooij, MW, Wang, JJ, Wong, TY, Wardlaw, JM, Windham, BG, Wittfeld, K, Wolf, C, Wright, CB, Yang, Q, Zhao, W, Zijdenbos, A, Jukema, JW, Sacco, RL, Kardia, SLR, Amouyel, P, Mosley, TH, Longstreth, WT, DeCarli, CC, Van Duijn, CM, Schmidt, R, Launer, LJ, and Grabe, HJ
Subjects: genome-wide association study, hypertension, leukoencephalopathies, polymorphisms, single nucleotide, cerebrovascular disorders, cerebral small vessel diseases
Abstract: © 2015 American Heart Association, Inc. Background-The burden of cerebral white matter hyperintensities (WMH) is associated with an increased risk of stroke, dementia, and death. WMH are highly heritable, but their genetic underpinnings are incompletely characterized. To identify novel genetic variants influencing WMH burden, we conducted a meta-analysis of multiethnic genome-wide association studies. Methods and Results-We included 21 079 middle-aged to elderly individuals from 29 population-based cohorts, who were free of dementia and stroke and were of European (n=17 936), African (n=1943), Hispanic (n=795), and Asian (n=405) descent. WMH burden was quantified on MRI either by a validated automated segmentation method or a validated visual grading scale. Genotype data in each study were imputed to the 1000 Genomes reference. Within each ethnic group, we investigated the relationship between each single-nucleotide polymorphism and WMH burden using a linear regression model adjusted for age, sex, intracranial volume, and principal components of ancestry. A meta-analysis was conducted for each ethnicity separately and for the combined sample. In the European descent samples, we confirmed a previously known locus on chr17q25 (P=2.7×10-19) and identified novel loci on chr10q24 (P=1.6×10-9) and chr2p21 (P=4.4×10-8). In the multiethnic meta-analysis, we identified 2 additional loci, on chr1q22 (P=2.0×10-8) and chr2p16 (P=1.5×10-8). The novel loci contained genes that have been implicated in Alzheimer disease (chr2p21 and chr10q24), intracerebral hemorrhage (chr1q22), neuroinflammatory diseases (chr2p21), and glioma (chr10q24 and chr2p16). Conclusions-We identified 4 novel genetic loci that implicate inflammatory and glial proliferative pathways in the development of WMH in addition to previously proposed ischemic mechanisms.
Published: 2015
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137. Novel genetic loci underlying human intracranial volume identified through genome-wide association

Author: Adams, H.H.H., Hibar, D.P., Chouraki, V., Stein, J.L., Nyquist, P.A., Renteria, M.E., Trompet, S., Arias-Vasquez, A., Seshadri, S., Desrivières, S., Beecham, A.H., Jahanshad, N., Wittfeld, K., van der Lee, S.J., Abramovic, L., Alhusaini, S., Amin, N., Andersson, M., Arfanakis, K., Aribisala, B.S., Armstrong, N.J., Athanasiu, L., Axelsson, T., Beiser, A., Bernard, M., Bis, J.C., Blanken, L.M.E., Blanton, S.H., Bohlken, M.M., Boks, M.P., Bralten, J., Brickman, A.M., Carmichael, O., Chakravarty, M.M., Chauhan, G., Chen, Q., Ching, C.R.K., Cuellar-Partida, G., Braber, A.D., Doan, N.T., Ehrlich, S., Filippi, I., Ge, T., Giddaluru, S., Goldman, A.L., Gottesman, R.F., Greven, C.U., Grimm, O., Griswold, M.E., Guadalupe, T., Hass, J., Haukvik, U.K., Hilal, S., Hofer, E., Hoehn, D., Holmes, A.J., Hoogman, M., Janowitz, D., Jia, T., Kasperaviciute, D., Kim, S., Klein, M., Kraemer, B., Lee, P.H., Liao, J., Liewald, D.C.M., Lopez, L.M., Luciano, M., Macare, C., Marquand, A., Matarin, M., Mather, K.A., Mattheisen, M., Mazoyer, B., McKay, D.R., McWhirter, R., Milaneschi, Y., Mirza-Schreiber, N., Muetzel, R.L., Maniega, S.M., Nho, K., Nugent, A.C., Loohuis, L.M.O., Oosterlaan, J., Papmeyer, M., Pappa, I., Pirpamer, L., Pudas, S., Pütz, B., Rajan, K.B., Ramasamy, A., Richards, J.S., Risacher, S.L., Roiz-Santiañez, R., Rommelse, N., Rose, E.J., Royle, N.A., Rundek, T., Sämann, P.G., Satizabal, C.L., Schmaal, L., Schork, A.J., Shen, L., Shin, J., Shumskaya, E., Smith, A.V., Sprooten, E., Strike, L.T., Teumer, A., Thomson, R., Tordesillas-Gutierrez, D., Toro, R., Trabzuni, D., Vaidya, D., Van der Grond, J., van der Meer, D., van Donkelaar, M.M.J., van Eijk, K.R., Van Erp, T.G.M., Van Rooij, D., Walton, E., Westlye, L.T., Whelan, C.D., Windham, B.G., Winkler, A.M., Woldehawariat, G., Wolf, C., Wolfers, T., Xu, B., Yanek, L.R., Yang, J., Zijdenbos, A., Zwiers, M.P., Agartz, I., Aggarwal, N.T., Almasy, L., Ames, D., Amouyel, P., Andreassen, O.A., Arepalli, S., Assareh, A.A., Barral, S., Bastin, M.E., Becker, D.M., Becker, J.T., Bennett, D.A., Blangero, J., van Bokhoven, H., Boomsma, D.I., Brodaty, H., Brouwer, R.M., Brunner, H.G., Buckner, R.L., Buitelaar, J.K., Bulayeva, K.B., Cahn, W., Calhoun, V.D., Cannon, D.M., Cavalleri, G.L., Chen, C., Cheng, C-Y, Cichon, S., Cookson, M.R., Corvin, A., Crespo-Facorro, B., Curran, J.E., Czisch, M., Dale, A.M., Davies, G.E., De Geus, E.J.C., De Jager, P.L., de Zubicaray, G.I., Delanty, N., Depondt, C., DeStefano, A.L., Dillman, A., Djurovic, S., Donohoe, G., Drevets, W.C., Duggirala, R., Dyer, T.D., Erk, S., Espeseth, T., Evans, D.A., Fedko, I.O., Fernández, G., Ferrucci, L., Fisher, S.E., Fleischman, D.A., Ford, I., Foroud, T.M., Fox, P.T., Francks, C., Fukunaga, M., Gibbs, J.R., Glahn, D.C., Gollub, R.L., Göring, H.H.H., Grabe, H.J., Green, R.C., Gruber, O., Gudnason, V., Guelfi, S., Hansell, N.K., Hardy, J., Hartman, C.A., Hashimoto, R., Hegenscheid, K., Heinz, A., Le Hellard, S., Hernandez, D.G., Heslenfeld, D.J., Ho, B-C., Hoekstra, P.J., Hoffmann, W., Hofman, A., Holsboer, F., Homuth, G., Hosten, N., Hottenga, J-J, Pol, H.E.H., Ikeda, M., Ikram, M.K., Jack, C.R., Jenkinson, M., Johnson, R., Jönsson, E.G., Jukema, J.W., Kahn, R.S., Kanai, R., Kloszewska, I., Knopman, D.S., Kochunov, P., Kwok, J.B., Lawrie, S.M., Lemaitre, H., Liu, X., Longo, D.L., Longstreth, W.T., Lopez, O.L., Lovestone, S., Martinez, O.P., Martinot, J-L, Mattay, V.S., McDonald, C., McIntosh, A.M., McMahon, K.L., McMahon, F.J., Mecocci, P., Melle, I., Meyer-Lindenberg, A., Mohnke, S., Montgomery, G.W., Morris, D.W., Mosley, T.H., Mühleisen, T.W., Müller-Myhsok, B., Nalls, M.A., Nauck, M., Nichols, T.E., Niessen, W.J., Nöthen, M.M., Nyberg, L., Ohi, K., Olvera, R.L., Ophoff, R.A., Pandolfo, M., Paus, T., Pausova, Z., Penninx, B.W.J.H., Pike, G.B., Potkin, S.G., Psaty, B.M., Reppermund, S., Rietschel, M., Roffman, J.L., Romanczuk-Seiferth, N., Rotter, J.I., Ryten, M., Sacco, R.L., Sachdev, P.S., Saykin, A.J., Schmidt, R., Schofield, P.R., Sigurdsson, S., Simmons, A., Singleton, A., Sisodiya, S.M., Smith, C., Smoller, J.W., Soininen, H., Srikanth, V., Steen, V.M., Stott, D.J., Sussmann, J.E., Thalamuthu, A., Tiemeier, H., Toga, A.W., Traynor, B.J., Troncoso, J., Turner, J.A., Tzourio, C., Uitterlinden, A.G., Hernández, M.C.V., van der Brug, M., Van der Lugt, A., van der Wee, N.J.A., van Duijn, C.M., van Haren, N.E.M., Van′t Ent, D., van Tol, M-J, Vardarajan, B.N., Veltman, D.J., Vernooij, M.W., Volzke, H., Walter, H., Wardlaw, J.M., Wassink, T.H., Weale, M.E., Weinberger, D.R., Weiner, M.W., Wen, W., Westman, E., White, T., Wong, T.Y., Wright, C.B., Zielke, H.R., Zonderman, A.B., Deary, I.J., DeCarli, C., Schmidt, H., Martin, N.G., de Craen, A.J.M., Wright, M.J., Launer, L.J., Schumann, G., Fornage, M., Franke, B., Debette, S., Medland, S.E., Ikram, M.A., Thompson, P.M., Adams, H.H.H., Hibar, D.P., Chouraki, V., Stein, J.L., Nyquist, P.A., Renteria, M.E., Trompet, S., Arias-Vasquez, A., Seshadri, S., Desrivières, S., Beecham, A.H., Jahanshad, N., Wittfeld, K., van der Lee, S.J., Abramovic, L., Alhusaini, S., Amin, N., Andersson, M., Arfanakis, K., Aribisala, B.S., Armstrong, N.J., Athanasiu, L., Axelsson, T., Beiser, A., Bernard, M., Bis, J.C., Blanken, L.M.E., Blanton, S.H., Bohlken, M.M., Boks, M.P., Bralten, J., Brickman, A.M., Carmichael, O., Chakravarty, M.M., Chauhan, G., Chen, Q., Ching, C.R.K., Cuellar-Partida, G., Braber, A.D., Doan, N.T., Ehrlich, S., Filippi, I., Ge, T., Giddaluru, S., Goldman, A.L., Gottesman, R.F., Greven, C.U., Grimm, O., Griswold, M.E., Guadalupe, T., Hass, J., Haukvik, U.K., Hilal, S., Hofer, E., Hoehn, D., Holmes, A.J., Hoogman, M., Janowitz, D., Jia, T., Kasperaviciute, D., Kim, S., Klein, M., Kraemer, B., Lee, P.H., Liao, J., Liewald, D.C.M., Lopez, L.M., Luciano, M., Macare, C., Marquand, A., Matarin, M., Mather, K.A., Mattheisen, M., Mazoyer, B., McKay, D.R., McWhirter, R., Milaneschi, Y., Mirza-Schreiber, N., Muetzel, R.L., Maniega, S.M., Nho, K., Nugent, A.C., Loohuis, L.M.O., Oosterlaan, J., Papmeyer, M., Pappa, I., Pirpamer, L., Pudas, S., Pütz, B., Rajan, K.B., Ramasamy, A., Richards, J.S., Risacher, S.L., Roiz-Santiañez, R., Rommelse, N., Rose, E.J., Royle, N.A., Rundek, T., Sämann, P.G., Satizabal, C.L., Schmaal, L., Schork, A.J., Shen, L., Shin, J., Shumskaya, E., Smith, A.V., Sprooten, E., Strike, L.T., Teumer, A., Thomson, R., Tordesillas-Gutierrez, D., Toro, R., Trabzuni, D., Vaidya, D., Van der Grond, J., van der Meer, D., van Donkelaar, M.M.J., van Eijk, K.R., Van Erp, T.G.M., Van Rooij, D., Walton, E., Westlye, L.T., Whelan, C.D., Windham, B.G., Winkler, A.M., Woldehawariat, G., Wolf, C., Wolfers, T., Xu, B., Yanek, L.R., Yang, J., Zijdenbos, A., Zwiers, M.P., Agartz, I., Aggarwal, N.T., Almasy, L., Ames, D., Amouyel, P., Andreassen, O.A., Arepalli, S., Assareh, A.A., Barral, S., Bastin, M.E., Becker, D.M., Becker, J.T., Bennett, D.A., Blangero, J., van Bokhoven, H., Boomsma, D.I., Brodaty, H., Brouwer, R.M., Brunner, H.G., Buckner, R.L., Buitelaar, J.K., Bulayeva, K.B., Cahn, W., Calhoun, V.D., Cannon, D.M., Cavalleri, G.L., Chen, C., Cheng, C-Y, Cichon, S., Cookson, M.R., Corvin, A., Crespo-Facorro, B., Curran, J.E., Czisch, M., Dale, A.M., Davies, G.E., De Geus, E.J.C., De Jager, P.L., de Zubicaray, G.I., Delanty, N., Depondt, C., DeStefano, A.L., Dillman, A., Djurovic, S., Donohoe, G., Drevets, W.C., Duggirala, R., Dyer, T.D., Erk, S., Espeseth, T., Evans, D.A., Fedko, I.O., Fernández, G., Ferrucci, L., Fisher, S.E., Fleischman, D.A., Ford, I., Foroud, T.M., Fox, P.T., Francks, C., Fukunaga, M., Gibbs, J.R., Glahn, D.C., Gollub, R.L., Göring, H.H.H., Grabe, H.J., Green, R.C., Gruber, O., Gudnason, V., Guelfi, S., Hansell, N.K., Hardy, J., Hartman, C.A., Hashimoto, R., Hegenscheid, K., Heinz, A., Le Hellard, S., Hernandez, D.G., Heslenfeld, D.J., Ho, B-C., Hoekstra, P.J., Hoffmann, W., Hofman, A., Holsboer, F., Homuth, G., Hosten, N., Hottenga, J-J, Pol, H.E.H., Ikeda, M., Ikram, M.K., Jack, C.R., Jenkinson, M., Johnson, R., Jönsson, E.G., Jukema, J.W., Kahn, R.S., Kanai, R., Kloszewska, I., Knopman, D.S., Kochunov, P., Kwok, J.B., Lawrie, S.M., Lemaitre, H., Liu, X., Longo, D.L., Longstreth, W.T., Lopez, O.L., Lovestone, S., Martinez, O.P., Martinot, J-L, Mattay, V.S., McDonald, C., McIntosh, A.M., McMahon, K.L., McMahon, F.J., Mecocci, P., Melle, I., Meyer-Lindenberg, A., Mohnke, S., Montgomery, G.W., Morris, D.W., Mosley, T.H., Mühleisen, T.W., Müller-Myhsok, B., Nalls, M.A., Nauck, M., Nichols, T.E., Niessen, W.J., Nöthen, M.M., Nyberg, L., Ohi, K., Olvera, R.L., Ophoff, R.A., Pandolfo, M., Paus, T., Pausova, Z., Penninx, B.W.J.H., Pike, G.B., Potkin, S.G., Psaty, B.M., Reppermund, S., Rietschel, M., Roffman, J.L., Romanczuk-Seiferth, N., Rotter, J.I., Ryten, M., Sacco, R.L., Sachdev, P.S., Saykin, A.J., Schmidt, R., Schofield, P.R., Sigurdsson, S., Simmons, A., Singleton, A., Sisodiya, S.M., Smith, C., Smoller, J.W., Soininen, H., Srikanth, V., Steen, V.M., Stott, D.J., Sussmann, J.E., Thalamuthu, A., Tiemeier, H., Toga, A.W., Traynor, B.J., Troncoso, J., Turner, J.A., Tzourio, C., Uitterlinden, A.G., Hernández, M.C.V., van der Brug, M., Van der Lugt, A., van der Wee, N.J.A., van Duijn, C.M., van Haren, N.E.M., Van′t Ent, D., van Tol, M-J, Vardarajan, B.N., Veltman, D.J., Vernooij, M.W., Volzke, H., Walter, H., Wardlaw, J.M., Wassink, T.H., Weale, M.E., Weinberger, D.R., Weiner, M.W., Wen, W., Westman, E., White, T., Wong, T.Y., Wright, C.B., Zielke, H.R., Zonderman, A.B., Deary, I.J., DeCarli, C., Schmidt, H., Martin, N.G., de Craen, A.J.M., Wright, M.J., Launer, L.J., Schumann, G., Fornage, M., Franke, B., Debette, S., Medland, S.E., Ikram, M.A., and Thompson, P.M.
Abstract: Intracranial volume reflects the maximally attained brain size during development, and remains stable with loss of tissue in late life. It is highly heritable, but the underlying genes remain largely undetermined. In a genome-wide association study of 32,438 adults, we discovered five previously unknown loci for intracranial volume and confirmed two known signals. Four of the loci were also associated with adult human stature, but these remained associated with intracranial volume after adjusting for height. We found a high genetic correlation with child head circumference (ρgenetic = 0.748), which indicates a similar genetic background and allowed us to identify four additional loci through meta-analysis (Ncombined = 37,345). Variants for intracranial volume were also related to childhood and adult cognitive function, and Parkinson's disease, and were enriched near genes involved in growth pathways, including PI3K-AKT signaling. These findings identify the biological underpinnings of intracranial volume and their link to physiological and pathological traits.
Published: 2016

138. Cystatin C and Cardiovascular Disease: A Mendelian Randomization Study

Author: Laan, S.W. van der, Fall, T., Soumare, A., Teumer, A., Sedaghat, S., Baumert, J., Zabaneh, D., Setten, J. van, Isgum, I., Galesloot, T.E., Arpegard, J., Amouyel, P., Trompet, S., Waldenberger, M., Dorr, M., Magnusson, P.K., Giedraitis, V., Larsson, A., Morris, A.P., Felix, J.F., Morrison, A.C., Franceschini, N., Bis, J.C., Kavousi, M., O'Donnell, C., Drenos, F., Tragante, V., Munroe, P.B., Malik, R., Dichgans, M., Worrall, B.B., Erdmann, J., Nelson, C.P., Samani, N.J., Schunkert, H., Marchini, J., Patel, R.S., Hingorani, A.D., Lind, L., Pedersen, N.L., Graaf, J. de, Kiemeney, L.A.L.M., Baumeister, S.E., Franco, O.H., Hofman, A., Uitterlinden, A.G., Koenig, W., Meisinger, C., Peters, A., Thorand, B., Jukema, J.W., Eriksen, B.O., Toft, I., Wilsgaard, T., Onland-Moret, N.C., Schouw, Y.T. van der, Debette, S., Kumari, M., Svensson, P., Harst, P. van der, Kivimäki, M., Keating, B.J., Sattar, N., Dehghan, A., Reiner, A.P., Ingelsson, E., Ruijter, H.M. Den, Bakker, P.I. de, Pasterkamp, G., Arnlov, J., Holmes, M.V., Asselbergs, F.W., Laan, S.W. van der, Fall, T., Soumare, A., Teumer, A., Sedaghat, S., Baumert, J., Zabaneh, D., Setten, J. van, Isgum, I., Galesloot, T.E., Arpegard, J., Amouyel, P., Trompet, S., Waldenberger, M., Dorr, M., Magnusson, P.K., Giedraitis, V., Larsson, A., Morris, A.P., Felix, J.F., Morrison, A.C., Franceschini, N., Bis, J.C., Kavousi, M., O'Donnell, C., Drenos, F., Tragante, V., Munroe, P.B., Malik, R., Dichgans, M., Worrall, B.B., Erdmann, J., Nelson, C.P., Samani, N.J., Schunkert, H., Marchini, J., Patel, R.S., Hingorani, A.D., Lind, L., Pedersen, N.L., Graaf, J. de, Kiemeney, L.A.L.M., Baumeister, S.E., Franco, O.H., Hofman, A., Uitterlinden, A.G., Koenig, W., Meisinger, C., Peters, A., Thorand, B., Jukema, J.W., Eriksen, B.O., Toft, I., Wilsgaard, T., Onland-Moret, N.C., Schouw, Y.T. van der, Debette, S., Kumari, M., Svensson, P., Harst, P. van der, Kivimäki, M., Keating, B.J., Sattar, N., Dehghan, A., Reiner, A.P., Ingelsson, E., Ruijter, H.M. Den, Bakker, P.I. de, Pasterkamp, G., Arnlov, J., Holmes, M.V., and Asselbergs, F.W.
Abstract: Contains fulltext : 172252.pdf (Publisher’s version ) (Open Access), BACKGROUND: Epidemiological studies show that high circulating cystatin C is associated with risk of cardiovascular disease (CVD), independent of creatinine-based renal function measurements. It is unclear whether this relationship is causal, arises from residual confounding, and/or is a consequence of reverse causation. OBJECTIVES: The aim of this study was to use Mendelian randomization to investigate whether cystatin C is causally related to CVD in the general population. METHODS: We incorporated participant data from 16 prospective cohorts (n = 76,481) with 37,126 measures of cystatin C and added genetic data from 43 studies (n = 252,216) with 63,292 CVD events. We used the common variant rs911119 in CST3 as an instrumental variable to investigate the causal role of cystatin C in CVD, including coronary heart disease, ischemic stroke, and heart failure. RESULTS: Cystatin C concentrations were associated with CVD risk after adjusting for age, sex, and traditional risk factors (relative risk: 1.82 per doubling of cystatin C; 95% confidence interval [CI]: 1.56 to 2.13; p = 2.12 x 10(-14)). The minor allele of rs911119 was associated with decreased serum cystatin C (6.13% per allele; 95% CI: 5.75 to 6.50; p = 5.95 x 10(-211)), explaining 2.8% of the observed variation in cystatin C. Mendelian randomization analysis did not provide evidence for a causal role of cystatin C, with a causal relative risk for CVD of 1.00 per doubling cystatin C (95% CI: 0.82 to 1.22; p = 0.994), which was statistically different from the observational estimate (p = 1.6 x 10(-5)). A causal effect of cystatin C was not detected for any individual component of CVD. CONCLUSIONS: Mendelian randomization analyses did not support a causal role of cystatin C in the etiology of CVD. As such, therapeutics targeted at lowering circulating cystatin C are unlikely to be effective in preventing CVD.
Published: 2016

139. Cystatin C and Cardiovascular Disease: A Mendelian Randomization Study

Author: Van Der Laan, S.W. (Sander W.), Fall, M. (Magnus), Soumaré, A. (Aicha), Teumer, A. (Alexander), Sedaghat, S. (Sanaz), Baumert, J. (Jens), Zabaneh, D. (Delilah), Setten, J. (Jessica) van, Isgum, I. (Ivana), Galesloot, T.E. (Tessel), Arpegård, J. (Johannes), Amouyel, P. (Philippe), Trompet, S. (Stella), Waldenberger, M. (Melanie), Dörr, M. (Marcus), Magnusson, P.K. (Patrik), Giedraitis, V. (Vilmantas), Larsson, A. (Anders), Morris, A.P. (Andrew), Felix, J.F. (Janine), Morrison, A.C. (Alanna C.), Franceschini, N. (Nora), Bis, J.C. (Joshua), Kavousi, M. (Maryam), O'Donnell, C.J. (Christopher), Drenos, F. (Fotios), Tragante, V. (Vinicius), Munroe, P. (Patricia), Malik, R. (Rainer), Kubisch, C. (Christian), Worrall, B.B. (Bradford B.), Erdmann, J. (Jeanette), Nelson, C.P. (Christopher P.), Samani, N.J. (Nilesh), Schunkert, H. (Heribert), Marchini, J. (Jonathan), Patel, R.S. (Riyaz), Hingorani, A. (Aroon), Kao, W.H.L. (Wen), Pedersen, N.L. (Nancy), Graaf, J. (Jacqueline) de, Kiemeney, L.A.L.M. (Bart), Baumeister, S.E. (Sebastian), Franco, O.H. (Oscar), Hofman, A. (Albert), Uitterlinden, A.G. (André), Koenig, W. (Wolfgang), Meisinger, C. (Christa), Peters, A. (Annette), Thorand, B. (Barbara), Jukema, J.W. (Jan Wouter), Eriksen, B.O. (Bjørn Odvar), Toft, I. (Ingrid), Wilsgaard, T. (Tom), Onland-Moret, N.C. (N. Charlotte), Schouw, Y.T. (Yvonne) van der, Debette, S. (Stéphanie), Kumari, M. (Meena), Svensson, P. (Per), van der Harst, P. (Pim), Kivimaki, M. (Mika), Keating, J. (John), Sattar, N. (Naveed), Dehghan, A. (Abbas), Reiner, A. (Alexander), Ingelsson, E. (Erik), Ruijter, H.M. (Hester ) den, Bakker, P.I.W. (Paul) de, Pasterkamp, G. (Gerard), Ärnlöv, J. (Johan), Holmes, M.V. (Michael), Asselbergs, F.W. (Folkert), Van Der Laan, S.W. (Sander W.), Fall, M. (Magnus), Soumaré, A. (Aicha), Teumer, A. (Alexander), Sedaghat, S. (Sanaz), Baumert, J. (Jens), Zabaneh, D. (Delilah), Setten, J. (Jessica) van, Isgum, I. (Ivana), Galesloot, T.E. (Tessel), Arpegård, J. (Johannes), Amouyel, P. (Philippe), Trompet, S. (Stella), Waldenberger, M. (Melanie), Dörr, M. (Marcus), Magnusson, P.K. (Patrik), Giedraitis, V. (Vilmantas), Larsson, A. (Anders), Morris, A.P. (Andrew), Felix, J.F. (Janine), Morrison, A.C. (Alanna C.), Franceschini, N. (Nora), Bis, J.C. (Joshua), Kavousi, M. (Maryam), O'Donnell, C.J. (Christopher), Drenos, F. (Fotios), Tragante, V. (Vinicius), Munroe, P. (Patricia), Malik, R. (Rainer), Kubisch, C. (Christian), Worrall, B.B. (Bradford B.), Erdmann, J. (Jeanette), Nelson, C.P. (Christopher P.), Samani, N.J. (Nilesh), Schunkert, H. (Heribert), Marchini, J. (Jonathan), Patel, R.S. (Riyaz), Hingorani, A. (Aroon), Kao, W.H.L. (Wen), Pedersen, N.L. (Nancy), Graaf, J. (Jacqueline) de, Kiemeney, L.A.L.M. (Bart), Baumeister, S.E. (Sebastian), Franco, O.H. (Oscar), Hofman, A. (Albert), Uitterlinden, A.G. (André), Koenig, W. (Wolfgang), Meisinger, C. (Christa), Peters, A. (Annette), Thorand, B. (Barbara), Jukema, J.W. (Jan Wouter), Eriksen, B.O. (Bjørn Odvar), Toft, I. (Ingrid), Wilsgaard, T. (Tom), Onland-Moret, N.C. (N. Charlotte), Schouw, Y.T. (Yvonne) van der, Debette, S. (Stéphanie), Kumari, M. (Meena), Svensson, P. (Per), van der Harst, P. (Pim), Kivimaki, M. (Mika), Keating, J. (John), Sattar, N. (Naveed), Dehghan, A. (Abbas), Reiner, A. (Alexander), Ingelsson, E. (Erik), Ruijter, H.M. (Hester ) den, Bakker, P.I.W. (Paul) de, Pasterkamp, G. (Gerard), Ärnlöv, J. (Johan), Holmes, M.V. (Michael), and Asselbergs, F.W. (Folkert)
Abstract: __Background__ Epidemiological studies show that high circulating cystatin C is associated with risk of cardiovascular disease (CVD), independent of creatinine-based renal function measurements. It is unclear whether this relationship is causal, arises from residual confounding, and/or is a consequence of reverse causation. __Objectives__ The aim of this study was to use Mendelian randomization to investigate whether cystatin C is causally related to CVD in the general population. __Methods__ We incorporated participant data from 16 prospective cohorts (n = 76,481) with 37,126 measures of cystatin C and added genetic data from 43 studies (n = 252,216) with 63,292 CVD events. We used the common variant rs911119 in CST3 as an instrumental variable to investigate the causal role of cystatin C in CVD, including coronary heart disease, ischemic stroke, and heart failure. __Results__ Cystatin C concentrations were associated with CVD risk after adjusting for age, sex, and traditional risk factors (relative risk: 1.82 per doubling of cystatin C; 95% confidence interval [CI]: 1.56 to 2.13; p = 2.12 × 10−14). The minor allele of rs911119 was associated with decreased serum cystatin C (6.13% per allele; 95% CI: 5.75 to 6.50; p = 5.95 × 10−211), explaining 2.8% of the observed variation in cystatin C. Mendelian randomization analysis did not provide evidence for a causal role of cystatin C, with a causal relative risk for CVD of 1.00 per doubling cystatin C (95% CI: 0.82 to 1.22; p = 0.994), which was statistically different from the observational estimate (p = 1.6 × 10−5). A causal effect of cystatin C was not detected for any individual component of CVD. __Conclusions__ Mendelian randomization analyses did not support a causal role of cystatin C in the etiology of CVD. As such, therapeutics targeted at lowering circulating cystatin C are unlikely to be effective in preventing CVD.
Published: 2016
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140. Genome-Wide Association Analysis of Young-Onset Stroke Identifies a Locus on Chromosome 10q25 Near HABP2

Author: Cheng, Y.-C. (Yu-Ching), Stanne, T.M. (Tara M.), Giese, A.-K. (Anne-Katrin), Ho, W.K. (Weang K.), Traylor, M. (Matthew), Amouyel, P. (Philippe), Holliday, E.G. (Elizabeth), Malik, R. (Rainer), Xu, H. (Huichun), Kittner, T. (Thomas), Cole, J.W. (John W.), O´Connell, J.R., Danesh, J. (John), Rasheed, A. (Asif), Zhao, W. (Wei), Engelter, S.T. (Stefan), Grond-Ginsbach, C. (Caspar), Kamatani, Y. (Yoichiro), Lathrop, M. (Mark), Leys, D. (Didier), Thijs, V. (Vincent), Metso, T.M. (Tiina M.), Tatlisumak, T. (Turgut), Pezzini, A. (Alessandro), Parati, E.A. (Eugenio A.), Norrving, B. (Bo), Bevan, S. (Steve), Rothwell, P.M. (Peter), Sudlow, C. (Cathie), Slowik, A. (Agnieszka), Lindgren, A.G. (Arne G.), Walters, M. (Matthew), Jannes, J. (Jim), Shen, J. (Jess), Crosslin, D.R. (David), Doheny, K.F. (Kimberly), Laurie, C.C. (Cathy), Kanse, S.M. (Sandip ), Bis, J.C. (Joshua), Fornage, M. (Myriam), Mosley, T.H. (Thomas H.), Hopewell, J., Strauch, K. (Konstantin), Müller-Nurasyid, M. (Martina), Gieger, C. (Christian), Waldenberger, M. (Melanie), Peters, A. (Annette), Meisinger, C. (Christine), Ikram, M.A. (Arfan), Longstreth Jr, W.T., Meschia, J.F. (James F.), Seshadri, S. (Sudha), Sharma, P. (Pankaj), Worrall, B.B. (Bradford B.), Jern, C. (Christina), Levi, C. (Christopher), Kubisch, C. (Christian), Boncoraglio, G. (Giorgio Battista), Markus, H.S. (Hugh), Debette, S. (Stéphanie), Rolfs, A. (Arndt), Saleheen, D., Mitchell, B.D. (Braxton), Cheng, Y.-C. (Yu-Ching), Stanne, T.M. (Tara M.), Giese, A.-K. (Anne-Katrin), Ho, W.K. (Weang K.), Traylor, M. (Matthew), Amouyel, P. (Philippe), Holliday, E.G. (Elizabeth), Malik, R. (Rainer), Xu, H. (Huichun), Kittner, T. (Thomas), Cole, J.W. (John W.), O´Connell, J.R., Danesh, J. (John), Rasheed, A. (Asif), Zhao, W. (Wei), Engelter, S.T. (Stefan), Grond-Ginsbach, C. (Caspar), Kamatani, Y. (Yoichiro), Lathrop, M. (Mark), Leys, D. (Didier), Thijs, V. (Vincent), Metso, T.M. (Tiina M.), Tatlisumak, T. (Turgut), Pezzini, A. (Alessandro), Parati, E.A. (Eugenio A.), Norrving, B. (Bo), Bevan, S. (Steve), Rothwell, P.M. (Peter), Sudlow, C. (Cathie), Slowik, A. (Agnieszka), Lindgren, A.G. (Arne G.), Walters, M. (Matthew), Jannes, J. (Jim), Shen, J. (Jess), Crosslin, D.R. (David), Doheny, K.F. (Kimberly), Laurie, C.C. (Cathy), Kanse, S.M. (Sandip ), Bis, J.C. (Joshua), Fornage, M. (Myriam), Mosley, T.H. (Thomas H.), Hopewell, J., Strauch, K. (Konstantin), Müller-Nurasyid, M. (Martina), Gieger, C. (Christian), Waldenberger, M. (Melanie), Peters, A. (Annette), Meisinger, C. (Christine), Ikram, M.A. (Arfan), Longstreth Jr, W.T., Meschia, J.F. (James F.), Seshadri, S. (Sudha), Sharma, P. (Pankaj), Worrall, B.B. (Bradford B.), Jern, C. (Christina), Levi, C. (Christopher), Kubisch, C. (Christian), Boncoraglio, G. (Giorgio Battista), Markus, H.S. (Hugh), Debette, S. (Stéphanie), Rolfs, A. (Arndt), Saleheen, D., and Mitchell, B.D. (Braxton)
Abstract: Background and Purpose - Although a genetic contribution to ischemic stroke is well recognized, only a handful of stroke loci have been identified by large-scale genetic association studies to date. Hypothesizing that genetic effects might be stronger for early-versus late-onset str
Published: 2016
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141. Molecular genetic aetiology of general cognitive function is enriched in evolutionarily conserved regions

Author: Hill, W.D. (W. David), Davies, G. (Gail), Harris, S.E. (Sarah), Hagenaars, S. (Saskia), Liewald, D.C.M. (David), Penke, L., Gale, C.R., Deary, I.J., Deary, I.J. (Ian), Debette, S. (Stéphanie), Verbaas, C.I. (Carla I.), Bressler, J. (Jan), Schuur, M. (Maaike), Smith, A.V. (Albert Vernon), Bis, J.C. (Joshua), Bennett, D.A. (David), Ikram, M.K. (Kamran), Launer, L.J. (Lenore), Fitzpatrick, A.L. (Annette), Seshadri, S. (Sudha), Duijn, C.M. (Cornelia) van, Mosley, T.H. (Thomas H.), Hill, W.D. (W. David), Davies, G. (Gail), Harris, S.E. (Sarah), Hagenaars, S. (Saskia), Liewald, D.C.M. (David), Penke, L., Gale, C.R., Deary, I.J., Deary, I.J. (Ian), Debette, S. (Stéphanie), Verbaas, C.I. (Carla I.), Bressler, J. (Jan), Schuur, M. (Maaike), Smith, A.V. (Albert Vernon), Bis, J.C. (Joshua), Bennett, D.A. (David), Ikram, M.K. (Kamran), Launer, L.J. (Lenore), Fitzpatrick, A.L. (Annette), Seshadri, S. (Sudha), Duijn, C.M. (Cornelia) van, and Mosley, T.H. (Thomas H.)
Abstract: Differences in general cognitive function have been shown to be partly heritable and to show genetic correlations with several psychiatric and physical disease states. However, to date, few single-nucleotide polymorphisms (SNPs) have demonstrated genome-wide significance, hampering efforts aimed at determining which genetic variants are most important for cognitive function and which regions drive the genetic associations between cognitive function and disease states. Here, we combine multiple large genome-wide association study (GWAS) data sets, from the CHARGE cognitive consortium (n =53 949) and UK Biobank (n=36 035), to partition the genome into 52 functional annotations and an additional 10 annotations describing tissuespecific histone marks. Using stratified linkage disequilibrium score regression we show that, in two measures of cognitive function, SNPs associated with cognitive function cluster in regions of the genome that are under evolutionary negative selective pressure. These conserved regions contained ∼2.6% of the SNPs from each GWAS but accounted for ∼ 40% of the SNP-based heritability. The results suggest that the search for causal variants associated with cognitive function, and those variants that exert a pleiotropic effect between cognitive function and health, will be facilitated by examining these enriched regions.
Published: 2016
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142. GWAS for executive function and processing speed suggests involvement of the CADM2 gene

Author: Ibrahim-Verbaas, C.A. (Carla), Bressler, J., Debette, S. (Stéphanie), Schuur, M. (Maaike), Smith, A.V. (Albert), Bis, J.C. (Joshua), Davies, G. (Gail), Trompet, S. (Stella), Smith, J.A., Björnsson, A. (Asgeir), Chibnik, L.B. (Lori), Liu, Y., Vitart, V. (Veronique), Kirin, M. (Mirna), Petrovic, K. (Katja), Polasek, O. (Ozren), Zgaga, L. (Lina), Fawns-Ritchie, C., Hoffmann, P. (Per), Karjalainen, J. (Juha), Lahti, J., Llewellyn, D.J., Schmidt, C.O. (Carsten O.), Mather, R., Chouraki, V. (Vincent), Sun, Q., Resnick, S.M. (Susan), Rose, L.M. (Lynda M.), Oldmeadow, C. (Christopher), Stewart, M., Smith, B.H., Gudnason, V. (Vilmundur), Yang, Q. (Qiong), Mirza, S.S. (Saira), Jukema, J.W., DeJager, P.L. (Philip L.), Harris, T.B. (Tamara), Liewald, D.C.M. (David), Amin, N. (Najaf), Coker, L.H. (Laura), Stegle, O. (Oliver), Lopez, O.L., Schmidt, R., Teumer, A. (Alexander), Ford, I., Karbalai, N. (Nazanin), Becker, J.T. (James), Jonsdottir, M.K. (Maria K.), Au, R., Fehrmann, R.S.N. (Rudolf), Herms, S. (Stefan), Nalls, M.A. (Michael), Zhao, W., Turner, S.T., Yaffe, K., Lohman, K. (Kurt), Swieten, J.C. (John) van, Kardia, S.L.R., Knopman, D.S. (David), Meeks, W.M. (William), Heiss, G. (Gerardo), Holliday, E.G. (Elizabeth), Schofield, P.W., Tanaka, T. (Toshiko), Stott, D.J. (David J.), Wang, J. (Jing), Ridker, P.M. (Paul), Gow, A.J., Pattie, A. (Alison), Starr, J.M. (John), Hocking, L.J., Armstrong, N.J. (Nicola), McLachlan, S. (Stela), Shulman, L. (Lee), Pilling, L.C. (Luke), Eiriksdottir, G. (Gudny), Scott, R.J., Kochan, N.A. (Nicole A.), Palotie, A., Hsieh, Y.-C. (Yi-Chen), Eriksson, J.G. (Johan G.), Penman, A.D. (Alan), Gottesman, R.F. (Rebecca), Oostra, B.A. (Ben), Yu, L., DeStefano, A.L. (Anita L.), Beiser, A., Garcia, M., Rotter, J.I., Nöthen, M.M., Hofman, A. (Albert), Slagboom, P.E. (Eline), Westendorp, R.G.J., Buckley, B.M. (Brendan M.), Wolf, P.A., Uitterlinden, A.G. (André), Psaty, B.M. (Bruce), Grabe, H.J. (Hans Jörgen), Bandinelli, S. (Stefania), Chasman, D.I. (Daniel), Grodstein, F. (Francine), Räikkönen, K. (Katri), Lambert, J.-C., Porteous, D.J. (David J.), Price, J.F. (Jackie F.), Sachdev, P.S. (Perminder), Ferrucci, L. (Luigi), Attia, J. (John), Rudan, I. (Igor), Hayward, C., Wright, A.F., Wilson, J.F. (James F), Cichon, S. (Sven), Franke, L. (Lude), Schmidt, H., Ding, J. (Jingzhong), Craen, A.J. (Anton) de, Fornage, M. (Myriam), Bennett, D.A. (David), Deary, I.J. (Ian), Ikram, M.A. (Arfan), Launer, L.J. (Lenore), Fitzpatrick, A.L., Seshadri, S. (Sudha), Duijn, C.M. (Cornelia) van, Mosley, T.H. (Thomas H.), Ibrahim-Verbaas, C.A. (Carla), Bressler, J., Debette, S. (Stéphanie), Schuur, M. (Maaike), Smith, A.V. (Albert), Bis, J.C. (Joshua), Davies, G. (Gail), Trompet, S. (Stella), Smith, J.A., Björnsson, A. (Asgeir), Chibnik, L.B. (Lori), Liu, Y., Vitart, V. (Veronique), Kirin, M. (Mirna), Petrovic, K. (Katja), Polasek, O. (Ozren), Zgaga, L. (Lina), Fawns-Ritchie, C., Hoffmann, P. (Per), Karjalainen, J. (Juha), Lahti, J., Llewellyn, D.J., Schmidt, C.O. (Carsten O.), Mather, R., Chouraki, V. (Vincent), Sun, Q., Resnick, S.M. (Susan), Rose, L.M. (Lynda M.), Oldmeadow, C. (Christopher), Stewart, M., Smith, B.H., Gudnason, V. (Vilmundur), Yang, Q. (Qiong), Mirza, S.S. (Saira), Jukema, J.W., DeJager, P.L. (Philip L.), Harris, T.B. (Tamara), Liewald, D.C.M. (David), Amin, N. (Najaf), Coker, L.H. (Laura), Stegle, O. (Oliver), Lopez, O.L., Schmidt, R., Teumer, A. (Alexander), Ford, I., Karbalai, N. (Nazanin), Becker, J.T. (James), Jonsdottir, M.K. (Maria K.), Au, R., Fehrmann, R.S.N. (Rudolf), Herms, S. (Stefan), Nalls, M.A. (Michael), Zhao, W., Turner, S.T., Yaffe, K., Lohman, K. (Kurt), Swieten, J.C. (John) van, Kardia, S.L.R., Knopman, D.S. (David), Meeks, W.M. (William), Heiss, G. (Gerardo), Holliday, E.G. (Elizabeth), Schofield, P.W., Tanaka, T. (Toshiko), Stott, D.J. (David J.), Wang, J. (Jing), Ridker, P.M. (Paul), Gow, A.J., Pattie, A. (Alison), Starr, J.M. (John), Hocking, L.J., Armstrong, N.J. (Nicola), McLachlan, S. (Stela), Shulman, L. (Lee), Pilling, L.C. (Luke), Eiriksdottir, G. (Gudny), Scott, R.J., Kochan, N.A. (Nicole A.), Palotie, A., Hsieh, Y.-C. (Yi-Chen), Eriksson, J.G. (Johan G.), Penman, A.D. (Alan), Gottesman, R.F. (Rebecca), Oostra, B.A. (Ben), Yu, L., DeStefano, A.L. (Anita L.), Beiser, A., Garcia, M., Rotter, J.I., Nöthen, M.M., Hofman, A. (Albert), Slagboom, P.E. (Eline), Westendorp, R.G.J., Buckley, B.M. (Brendan M.), Wolf, P.A., Uitterlinden, A.G. (André), Psaty, B.M. (Bruce), Grabe, H.J. (Hans Jörgen), Bandinelli, S. (Stefania), Chasman, D.I. (Daniel), Grodstein, F. (Francine), Räikkönen, K. (Katri), Lambert, J.-C., Porteous, D.J. (David J.), Price, J.F. (Jackie F.), Sachdev, P.S. (Perminder), Ferrucci, L. (Luigi), Attia, J. (John), Rudan, I. (Igor), Hayward, C., Wright, A.F., Wilson, J.F. (James F), Cichon, S. (Sven), Franke, L. (Lude), Schmidt, H., Ding, J. (Jingzhong), Craen, A.J. (Anton) de, Fornage, M. (Myriam), Bennett, D.A. (David), Deary, I.J. (Ian), Ikram, M.A. (Arfan), Launer, L.J. (Lenore), Fitzpatrick, A.L., Seshadri, S. (Sudha), Duijn, C.M. (Cornelia) van, and Mosley, T.H. (Thomas H.)
Abstract: To identify common variants contributing to normal variation in two specific domains of cognitive functioning, we conducted a genome-wide association study (GWAS) of executive functioning and information processing speed in non-demented older adults from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) consortium. Neuropsychological testing was available for 5429-32 070 subjects of European ancestry aged 45 years or older, free of dementia and clinical stroke at the time of cognitive testing from 20 cohorts in the discovery phase. We analyzed performance on the Trail Making Test parts A and B, the Letter Digit Substitution Test (LDST), the Digit Symbol Substitution Task (DSST), semantic and phonemic fluency tests, and the Stroop Color and Word Test. Replication was sought in 1311-21860 subjects from 20 independent cohorts. A significant association was observed in the discovery cohorts for the single-nucleotide polymorphism (SNP) rs17518584 (discovery P-value=3.12 × 10 -8) and in the joint discovery and replication meta-analysis (P-value=3.28 × 10 -9 after adjustment for age, gender and education) in an intron of the gene cell adhesion molecule 2 (CADM2) for performance on the LDST/DSST. Rs17518584 is located about 170 kb upstream of the transcription start site of the major transcript for the CADM2 gene, but is within an intron of a variant transcript that includes an alternative first exon. The variant is associated with expression of CADM2 in the cingulate cortex (P-value=4 × 10 -4). The protein encoded by CADM2 is involved in glutamate signaling (P-value=7.22 × 10 -15), gamma-aminobutyric acid (GABA) transport (P-value=1.36 × 10 -11) and neuron cell-cell adhesion (P-value=1.48 × 10 -13).
Published: 2016
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143. Prognostic significance of pulsatile tinnitus in cervical artery dissection

Author: Kellert, L, Kloss, M, Pezzini, A, Debette, S, Leys, D, Caso, V, Thijs, VN, Bersano, A, Touze, E, Tatlisumak, T, Traenka, C, Lyrer, PA, Engelter, ST, Metso, TM, Grond-Ginsbach, C, Kellert, L, Kloss, M, Pezzini, A, Debette, S, Leys, D, Caso, V, Thijs, VN, Bersano, A, Touze, E, Tatlisumak, T, Traenka, C, Lyrer, PA, Engelter, ST, Metso, TM, and Grond-Ginsbach, C
Abstract: BACKGROUND AND PURPOSE: Our aim was to investigate whether pulsatile tinnitus (PT) in cervical artery dissection (CeAD) has prognostic significance. METHODS: All CeAD patients from the CADISP (Cervical Artery Dissection and Ischemic Stroke Patients) study with documentation of PT were analysed. The presence of PT was systematically assessed using a standardized questionnaire. Stroke severity at admission was defined according to the National Institutes of Health Stroke Scale (NIHSS). Excellent outcome after 3 months was defined as a modified Rankin Scale of 0-1. RESULTS: Sixty-three of 778 patients (8.1%) reported PT. PT+ patients presented less often with ischaemic stroke (41.3% vs. 63.9%, P < 0.001), more often with dissection in the internal carotid artery (85.7% vs. 64.2%, P = 0.001), less often with vessel occlusion (19.0% vs. 34.1%, P = 0.017) and more often with excellent outcome at 3 months (92.1% vs. 75.4%, P = 0.002). Logistic regression analysis identified PT as an independent predictor of excellent outcome after 3 months [odds ratio (OR) 3.96, 95% confidence interval (CI) 1.22-12.87] adjusted to significant outcome predictors NIHSS on admission (OR 0.82, 95% CI 0.79-0.86), Horner syndrome (OR 1.95, 95% CI 1.16-3.29) and vessel occlusion (OR 0.62, 95% CI 0.40-0.94) and to non-significant predictors age, sex, pain and location of CeAD. CONCLUSION: The presence of PT in CeAD is associated with a benign clinical course and predicts a favourable outcome.
Published: 2016

144. Towards the genetic basis of cerebral venous thrombosis-the BEAST Consortium: a study protocol

Author: Cotlarciuc, I, Marjot, T, Khan, MS, Hiltunen, S, Haapaniemi, E, Metso, TM, Putaala, J, Zuurbier, SM, Brouwer, MC, Passamonti, SM, Bucciarelli, P, Pappalardo, E, Patel, T, Costa, P, Colombi, M, Canhao, P, Tkach, A, Santacroce, R, Margaglione, M, Favuzzi, G, Grandone, E, Colaizzo, D, Spengos, K, Arauz, A, Hodge, A, Ditta, R, Debette, S, Zedde, M, Pare, G, Ferro, JM, Thijs, V, Pezzini, A, Majersik, JJ, Martinelli, I, Coutinho, JM, Tatlisumak, T, Sharma, P, Cotlarciuc, I, Marjot, T, Khan, MS, Hiltunen, S, Haapaniemi, E, Metso, TM, Putaala, J, Zuurbier, SM, Brouwer, MC, Passamonti, SM, Bucciarelli, P, Pappalardo, E, Patel, T, Costa, P, Colombi, M, Canhao, P, Tkach, A, Santacroce, R, Margaglione, M, Favuzzi, G, Grandone, E, Colaizzo, D, Spengos, K, Arauz, A, Hodge, A, Ditta, R, Debette, S, Zedde, M, Pare, G, Ferro, JM, Thijs, V, Pezzini, A, Majersik, JJ, Martinelli, I, Coutinho, JM, Tatlisumak, T, and Sharma, P
Abstract: INTRODUCTION: Cerebral venous thrombosis (CVT) is a rare cerebrovascular condition accounting for <1% of all stroke cases and mainly affects young adults. Its genetic aetiology is not clearly elucidated. METHODS AND ANALYSIS: To better understand the genetic basis of CVT, we have established an international biobank of CVT cases, Biorepository to Establish the Aetiology of Sinovenous Thrombosis (BEAST) which aims to recruit highly phenotyped cases initially of European descent and later from other populations. To date we have recruited 745 CVT cases from 12 research centres. As an initial step, the consortium plans to undertake a genome-wide association analysis of CVT using the Illumina Infinium HumanCoreExome BeadChip to assess the association and impact of common and low-frequency genetic variants on CVT risk by using a case-control study design. Replication will be performed to confirm putative findings. Furthermore, we aim to identify interactions of genetic variants with several environmental and comorbidity factors which will likely contribute to improve the understanding of the biological mechanisms underlying this complex disease. ETHICS AND DISSEMINATION: BEAST meets all ethical standards set by local institutional review boards for each of the participating sites. The research outcomes will be published in international peer-reviewed open-access journals with high impact and visibility. The results will be presented at national and international meetings to highlight the contributions into improving the understanding of the mechanisms underlying this uncommon but important disease. This international DNA repository will become an important resource for investigators in the field of haematological and vascular disorders.
Published: 2016

145. Cystatin C and Cardiovascular Disease A Mendelian Randomization Study

Author: van der Laan, SW, Fall, T, Soumare, A, Teumer, A, Sedaghat, Sanaz, Baumert, J, Zabaneh, D, van Setten, J, Isgum, I, Galesloot, TE, Arpegard, J, Amouyel, P, Trompet, S, Waldenberger, M, Dorr, M, Magnusson, PK, Giedraitis, V, Larsson, A, Morris, AP, Felix, Janine, Morrison, AC, Franceschini, N, Bis, JC, Kavousi, Maryam, O'Donnell, C, Drenos, F, Tragante, V, Munroe, PB, Malik, R, Dichgans, M, Worrall, BB, Erdmann, J, Nelson, CP, Samani, NJ, Schunkert, H, Marchini, J, Patel, RS, Hingorani, AD, Lind, L, Pedersen, NL, van der Graaf, J, Kiemeney, LALM, Baumeister, SE, Franco Duran, OH, Hofman, Bert, Uitterlinden, André, Koenig, W, Meisinger, C, Peters, A, Thorand, B, Jukema, JW, Eriksen, B O, Toft, I, Wilsgaard, T, Onland-Moret, NC, van der Schouw, YT, Debette, S, Kumari, M, Svensson, P, van der Harst, P, Kivimaki, M, Keating, BJ, Sattar, N, Dehghan, Abbas, Reiner, AP, Ingelsson, E, den Ruijter, HM, de Bakker, PIW, Pasterkamp, G, Arnlov, J, Holmes, MV, Asselbergs, FW, van der Laan, SW, Fall, T, Soumare, A, Teumer, A, Sedaghat, Sanaz, Baumert, J, Zabaneh, D, van Setten, J, Isgum, I, Galesloot, TE, Arpegard, J, Amouyel, P, Trompet, S, Waldenberger, M, Dorr, M, Magnusson, PK, Giedraitis, V, Larsson, A, Morris, AP, Felix, Janine, Morrison, AC, Franceschini, N, Bis, JC, Kavousi, Maryam, O'Donnell, C, Drenos, F, Tragante, V, Munroe, PB, Malik, R, Dichgans, M, Worrall, BB, Erdmann, J, Nelson, CP, Samani, NJ, Schunkert, H, Marchini, J, Patel, RS, Hingorani, AD, Lind, L, Pedersen, NL, van der Graaf, J, Kiemeney, LALM, Baumeister, SE, Franco Duran, OH, Hofman, Bert, Uitterlinden, André, Koenig, W, Meisinger, C, Peters, A, Thorand, B, Jukema, JW, Eriksen, B O, Toft, I, Wilsgaard, T, Onland-Moret, NC, van der Schouw, YT, Debette, S, Kumari, M, Svensson, P, van der Harst, P, Kivimaki, M, Keating, BJ, Sattar, N, Dehghan, Abbas, Reiner, AP, Ingelsson, E, den Ruijter, HM, de Bakker, PIW, Pasterkamp, G, Arnlov, J, Holmes, MV, and Asselbergs, FW
Published: 2016

146. Are migraine and non-migrainous headache risk factors for stroke in the elderly? Findings from a 12-year cohort follow-up

Author: Norton, J., primary, Portet, F., additional, Gabelle, A., additional, Debette, S., additional, Ritchie, K., additional, Touchon, J., additional, and Berr, C., additional
Published: 2016
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147. Common variation in PHACTR1 is associated with susceptibility to cervical artery dissection

Author: Debette, S., Kamatani, Y., Metso, T.M., Kloss, M., Chauhan, G., Engelter, S.T., Pezzini, S, Thijs, V., Markus, H.S., Dichgans, M., Wolf, C., Dittrich, R., Touze, E., Southerland, A.M., Samson, Y., Abboud, S., Bejot, Y., Caso, V., Bersano, A., Gschwendtner, A., Sessa, M., Cole, J., Lamy, C., Medeiros, E., Beretta, S., Bonati, L.H., Grau, A.J., Michel, P., Majersik, J.J., Sharma, P., Kalashnikova, L., Nazarova, M., Dobrynina, L., Bartels, E., Guillon, B., Herik, E.G. van den, Fernandez-Cadenas, I., Jood, K., Nalls, M.A., Leeuw, H.F. de, Jern, C., Cheng, Y.C., Werner, I., Metso, A.J., Lichy, C., Lyrer, P.A., Brandt, T., Boncoraglio, G.B., Wichmann, H.E., Gieger, C., Johnson, A.D., Bottcher, T., Castellano, M., Arveiler, D., Ikram, M.A., Breteler, M.M., Padovani, A., Meschia, J.F., Kuhlenbaumer, G., Rolfs, A., Worrall, B.B., Ringelstein, E.B., Zelenika, D., Tatlisumak, T., Lathrop, M., Leys, D., Amouyel, P., Dallongeville, J., Debette, S., Kamatani, Y., Metso, T.M., Kloss, M., Chauhan, G., Engelter, S.T., Pezzini, S, Thijs, V., Markus, H.S., Dichgans, M., Wolf, C., Dittrich, R., Touze, E., Southerland, A.M., Samson, Y., Abboud, S., Bejot, Y., Caso, V., Bersano, A., Gschwendtner, A., Sessa, M., Cole, J., Lamy, C., Medeiros, E., Beretta, S., Bonati, L.H., Grau, A.J., Michel, P., Majersik, J.J., Sharma, P., Kalashnikova, L., Nazarova, M., Dobrynina, L., Bartels, E., Guillon, B., Herik, E.G. van den, Fernandez-Cadenas, I., Jood, K., Nalls, M.A., Leeuw, H.F. de, Jern, C., Cheng, Y.C., Werner, I., Metso, A.J., Lichy, C., Lyrer, P.A., Brandt, T., Boncoraglio, G.B., Wichmann, H.E., Gieger, C., Johnson, A.D., Bottcher, T., Castellano, M., Arveiler, D., Ikram, M.A., Breteler, M.M., Padovani, A., Meschia, J.F., Kuhlenbaumer, G., Rolfs, A., Worrall, B.B., Ringelstein, E.B., Zelenika, D., Tatlisumak, T., Lathrop, M., Leys, D., Amouyel, P., and Dallongeville, J.
Abstract: Item does not contain fulltext, Cervical artery dissection (CeAD), a mural hematoma in a carotid or vertebral artery, is a major cause of ischemic stroke in young adults although relatively uncommon in the general population (incidence of 2.6/100,000 per year). Minor cervical traumas, infection, migraine and hypertension are putative risk factors, and inverse associations with obesity and hypercholesterolemia are described. No confirmed genetic susceptibility factors have been identified using candidate gene approaches. We performed genome-wide association studies (GWAS) in 1,393 CeAD cases and 14,416 controls. The rs9349379[G] allele (PHACTR1) was associated with lower CeAD risk (odds ratio (OR) = 0.75, 95% confidence interval (CI) = 0.69-0.82; P = 4.46 x 10(-10)), with confirmation in independent follow-up samples (659 CeAD cases and 2,648 controls; P = 3.91 x 10(-3); combined P = 1.00 x 10(-11)). The rs9349379[G] allele was previously shown to be associated with lower risk of migraine and increased risk of myocardial infarction. Deciphering the mechanisms underlying this pleiotropy might provide important information on the biological underpinnings of these disabling conditions.
Published: 2015

148. Genes from a translational analysis support a multifactorial nature of white matter hyperintensities

Author: Lopez, L.M. (Lorna), Hill, W.D. (W. David), Harris, S.E. (Sarah), Valdés Hernández, M.C. (Maria), Muñoz Maniega, S. (Susana), Bastin, M.E. (Mark), Bailey, E. (Emma), Smith, C. (Colin), McBride, M. (Martin), McClure, J. (John), Graham, D. (Delyth), Dominiczak, A. (Anna), Yang, Q. (Qiong Fang), Fornage, M. (Myriam), Ikram, M.A. (Arfan), Debette, S. (Stéphanie), Launer, L.J. (Lenore), Bis, J.C. (Joshua), Schmidt, R. (Reinhold), Seshadri, S. (Sudha), Porteous, D.J. (David J.), Starr, J.M. (John), Deary, I.J. (Ian), Wardlaw, J.M. (J.), Lopez, L.M. (Lorna), Hill, W.D. (W. David), Harris, S.E. (Sarah), Valdés Hernández, M.C. (Maria), Muñoz Maniega, S. (Susana), Bastin, M.E. (Mark), Bailey, E. (Emma), Smith, C. (Colin), McBride, M. (Martin), McClure, J. (John), Graham, D. (Delyth), Dominiczak, A. (Anna), Yang, Q. (Qiong Fang), Fornage, M. (Myriam), Ikram, M.A. (Arfan), Debette, S. (Stéphanie), Launer, L.J. (Lenore), Bis, J.C. (Joshua), Schmidt, R. (Reinhold), Seshadri, S. (Sudha), Porteous, D.J. (David J.), Starr, J.M. (John), Deary, I.J. (Ian), and Wardlaw, J.M. (J.)
Abstract: BACKGROUND AND PURPOSE - : White matter hyperintensities (WMH) of presumed vascular origin increase the risk of stroke and dementia. Despite strong WMH heritability, few gene associations have been identified. Relevant experimental models may be informative. METHODS - : We tested the associations between genes that were differentially expressed in brains of young spontaneously hypertensive stroke-prone rats and human WMH (using volume and visual score) in 621 subjects from the Lothian Birth Cohort 1936 (LBC1936). We then attempted replication in 9361 subjects from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE). We also tested the subjects from LBC1936 for previous genome-wide WMH associations found in subjects from CHARGE. RESULTS - : Of 126 spontaneously hypertensive stroke-prone rat genes, 10 were nominally associated with WMH volume or score in subjects from LBC1936, of which 5 (AFP, ALB, GNAI1, RBM8a, and MRPL18) were associated with both WMH volume and score (P<0.05); 2 of the 10 (XPNPEP1, P=6.7×10; FARP1, P=0.024) plus another spontaneously hypertensive stroke-prone rat gene (USMG5, P=0.00014), on chromosomes 10, 13, and 10 respectively, were associated with WMH in subjects from CHARGE. Gene set enrichment showed significant associations for downregulated spontaneously hypertensive stroke-prone rat genes with WMH in humans. In subjects from LBC1936, we replicated CHARGE's genome-wide WMH associations on chromosomes 17 (TRIM6
Published: 2015
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149. Structural Brain MRI Trait Polygenic Score Prediction of Cognitive Abilities

Author: Luciano, M. (Michelle), Marioni, R.E. (Riccardo), Valdés Hernández, M.C. (Maria), Maniega, S.M. (Susana Muñoz), Hamilton, I.F. (Iona F.), Royle, N.A. (Natalie), Chauhan, G. (Ganesh), Bis, J.C. (Joshua), Debette, S. (Stéphanie), DeCarli, C. (Charles), Fornage, M. (Myriam), Schmidt, R. (Reinhold), Ikram, M.A. (Arfan), Launer, L.J. (Lenore), Seshadri, S. (Sudha), Bastin, M.E. (Mark), Porteous, D.J. (David J.), Wardlaw, J. (Joanna), Deary, I.J. (Ian), Luciano, M. (Michelle), Marioni, R.E. (Riccardo), Valdés Hernández, M.C. (Maria), Maniega, S.M. (Susana Muñoz), Hamilton, I.F. (Iona F.), Royle, N.A. (Natalie), Chauhan, G. (Ganesh), Bis, J.C. (Joshua), Debette, S. (Stéphanie), DeCarli, C. (Charles), Fornage, M. (Myriam), Schmidt, R. (Reinhold), Ikram, M.A. (Arfan), Launer, L.J. (Lenore), Seshadri, S. (Sudha), Bastin, M.E. (Mark), Porteous, D.J. (David J.), Wardlaw, J. (Joanna), and Deary, I.J. (Ian)
Abstract: Copyright
Published: 2015
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150. White Matter Lesion Progression: Genome-Wide Search for Genetic Influences

Author: Hofer, E. (Edith), Cavalieri, M. (Margherita), Bis, J.C. (Joshua), DeCarli, C. (Charles), Fornage, M. (Myriam), Sigurdsson, S. (Sigurdur), Srikanth, V. (Velandai), Trompet, S. (Stella), Verhaaren, B.F.J. (Benjamin), Wolf, C. (Christiane), Yang, Q. (Qiong Fang), Adams, H.H.H. (Hieab), Amouyel, P. (Philippe), Beiser, A. (Alexa), Buckley, B.M. (Brendan M.), Callisaya, M. (Michele), Chauhan, G. (Ganesh), De Craen, A.J.M. (Anton J. M.), Dufouil, C. (Carole), Duijn, C.M. (Cornelia) van, Ford, I., Freudenberger, P. (Paul), Gottesman, R.F. (Rebecca), Gudnason, V. (Vilmundur), Heiss, G. (Gerardo), Hofman, A. (Albert), Lumley, T. (Thomas), Martinez, O. (Oliver), Mazoyer, B. (Bernard), Moran, C. (Chris), Niessen, W.J. (Wiro), Phan, T.G. (Thanh), Psaty, B.M. (Bruce), Satizabal, C.L. (Claudia), Sattar, N. (Naveed), Schilling, S. (Sabrina), Shibata, D.K. (Dean), Slagboom, P.E. (Eline), Smith, A.V. (Davey), Stott, D.J. (David. J.), Taylor, K.D. (Kent), Thomson, R. (Russell), Töglhofer, A.M. (Anna Maria), Tzourio, C. (Christophe), Buchem, M.A. (Mark) van, Wang, J. (Jing), Westendorp, R.G.J. (Rudi), Windham, B.G. (Gwen), Vernooij, M.W. (Meike), Zijdenbos, A.P., Beare, R.J. (Richard), Debette, S. (Stéphanie), Ikram, M.A. (Arfan), Jukema, J.W. (Jan Wouter), Launer, L.J. (Lenore), Longstreth Jr, W.T., Mosley, T.H. (Thomas H.), Seshadri, S. (Sudha), Schmidt, R. (Reinhold), Hofer, E. (Edith), Cavalieri, M. (Margherita), Bis, J.C. (Joshua), DeCarli, C. (Charles), Fornage, M. (Myriam), Sigurdsson, S. (Sigurdur), Srikanth, V. (Velandai), Trompet, S. (Stella), Verhaaren, B.F.J. (Benjamin), Wolf, C. (Christiane), Yang, Q. (Qiong Fang), Adams, H.H.H. (Hieab), Amouyel, P. (Philippe), Beiser, A. (Alexa), Buckley, B.M. (Brendan M.), Callisaya, M. (Michele), Chauhan, G. (Ganesh), De Craen, A.J.M. (Anton J. M.), Dufouil, C. (Carole), Duijn, C.M. (Cornelia) van, Ford, I., Freudenberger, P. (Paul), Gottesman, R.F. (Rebecca), Gudnason, V. (Vilmundur), Heiss, G. (Gerardo), Hofman, A. (Albert), Lumley, T. (Thomas), Martinez, O. (Oliver), Mazoyer, B. (Bernard), Moran, C. (Chris), Niessen, W.J. (Wiro), Phan, T.G. (Thanh), Psaty, B.M. (Bruce), Satizabal, C.L. (Claudia), Sattar, N. (Naveed), Schilling, S. (Sabrina), Shibata, D.K. (Dean), Slagboom, P.E. (Eline), Smith, A.V. (Davey), Stott, D.J. (David. J.), Taylor, K.D. (Kent), Thomson, R. (Russell), Töglhofer, A.M. (Anna Maria), Tzourio, C. (Christophe), Buchem, M.A. (Mark) van, Wang, J. (Jing), Westendorp, R.G.J. (Rudi), Windham, B.G. (Gwen), Vernooij, M.W. (Meike), Zijdenbos, A.P., Beare, R.J. (Richard), Debette, S. (Stéphanie), Ikram, M.A. (Arfan), Jukema, J.W. (Jan Wouter), Launer, L.J. (Lenore), Longstreth Jr, W.T., Mosley, T.H. (Thomas H.), Seshadri, S. (Sudha), and Schmidt, R. (Reinhold)
Abstract: Background and Purpose-White matter lesion (WML) progression on magnetic resonance imaging is related to cognitive decline and stroke, but its determinants besides baseline WML burden are largely unknown. Here, we estimated heritability of WML progression, and sought common genetic variants associated with WML progression in elderly participants from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium. Methods-Heritability of WML progression was calculated in the Framingham Heart Study. The genome-wide association study included 7773 elderly participants from 10 cohorts. To assess the relative contribution of genetic factors to progression of WML, we compared in 7 cohorts risk models including demographics, vascular risk factors plus single-nucleotide polymorphisms that have been shown to be associated cross-sectionally with WML in the current and previous association studies. Results-A total of 1085 subjects showed WML progression. The heritability estimate for WML progression was low at 6.5%, and no single-nucleotide polymorphisms achieved genome-wide significance (P<5×10-8). Four loci were suggestive (P<1×10-5) of an association with WML progression: 10q24.32 (rs10883817, P=1.46×10-6); 12q13.13 (rs4
Published: 2015
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