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1. 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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2. GWAS for executive function and processing speed suggests involvement of the CADM2 gene

Author

Ibrahim-Verbaas, C.A. (Carla), Bressler, J. (Jan), 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), 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. (David C.), 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. (Rhoda), Fehrmann, R.S.N. (Rudolf), Herms, S. (Stefan), Nalls, M.A. (Michael), Zhao, W., Turner, S.T. (Stephen), Yaffe, K., Lohman, K. (Kurt), Swieten, J.C. (John) van, Kardia, S.L. (Sharon 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, J.M., Pilling, L.C. (Luke), Eiriksdottir, G. (Gudny), Scott, R. (Rodney), Kochan, N.A. (Nicole A.), Palotie, A. (Aarno), Hsieh, Y.-C. (Yi-Chen), Eriksson, J.G. (Johan G.), Penman, A.D. (Alan), Gottesman, R.F. (Rebecca), Oostra, B.A. (Ben), Yu, L. (Lei), DeStefano, A.L. (Anita), Beiser, A. (Alexa), Garcia, M., Rotter, J.I. (Jerome I.), Nöthen, M.M. (Markus 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. (J.), 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., 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. (Annette), Seshadri, S. (Sudha), Duijn, C.M. (Cornelia) van, Mosley, T.H. (Thomas H.), Ibrahim-Verbaas, C.A. (Carla), Bressler, J. (Jan), 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), 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. (David C.), 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. (Rhoda), Fehrmann, R.S.N. (Rudolf), Herms, S. (Stefan), Nalls, M.A. (Michael), Zhao, W., Turner, S.T. (Stephen), Yaffe, K., Lohman, K. (Kurt), Swieten, J.C. (John) van, Kardia, S.L. (Sharon 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, J.M., Pilling, L.C. (Luke), Eiriksdottir, G. (Gudny), Scott, R. (Rodney), Kochan, N.A. (Nicole A.), Palotie, A. (Aarno), Hsieh, Y.-C. (Yi-Chen), Eriksson, J.G. (Johan G.), Penman, A.D. (Alan), Gottesman, R.F. (Rebecca), Oostra, B.A. (Ben), Yu, L. (Lei), DeStefano, A.L. (Anita), Beiser, A. (Alexa), Garcia, M., Rotter, J.I. (Jerome I.), Nöthen, M.M. (Markus 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. (J.), 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., 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. (Annette), 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), semant

Published
2016
Full Text
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3. Genome-wide studies of verbal declarative memory in nondemented older people: The Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium

Author

Debette, S. (Stéphanie), Ibrahim-Verbaas, C.A. (Carla), Bressler, J. (Jan), Schuur, M. (Maaike), Smith, A.V. (Davey), Bis, J.C. (Joshua), Davies, G. (Gail), Wolf, C. (Christiane), Gudnason, V. (Vilmundur), Chibnik, L.B. (Lori), Yang, Q. (Qiong Fang), DeStefano, A.L. (Anita), De Quervain, D.J.F. (Dominique J.F.), Srikanth, V. (Velandai), Lahti, J. (Jari), Grabe, H.J. (Hans Jörgen), Smith, J.A. (Jennifer A), Priebe, L., Yu, L. (Lei), Karbalai, N. (Nazanin), Hayward, C. (Caroline), Wilson, J.F. (James F), Campbell, H. (Harry), Petrovic, K. (Katja), Fornage, M. (Myriam), Chauhan, G. (Ganesh), Yeo, R. (Robin), Boxall, R. (Ruth), Becker, J.T. (James), Stegle, O. (Oliver), Mather, R., Chouraki, V. (Vincent), Sun, Q. (Qi), Rose, L.M. (Lynda), Resnick, S.M. (Susan), Oldmeadow, C. (Christopher), Kirin, M. (Mirna), Wright, A. (Alan), Jonsdottir, M.K. (Maria K.), Au, R. (Rhoda), Becker, A. (Albert), Amin, N. (Najaf), Nalls, M.A. (Michael), Turner, S.T. (Stephen), Kardia, S.L.R. (Sharon), Oostra, B.A. (Ben), Windham, G. (Gwen), Coker, L.H. (Laura), Zhao, W. (Wei), Knopman, D.S. (David), Heiss, G. (Gerardo), Griswold, M.D. (Michael), Gottesman, R.F. (Rebecca), Vitart, V. (Veronique), Hastie, N. (Nick), Zgaga, L. (Lina), Rudan, I. (Igor), Polasek, O. (Ozren), Holliday, E.G. (Elizabeth), Schofield, P. (Peter), Choi, S.-H. (Seung-Hoan), Tanaka, T. (Toshiko), An, Y. (Yang), Perry, R.T. (Rodney T.), Kennedy, R.E. (Richard E.), Sale, M.M. (Michèle M.), Wang, J. (Jing), Wadley, V.G. (Virginia G.), Liewald, D.C. (David C.), Ridker, P.M. (Paul), Gow, A.J. (Alan J.), Pattie, A. (Alison), Starr, J.M. (John), Porteous, D.J. (David J.), Liu, X. (Xuan), Thomson, R. (Russell), Armstrong, N.J. (Nicola), Eiriksdottir, G. (Gudny), Assareh, A.A. (Arezoo), Kochan, N.A. (Nicole A.), Widen, E. (Elisabeth), Palotie, A. (Aarno), Hsieh, Y.-C. (Yi-Chen), Eriksson, J.G. (Johan G.), Vogler, C. (Christian), Swieten, J.C. (John) van, Shulman, L. (Lee), Beiser, A. (Alexa), Rotter, J.I. (Jerome I.), Schmidt, C.O. (Carsten O.), Hoffmann, W. (Wolfgang), Nöthen, M.M. (Markus M.), Ferrucci, L. (Luigi), Attia, J. (John), Uitterlinden, A.G. (André), Amouyel, P. (Philippe), Dartigues, J.-F. (Jean-François), Amieva, H. (Hélène), Räikkönen, K. (Katri), Garcia, M. (Melissa), Wolf, P.A. (Philip), Hofman, A. (Albert), Longstreth Jr, W.T., Psaty, B.M. (Bruce), Boerwinkle, E.A. (Eric), DeJager, P.L. (Philip L.), Sachdev, P.S. (Perminder), Schmidt, R. (Reinhold), Breteler, M.M.B. (Monique), Teumer, A. (Alexander), Lopez, O.L. (Oscar), Cichon, S. (Sven), Chasman, D.I. (Daniel), Grodstein, F. (Francine), Müller-Myhsok, B. (B.), Tzourio, C. (Christophe), Papassotiropoulos, A. (Andreas), Bennett, D.A. (David), Ikram, M.A. (Arfan), Deary, I.J. (Ian), Duijn, C.M. (Cornelia) van, Launer, L.J. (Lenore), Fitzpatrick, A.L. (Annette), Seshadri, S. (Sudha), Mosley, T.H. (Thomas H.), Debette, S. (Stéphanie), Ibrahim-Verbaas, C.A. (Carla), Bressler, J. (Jan), Schuur, M. (Maaike), Smith, A.V. (Davey), Bis, J.C. (Joshua), Davies, G. (Gail), Wolf, C. (Christiane), Gudnason, V. (Vilmundur), Chibnik, L.B. (Lori), Yang, Q. (Qiong Fang), DeStefano, A.L. (Anita), De Quervain, D.J.F. (Dominique J.F.), Srikanth, V. (Velandai), Lahti, J. (Jari), Grabe, H.J. (Hans Jörgen), Smith, J.A. (Jennifer A), Priebe, L., Yu, L. (Lei), Karbalai, N. (Nazanin), Hayward, C. (Caroline), Wilson, J.F. (James F), Campbell, H. (Harry), Petrovic, K. (Katja), Fornage, M. (Myriam), Chauhan, G. (Ganesh), Yeo, R. (Robin), Boxall, R. (Ruth), Becker, J.T. (James), Stegle, O. (Oliver), Mather, R., Chouraki, V. (Vincent), Sun, Q. (Qi), Rose, L.M. (Lynda), Resnick, S.M. (Susan), Oldmeadow, C. (Christopher), Kirin, M. (Mirna), Wright, A. (Alan), Jonsdottir, M.K. (Maria K.), Au, R. (Rhoda), Becker, A. (Albert), Amin, N. (Najaf), Nalls, M.A. (Michael), Turner, S.T. (Stephen), Kardia, S.L.R. (Sharon), Oostra, B.A. (Ben), Windham, G. (Gwen), Coker, L.H. (Laura), Zhao, W. (Wei), Knopman, D.S. (David), Heiss, G. (Gerardo), Griswold, M.D. (Michael), Gottesman, R.F. (Rebecca), Vitart, V. (Veronique), Hastie, N. (Nick), Zgaga, L. (Lina), Rudan, I. (Igor), Polasek, O. (Ozren), Holliday, E.G. (Elizabeth), Schofield, P. (Peter), Choi, S.-H. (Seung-Hoan), Tanaka, T. (Toshiko), An, Y. (Yang), Perry, R.T. (Rodney T.), Kennedy, R.E. (Richard E.), Sale, M.M. (Michèle M.), Wang, J. (Jing), Wadley, V.G. (Virginia G.), Liewald, D.C. (David C.), Ridker, P.M. (Paul), Gow, A.J. (Alan J.), Pattie, A. (Alison), Starr, J.M. (John), Porteous, D.J. (David J.), Liu, X. (Xuan), Thomson, R. (Russell), Armstrong, N.J. (Nicola), Eiriksdottir, G. (Gudny), Assareh, A.A. (Arezoo), Kochan, N.A. (Nicole A.), Widen, E. (Elisabeth), Palotie, A. (Aarno), Hsieh, Y.-C. (Yi-Chen), Eriksson, J.G. (Johan G.), Vogler, C. (Christian), Swieten, J.C. (John) van, Shulman, L. (Lee), Beiser, A. (Alexa), Rotter, J.I. (Jerome I.), Schmidt, C.O. (Carsten O.), Hoffmann, W. (Wolfgang), Nöthen, M.M. (Markus M.), Ferrucci, L. (Luigi), Attia, J. (John), Uitterlinden, A.G. (André), Amouyel, P. (Philippe), Dartigues, J.-F. (Jean-François), Amieva, H. (Hélène), Räikkönen, K. (Katri), Garcia, M. (Melissa), Wolf, P.A. (Philip), Hofman, A. (Albert), Longstreth Jr, W.T., Psaty, B.M. (Bruce), Boerwinkle, E.A. (Eric), DeJager, P.L. (Philip L.), Sachdev, P.S. (Perminder), Schmidt, R. (Reinhold), Breteler, M.M.B. (Monique), Teumer, A. (Alexander), Lopez, O.L. (Oscar), Cichon, S. (Sven), Chasman, D.I. (Daniel), Grodstein, F. (Francine), Müller-Myhsok, B. (B.), Tzourio, C. (Christophe), Papassotiropoulos, A. (Andreas), Bennett, D.A. (David), Ikram, M.A. (Arfan), Deary, I.J. (Ian), Duijn, C.M. (Cornelia) van, Launer, L.J. (Lenore), Fitzpatrick, A.L. (Annette), Seshadri, S. (Sudha), and Mosley, T.H. (Thomas H.)

Abstract

BACKGROUND: Memory performance in older persons can reflect genetic influences on cognitive function and dementing processes. We aimed to identify genetic contributions to verbal declarative memory in a community setting. MET

Published
2015
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4. Genome-wide studies of verbal declarative memory in nondemented older people: The cohorts for heart and aging research in genomic epidemiology consortium

Author

Debette, S., Ibrahim Verbaas, C.A., Bressler, J., Schuur, M., Smith, A., Bis, J.C., Davies, G., Wolf, C., Gudnason, V., Chibnik, L.B., Yang, Q., DeStefano, A.L., de Quervain, D.J.F., Srikanth, V., Lahti, J., Grabe, H.J., Smith, J.A., Priebe, L., Yu, L., Karbalai, N., Hayward, C., Wilson, J.F., Campbell, H., Petrovic, K., Fornage, M., Chauhan, G., Yeo, R., Boxall, R., Becker, J., Stegle, O., Mather, K.A., Chouraki, V., Sun, Q., Rose, L.M., Resnick, S., Oldmeadow, C., Kirin, M., Wright, A.F., Jonsdottir, M.K., Au, R., Becker, A., Amin, N., Nalls, M.A., Turner, S.T., Kardia, S.L.R., Oostra, B., Windham, G., Coker, L.H., Zhao, W., Knopman, D.S., Heiss, G., Griswold, M.E., Gottesman, R.F., Vitart, V., Hastie, N.D., Zgaga, L., Rudan, I., Polasek, O., Holliday, E.G., Schofield, P., Choi, S.H., Tanaka, T., An, Y., Perry, R.T., Kennedy, R.E., Sale, M.M., Wang, J., Wadley, V.G., Liewald, D.C., Ridker, P.M., Gow, A.J., Pattie, A., Starr, J.M., Porteous, D., Liu, X., Thomson, R., Armstrong, N.J., Eiriksdottir, G., Assareh, A.A., Kochan, N.A., Widen, E., Palotie, A., Hsieh, Y-C, Eriksson, J.G., Vogler, C., van Swieten, J.C., Shulman, J.M., Beiser, A., Rotter, J., Schmidt, C.O., Hoffmann, W., Nöthen, M.M., Ferrucci, L., Attia, J., Uitterlinden, A.G., Amouyel, P., Dartigues, J-F, Amieva, H., Räikkönen, K., Garcia, M., Wolf, P.A., Hofman, A., Longstreth, W.T., Psaty, B.M., Boerwinkle, E., DeJager, P.L., Sachdev, P.S., Schmidt, R., Breteler, M.M.B., Teumer, A., Lopez, O.L., Cichon, S., Chasman, D.I., Grodstein, F., Müller-Myhsok, B., Tzourio, C., Papassotiropoulos, A., Bennett, D.A., Ikram, M.A., Deary, I.J., van Duijn, C.M., Launer, L., Fitzpatrick, A.L., Seshadri, S., Mosley, T.H., Debette, S., Ibrahim Verbaas, C.A., Bressler, J., Schuur, M., Smith, A., Bis, J.C., Davies, G., Wolf, C., Gudnason, V., Chibnik, L.B., Yang, Q., DeStefano, A.L., de Quervain, D.J.F., Srikanth, V., Lahti, J., Grabe, H.J., Smith, J.A., Priebe, L., Yu, L., Karbalai, N., Hayward, C., Wilson, J.F., Campbell, H., Petrovic, K., Fornage, M., Chauhan, G., Yeo, R., Boxall, R., Becker, J., Stegle, O., Mather, K.A., Chouraki, V., Sun, Q., Rose, L.M., Resnick, S., Oldmeadow, C., Kirin, M., Wright, A.F., Jonsdottir, M.K., Au, R., Becker, A., Amin, N., Nalls, M.A., Turner, S.T., Kardia, S.L.R., Oostra, B., Windham, G., Coker, L.H., Zhao, W., Knopman, D.S., Heiss, G., Griswold, M.E., Gottesman, R.F., Vitart, V., Hastie, N.D., Zgaga, L., Rudan, I., Polasek, O., Holliday, E.G., Schofield, P., Choi, S.H., Tanaka, T., An, Y., Perry, R.T., Kennedy, R.E., Sale, M.M., Wang, J., Wadley, V.G., Liewald, D.C., Ridker, P.M., Gow, A.J., Pattie, A., Starr, J.M., Porteous, D., Liu, X., Thomson, R., Armstrong, N.J., Eiriksdottir, G., Assareh, A.A., Kochan, N.A., Widen, E., Palotie, A., Hsieh, Y-C, Eriksson, J.G., Vogler, C., van Swieten, J.C., Shulman, J.M., Beiser, A., Rotter, J., Schmidt, C.O., Hoffmann, W., Nöthen, M.M., Ferrucci, L., Attia, J., Uitterlinden, A.G., Amouyel, P., Dartigues, J-F, Amieva, H., Räikkönen, K., Garcia, M., Wolf, P.A., Hofman, A., Longstreth, W.T., Psaty, B.M., Boerwinkle, E., DeJager, P.L., Sachdev, P.S., Schmidt, R., Breteler, M.M.B., Teumer, A., Lopez, O.L., Cichon, S., Chasman, D.I., Grodstein, F., Müller-Myhsok, B., Tzourio, C., Papassotiropoulos, A., Bennett, D.A., Ikram, M.A., Deary, I.J., van Duijn, C.M., Launer, L., Fitzpatrick, A.L., Seshadri, S., and Mosley, T.H.

Abstract

Background Memory performance in older persons can reflect genetic influences on cognitive function and dementing processes. We aimed to identify genetic contributions to verbal declarative memory in a community setting. Methods We conducted genome-wide association studies for paragraph or word list delayed recall in 19 cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, comprising 29,076 dementia- and stroke-free individuals of European descent, aged ≥45 years. Replication of suggestive associations (p < 5 × 10−6) was sought in 10,617 participants of European descent, 3811 African-Americans, and 1561 young adults. Results rs4420638, near APOE, was associated with poorer delayed recall performance in discovery (p = 5.57 × 10−10) and replication cohorts (p = 5.65 × 10−8). This association was stronger for paragraph than word list delayed recall and in the oldest persons. Two associations with specific tests, in subsets of the total sample, reached genome-wide significance in combined analyses of discovery and replication (rs11074779 [HS3ST4], p = 3.11 × 10−8, and rs6813517 [SPOCK3], p = 2.58 × 10−8) near genes involved in immune response. A genetic score combining 58 independent suggestive memory risk variants was associated with increasing Alzheimer disease pathology in 725 autopsy samples. Association of memory risk loci with gene expression in 138 human hippocampus samples showed cis-associations with WDR48 and CLDN5, both related to ubiquitin metabolism. Conclusions This largest study to date exploring the genetics of memory function in ~40,000 older individuals revealed genome-wide associations and suggested an involvement of immune and ubiquitin pathways.

Published
2015

5. GWAS for executive function and processing speed suggests involvement of the CADM2 gene

Author

Ibrahim-Verbaas, C.A., Bressler, J., Debette, S., Schuur, M., Smith, A.V., Bis, J.C., Davies, G., Trompet, S., Smith, J.A., Wolf, C., Chibnik, L.B., Liu, Y., Vitart, V., Kirin, M., Petrovic, K., Polasek, O., Zgaga, L., Fawns-Ritchie, C., Hoffmann, P., Karjalainen, J., Lahti, J., Llewellyn, D.J., Schmidt, C.O., Mather, K.A., Chouraki, V., Sun, Q., Resnick, S.M., Rose, L.M., Oldmeadow, C., Stewart, M., Smith, B.H., Gudnason, V., Yang, Q., Mirza, S.S., Jukema, J.W., deJager, P.L., Harris, T.B., Liewald, D.C., Amin, N., Coker, L.H., Stegle, O., Lopez, O.L., Schmidt, R., Teumer, A., Ford, I., Karbalai, N., Becker, J.T., Jonsdottir, M.K., Au, R., Fehrmann, R.S.N., Herms, S., Nalls, M., Zhao, W., Turner, S.T., Yaffe, K., Lohman, K., van Swieten, J.C., Kardia, S.L.R, Knopman, D.S., Meeks, W.M., Heiss, G., Holliday, E.G., Schofield, P.W., Tanaka, T., Stott, D.J., Wang, J., Ridker, P., Gow, A.J., Pattie, A, Starr, J.M., Hocking, L.J., Armstrong, N.J., McLachlan, S., Shulman, J.M., Pilling, L.C., Eiriksdottir, G., Scott, R.J., Kochan, N.A., Palotie, A., Hsieh, Y-C, Eriksson, J.G., Penman, A., Gottesman, R.F., Oostra, B.A., Yu, L., DeStefano, A.L., Beiser, A., Garcia, M., Rotter, J.I., Nöthen, M.M., Hofman, A., Slagboom, P.E., Westendorp, R.G.J., Buckley, B.M., Wolf, P.A., Uitterlinden, A.G., Psaty, B.M., Grabe, H.J., Bandinelli, S., Chasman, D.I., Grodstein, F., Räikkönen, K., Lambert, J-C, Porteous, D.J., Price, J.F., Sachdev, P.S., Ferrucci, L., Attia, J.R., Rudan, I., Hayward, C., Wright, A.F., Wilson, J.F., Cichon, S., Franke, L., Schmidt, H., Ding, J., de Craen, A.J.M., Fornage, M., Bennett, D.A., Deary, I.J., Ikram, M.A., Launer, L.J., Fitzpatrick, A.L., Seshadri, S., van Duijn, C.M., Mosley, T.H., Ibrahim-Verbaas, C.A., Bressler, J., Debette, S., Schuur, M., Smith, A.V., Bis, J.C., Davies, G., Trompet, S., Smith, J.A., Wolf, C., Chibnik, L.B., Liu, Y., Vitart, V., Kirin, M., Petrovic, K., Polasek, O., Zgaga, L., Fawns-Ritchie, C., Hoffmann, P., Karjalainen, J., Lahti, J., Llewellyn, D.J., Schmidt, C.O., Mather, K.A., Chouraki, V., Sun, Q., Resnick, S.M., Rose, L.M., Oldmeadow, C., Stewart, M., Smith, B.H., Gudnason, V., Yang, Q., Mirza, S.S., Jukema, J.W., deJager, P.L., Harris, T.B., Liewald, D.C., Amin, N., Coker, L.H., Stegle, O., Lopez, O.L., Schmidt, R., Teumer, A., Ford, I., Karbalai, N., Becker, J.T., Jonsdottir, M.K., Au, R., Fehrmann, R.S.N., Herms, S., Nalls, M., Zhao, W., Turner, S.T., Yaffe, K., Lohman, K., van Swieten, J.C., Kardia, S.L.R, Knopman, D.S., Meeks, W.M., Heiss, G., Holliday, E.G., Schofield, P.W., Tanaka, T., Stott, D.J., Wang, J., Ridker, P., Gow, A.J., Pattie, A, Starr, J.M., Hocking, L.J., Armstrong, N.J., McLachlan, S., Shulman, J.M., Pilling, L.C., Eiriksdottir, G., Scott, R.J., Kochan, N.A., Palotie, A., Hsieh, Y-C, Eriksson, J.G., Penman, A., Gottesman, R.F., Oostra, B.A., Yu, L., DeStefano, A.L., Beiser, A., Garcia, M., Rotter, J.I., Nöthen, M.M., Hofman, A., Slagboom, P.E., Westendorp, R.G.J., Buckley, B.M., Wolf, P.A., Uitterlinden, A.G., Psaty, B.M., Grabe, H.J., Bandinelli, S., Chasman, D.I., Grodstein, F., Räikkönen, K., Lambert, J-C, Porteous, D.J., Price, J.F., Sachdev, P.S., Ferrucci, L., Attia, J.R., Rudan, I., Hayward, C., Wright, A.F., Wilson, J.F., Cichon, S., Franke, L., Schmidt, H., Ding, J., de Craen, A.J.M., Fornage, M., Bennett, D.A., Deary, I.J., Ikram, M.A., Launer, L.J., Fitzpatrick, A.L., Seshadri, S., van Duijn, C.M., and Mosley, T.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). Our findings suggest that genetic variation in the CADM2 gene is associated with individual differences in information processing speed.Molecular Psychiatry advance online publication, 14 April 2015; doi:10.1038/mp.2015.37.

Published
2015

6. Genome-wide studies of verbal declarative memory in nondemented older people: The cohorts for heart and aging research in genomic epidemiology consortium

Author

Debette, S., Ibrahim Verbaas, C.A., Bressler, J., Schuur, M., Smith, A., Bis, J.C., Davies, G., Wolf, C., Gudnason, V., Chibnik, L.B., Yang, Q., DeStefano, A.L., de Quervain, D.J.F., Srikanth, V., Lahti, J., Grabe, H.J., Smith, J.A., Priebe, L., Yu, L., Karbalai, N., Hayward, C., Wilson, J.F., Campbell, H., Petrovic, K., Fornage, M., Chauhan, G., Yeo, R., Boxall, R., Becker, J., Stegle, O., Mather, K.A., Chouraki, V., Sun, Q., Rose, L.M., Resnick, S., Oldmeadow, C., Kirin, M., Wright, A.F., Jonsdottir, M.K., Au, R., Becker, A., Amin, N., Nalls, M.A., Turner, S.T., Kardia, S.L.R., Oostra, B., Windham, G., Coker, L.H., Zhao, W., Knopman, D.S., Heiss, G., Griswold, M.E., Gottesman, R.F., Vitart, V., Hastie, N.D., Zgaga, L., Rudan, I., Polasek, O., Holliday, E.G., Schofield, P., Choi, S.H., Tanaka, T., An, Y., Perry, R.T., Kennedy, R.E., Sale, M.M., Wang, J., Wadley, V.G., Liewald, D.C., Ridker, P.M., Gow, A.J., Pattie, A., Starr, J.M., Porteous, D., Liu, X., Thomson, R., Armstrong, N.J., Eiriksdottir, G., Assareh, A.A., Kochan, N.A., Widen, E., Palotie, A., Hsieh, Y-C, Eriksson, J.G., Vogler, C., van Swieten, J.C., Shulman, J.M., Beiser, A., Rotter, J., Schmidt, C.O., Hoffmann, W., Nöthen, M.M., Ferrucci, L., Attia, J., Uitterlinden, A.G., Amouyel, P., Dartigues, J-F, Amieva, H., Räikkönen, K., Garcia, M., Wolf, P.A., Hofman, A., Longstreth, W.T., Psaty, B.M., Boerwinkle, E., DeJager, P.L., Sachdev, P.S., Schmidt, R., Breteler, M.M.B., Teumer, A., Lopez, O.L., Cichon, S., Chasman, D.I., Grodstein, F., Müller-Myhsok, B., Tzourio, C., Papassotiropoulos, A., Bennett, D.A., Ikram, M.A., Deary, I.J., van Duijn, C.M., Launer, L., Fitzpatrick, A.L., Seshadri, S., Mosley, T.H., Debette, S., Ibrahim Verbaas, C.A., Bressler, J., Schuur, M., Smith, A., Bis, J.C., Davies, G., Wolf, C., Gudnason, V., Chibnik, L.B., Yang, Q., DeStefano, A.L., de Quervain, D.J.F., Srikanth, V., Lahti, J., Grabe, H.J., Smith, J.A., Priebe, L., Yu, L., Karbalai, N., Hayward, C., Wilson, J.F., Campbell, H., Petrovic, K., Fornage, M., Chauhan, G., Yeo, R., Boxall, R., Becker, J., Stegle, O., Mather, K.A., Chouraki, V., Sun, Q., Rose, L.M., Resnick, S., Oldmeadow, C., Kirin, M., Wright, A.F., Jonsdottir, M.K., Au, R., Becker, A., Amin, N., Nalls, M.A., Turner, S.T., Kardia, S.L.R., Oostra, B., Windham, G., Coker, L.H., Zhao, W., Knopman, D.S., Heiss, G., Griswold, M.E., Gottesman, R.F., Vitart, V., Hastie, N.D., Zgaga, L., Rudan, I., Polasek, O., Holliday, E.G., Schofield, P., Choi, S.H., Tanaka, T., An, Y., Perry, R.T., Kennedy, R.E., Sale, M.M., Wang, J., Wadley, V.G., Liewald, D.C., Ridker, P.M., Gow, A.J., Pattie, A., Starr, J.M., Porteous, D., Liu, X., Thomson, R., Armstrong, N.J., Eiriksdottir, G., Assareh, A.A., Kochan, N.A., Widen, E., Palotie, A., Hsieh, Y-C, Eriksson, J.G., Vogler, C., van Swieten, J.C., Shulman, J.M., Beiser, A., Rotter, J., Schmidt, C.O., Hoffmann, W., Nöthen, M.M., Ferrucci, L., Attia, J., Uitterlinden, A.G., Amouyel, P., Dartigues, J-F, Amieva, H., Räikkönen, K., Garcia, M., Wolf, P.A., Hofman, A., Longstreth, W.T., Psaty, B.M., Boerwinkle, E., DeJager, P.L., Sachdev, P.S., Schmidt, R., Breteler, M.M.B., Teumer, A., Lopez, O.L., Cichon, S., Chasman, D.I., Grodstein, F., Müller-Myhsok, B., Tzourio, C., Papassotiropoulos, A., Bennett, D.A., Ikram, M.A., Deary, I.J., van Duijn, C.M., Launer, L., Fitzpatrick, A.L., Seshadri, S., and Mosley, T.H.

Abstract

Background Memory performance in older persons can reflect genetic influences on cognitive function and dementing processes. We aimed to identify genetic contributions to verbal declarative memory in a community setting. Methods We conducted genome-wide association studies for paragraph or word list delayed recall in 19 cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, comprising 29,076 dementia- and stroke-free individuals of European descent, aged ≥45 years. Replication of suggestive associations (p < 5 × 10−6) was sought in 10,617 participants of European descent, 3811 African-Americans, and 1561 young adults. Results rs4420638, near APOE, was associated with poorer delayed recall performance in discovery (p = 5.57 × 10−10) and replication cohorts (p = 5.65 × 10−8). This association was stronger for paragraph than word list delayed recall and in the oldest persons. Two associations with specific tests, in subsets of the total sample, reached genome-wide significance in combined analyses of discovery and replication (rs11074779 [HS3ST4], p = 3.11 × 10−8, and rs6813517 [SPOCK3], p = 2.58 × 10−8) near genes involved in immune response. A genetic score combining 58 independent suggestive memory risk variants was associated with increasing Alzheimer disease pathology in 725 autopsy samples. Association of memory risk loci with gene expression in 138 human hippocampus samples showed cis-associations with WDR48 and CLDN5, both related to ubiquitin metabolism. Conclusions This largest study to date exploring the genetics of memory function in ~40,000 older individuals revealed genome-wide associations and suggested an involvement of immune and ubiquitin pathways.

Published
2015

7. GWAS for executive function and processing speed suggests involvement of the CADM2 gene

Author

Ibrahim-Verbaas, C.A., Bressler, J., Debette, S., Schuur, M., Smith, A.V., Bis, J.C., Davies, G., Trompet, S., Smith, J.A., Wolf, C., Chibnik, L.B., Liu, Y., Vitart, V., Kirin, M., Petrovic, K., Polasek, O., Zgaga, L., Fawns-Ritchie, C., Hoffmann, P., Karjalainen, J., Lahti, J., Llewellyn, D.J., Schmidt, C.O., Mather, K.A., Chouraki, V., Sun, Q., Resnick, S.M., Rose, L.M., Oldmeadow, C., Stewart, M., Smith, B.H., Gudnason, V., Yang, Q., Mirza, S.S., Jukema, J.W., deJager, P.L., Harris, T.B., Liewald, D.C., Amin, N., Coker, L.H., Stegle, O., Lopez, O.L., Schmidt, R., Teumer, A., Ford, I., Karbalai, N., Becker, J.T., Jonsdottir, M.K., Au, R., Fehrmann, R.S.N., Herms, S., Nalls, M., Zhao, W., Turner, S.T., Yaffe, K., Lohman, K., van Swieten, J.C., Kardia, S.L.R, Knopman, D.S., Meeks, W.M., Heiss, G., Holliday, E.G., Schofield, P.W., Tanaka, T., Stott, D.J., Wang, J., Ridker, P., Gow, A.J., Pattie, A, Starr, J.M., Hocking, L.J., Armstrong, N.J., McLachlan, S., Shulman, J.M., Pilling, L.C., Eiriksdottir, G., Scott, R.J., Kochan, N.A., Palotie, A., Hsieh, Y-C, Eriksson, J.G., Penman, A., Gottesman, R.F., Oostra, B.A., Yu, L., DeStefano, A.L., Beiser, A., Garcia, M., Rotter, J.I., Nöthen, M.M., Hofman, A., Slagboom, P.E., Westendorp, R.G.J., Buckley, B.M., Wolf, P.A., Uitterlinden, A.G., Psaty, B.M., Grabe, H.J., Bandinelli, S., Chasman, D.I., Grodstein, F., Räikkönen, K., Lambert, J-C, Porteous, D.J., Price, J.F., Sachdev, P.S., Ferrucci, L., Attia, J.R., Rudan, I., Hayward, C., Wright, A.F., Wilson, J.F., Cichon, S., Franke, L., Schmidt, H., Ding, J., de Craen, A.J.M., Fornage, M., Bennett, D.A., Deary, I.J., Ikram, M.A., Launer, L.J., Fitzpatrick, A.L., Seshadri, S., van Duijn, C.M., Mosley, T.H., Ibrahim-Verbaas, C.A., Bressler, J., Debette, S., Schuur, M., Smith, A.V., Bis, J.C., Davies, G., Trompet, S., Smith, J.A., Wolf, C., Chibnik, L.B., Liu, Y., Vitart, V., Kirin, M., Petrovic, K., Polasek, O., Zgaga, L., Fawns-Ritchie, C., Hoffmann, P., Karjalainen, J., Lahti, J., Llewellyn, D.J., Schmidt, C.O., Mather, K.A., Chouraki, V., Sun, Q., Resnick, S.M., Rose, L.M., Oldmeadow, C., Stewart, M., Smith, B.H., Gudnason, V., Yang, Q., Mirza, S.S., Jukema, J.W., deJager, P.L., Harris, T.B., Liewald, D.C., Amin, N., Coker, L.H., Stegle, O., Lopez, O.L., Schmidt, R., Teumer, A., Ford, I., Karbalai, N., Becker, J.T., Jonsdottir, M.K., Au, R., Fehrmann, R.S.N., Herms, S., Nalls, M., Zhao, W., Turner, S.T., Yaffe, K., Lohman, K., van Swieten, J.C., Kardia, S.L.R, Knopman, D.S., Meeks, W.M., Heiss, G., Holliday, E.G., Schofield, P.W., Tanaka, T., Stott, D.J., Wang, J., Ridker, P., Gow, A.J., Pattie, A, Starr, J.M., Hocking, L.J., Armstrong, N.J., McLachlan, S., Shulman, J.M., Pilling, L.C., Eiriksdottir, G., Scott, R.J., Kochan, N.A., Palotie, A., Hsieh, Y-C, Eriksson, J.G., Penman, A., Gottesman, R.F., Oostra, B.A., Yu, L., DeStefano, A.L., Beiser, A., Garcia, M., Rotter, J.I., Nöthen, M.M., Hofman, A., Slagboom, P.E., Westendorp, R.G.J., Buckley, B.M., Wolf, P.A., Uitterlinden, A.G., Psaty, B.M., Grabe, H.J., Bandinelli, S., Chasman, D.I., Grodstein, F., Räikkönen, K., Lambert, J-C, Porteous, D.J., Price, J.F., Sachdev, P.S., Ferrucci, L., Attia, J.R., Rudan, I., Hayward, C., Wright, A.F., Wilson, J.F., Cichon, S., Franke, L., Schmidt, H., Ding, J., de Craen, A.J.M., Fornage, M., Bennett, D.A., Deary, I.J., Ikram, M.A., Launer, L.J., Fitzpatrick, A.L., Seshadri, S., van Duijn, C.M., and Mosley, T.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). Our findings suggest that genetic variation in the CADM2 gene is associated with individual differences in information processing speed.Molecular Psychiatry advance online publication, 14 April 2015; doi:10.1038/mp.2015.37.

Published
2015

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