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

C. A. Ibrahim-Verbaas; J. Bressler; S. Debette; M. Schuur; A. V. Smith; J. C. Bis; G. Davies; S. Trompet; J. A. Smith; C. Wolf; L. B. Chibnik; Y. Liu; V. Vitart; M. Kirin; K. Petrovic; O. Polasek; L. Zgaga; C. Fawns-Ritchie; P. Hoffmann; J. Karjalainen; J. Lahti; D. J. Llewellyn; C. O. Schmidt; K. A. Mather; V. Chouraki; Q. Sun; S. M. Resnick; L. M. Rose; C. Oldmeadow; M. Stewart; B. H. Smith; V. Gudnason; Q. Yang; S. S. Mirza; J. W. Jukema; P. L. DeJager; T. B. Harris; D. C. Liewald; N. Amin; L. H. Coker; O. Stegle; O. L. Lopez; R. Schmidt; A. Teumer; I. Ford; N. Karbalai; J. T. Becker; M. K. Jonsdottir; R. Au; R. S N Fehrmann; S. Herms; M. Nalls; W. Zhao; S. T. Turner; K. Yaffe; K. Lohman; J. C. Van Swieten; S. L R Kardia; D. S. Knopman; W. M. Meeks; G. Heiss; E. G. Holliday; P. W. Schofield; T. Tanaka; D. J. Stott; J. Wang; P. Ridker; A. J. Gow; A. Pattie; J. M. Starr; L. J. Hocking; N. J. Armstrong; S. McLachlan; J. M. Shulman; L. C. Pilling; G. Eiriksdottir; R. J. Scott; N. A. Kochan; A. Palotie; Y. C. Hsieh; J. G. Eriksson; A. Penman; R. F. Gottesman; B. A. Oostra; L. Yu; A. L. DeStefano; A. Beiser; M. Garcia; J. I. Rotter; M. M. Nöthen; A. Hofman; P. E. Slagboom; R. G J Westendorp; B. M. Buckley; P. A. Wolf; A. G. Uitterlinden; B. M. Psaty; H. J. Grabe; S. Bandinelli; D. I. Chasman; F. Grodstein; K. Räikkönen; J. C. Lambert; D. J. Porteous; J. F. Price; P. S. Sachdev; L. Ferrucci; J. R. Attia; I. Rudan; C. Hayward; A. F. Wright; J. F. Wilson; S. Cichon; L. Franke; H. Schmidt; J. Ding; A. J M De Craen; M. Fornage; D. A. Bennett; I. J. Deary; M. A. Ikram; L. J. Launer; A. L. Fitzpatrick; S. Seshadri; C. M. Van Duijn; T. H. Mosley

doi:10.1038/mp.2015.37

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

C. A. Ibrahim-Verbaas, J. Bressler, S. Debette, M. Schuur, A. V. Smith, J. C. Bis, G. Davies, S. Trompet, J. A. Smith, C. Wolf, L. B. Chibnik, Y. Liu, V. Vitart, M. Kirin, K. Petrovic, O. Polasek, L. Zgaga, C. Fawns-Ritchie, P. Hoffmann, J. KarjalainenJ. Lahti, D. J. Llewellyn, C. O. Schmidt, K. A. Mather, V. Chouraki, Q. Sun, S. M. Resnick, L. M. Rose, C. Oldmeadow, M. Stewart, B. H. Smith, V. Gudnason, Q. Yang, S. S. Mirza, J. W. Jukema, P. L. DeJager, T. B. Harris, D. C. Liewald, N. Amin, L. H. Coker, O. Stegle, O. L. Lopez, R. Schmidt, A. Teumer, I. Ford, N. Karbalai, J. T. Becker, M. K. Jonsdottir, R. Au, R. S N Fehrmann, S. Herms, M. Nalls, W. Zhao, S. T. Turner, K. Yaffe, K. Lohman, J. C. Van Swieten, S. L R Kardia, D. S. Knopman, W. M. Meeks, G. Heiss, E. G. Holliday, P. W. Schofield, T. Tanaka, D. J. Stott, J. Wang, P. Ridker, A. J. Gow, A. Pattie, J. M. Starr, L. J. Hocking, N. J. Armstrong, S. McLachlan, J. M. Shulman, L. C. Pilling, G. Eiriksdottir, R. J. Scott, N. A. Kochan, A. Palotie, Y. C. Hsieh, J. G. Eriksson, A. Penman, R. F. Gottesman, B. A. Oostra, L. Yu, A. L. DeStefano, A. Beiser, M. Garcia, J. I. Rotter, M. M. Nöthen, A. Hofman, P. E. Slagboom, R. G J Westendorp, B. M. Buckley, P. A. Wolf, A. G. Uitterlinden, B. M. Psaty, H. J. Grabe, S. Bandinelli, D. I. Chasman, F. Grodstein, K. Räikkönen, J. C. Lambert, D. J. Porteous, J. F. Price, P. S. Sachdev, L. Ferrucci, J. R. Attia, I. Rudan, C. Hayward, A. F. Wright, J. F. Wilson, S. Cichon, L. Franke, H. Schmidt, J. Ding, A. J M De Craen, M. Fornage, D. A. Bennett, I. J. Deary, M. A. Ikram, L. J. Launer, A. L. Fitzpatrick, S. Seshadri, C. M. Van Duijn, T. H. Mosley

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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.

Original language	English
Pages (from-to)	189-197
Number of pages	9
Journal	Molecular Psychiatry
Volume	21
Issue number	2
DOIs	https://doi.org/10.1038/mp.2015.37
Publication status	Published - Feb 1 2016

ASJC Scopus subject areas

Molecular Biology
Cellular and Molecular Neuroscience
Psychiatry and Mental health

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10.1038/mp.2015.37

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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., ... Mosley, T. H. (2016). GWAS for executive function and processing speed suggests involvement of the CADM2 gene. Molecular Psychiatry, 21(2), 189-197. https://doi.org/10.1038/mp.2015.37

Ibrahim-Verbaas, CA, Bressler, J, Debette, S, Schuur, M, Smith, AV, Bis, JC, Davies, G, Trompet, S, Smith, JA, Wolf, C, Chibnik, LB, Liu, Y, Vitart, V, Kirin, M, Petrovic, K, Polasek, O, Zgaga, L, Fawns-Ritchie, C, Hoffmann, P, Karjalainen, J, Lahti, J, Llewellyn, DJ, Schmidt, CO, Mather, KA, Chouraki, V, Sun, Q, Resnick, SM, Rose, LM, Oldmeadow, C, Stewart, M, Smith, BH, Gudnason, V, Yang, Q, Mirza, SS, Jukema, JW, DeJager, PL, Harris, TB, Liewald, DC, Amin, N, Coker, LH, Stegle, O, Lopez, OL, Schmidt, R, Teumer, A, Ford, I, Karbalai, N, Becker, JT, Jonsdottir, MK, Au, R, Fehrmann, RSN, Herms, S, Nalls, M, Zhao, W, Turner, ST, Yaffe, K, Lohman, K, Van Swieten, JC, Kardia, SLR, Knopman, DS, Meeks, WM, Heiss, G, Holliday, EG, Schofield, PW, Tanaka, T, Stott, DJ, Wang, J, Ridker, P, Gow, AJ, Pattie, A, Starr, JM, Hocking, LJ, Armstrong, NJ, McLachlan, S, Shulman, JM, Pilling, LC, Eiriksdottir, G, Scott, RJ, Kochan, NA, Palotie, A, Hsieh, YC, Eriksson, JG, Penman, A, Gottesman, RF, Oostra, BA, Yu, L, DeStefano, AL, Beiser, A, Garcia, M, Rotter, JI, Nöthen, MM, Hofman, A, Slagboom, PE, Westendorp, RGJ, Buckley, BM, Wolf, PA, Uitterlinden, AG, Psaty, BM, Grabe, HJ, Bandinelli, S, Chasman, DI, Grodstein, F, Räikkönen, K, Lambert, JC, Porteous, DJ, Price, JF, Sachdev, PS, Ferrucci, L, Attia, JR, Rudan, I, Hayward, C, Wright, AF, Wilson, JF, Cichon, S, Franke, L, Schmidt, H, Ding, J, De Craen, AJM, Fornage, M, Bennett, DA, Deary, IJ, Ikram, MA, Launer, LJ, Fitzpatrick, AL, Seshadri, S, Van Duijn, CM & Mosley, TH 2016, 'GWAS for executive function and processing speed suggests involvement of the CADM2 gene', Molecular Psychiatry, vol. 21, no. 2, pp. 189-197. https://doi.org/10.1038/mp.2015.37

@article{d0ef11c3283943be99de4f0a18f561c9,

title = "GWAS for executive function and processing speed suggests involvement of the CADM2 gene",

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.",

author = "Ibrahim-Verbaas, {C. A.} and J. Bressler and S. Debette and M. Schuur and Smith, {A. V.} and Bis, {J. C.} and G. Davies and S. Trompet and Smith, {J. A.} and C. Wolf and Chibnik, {L. B.} and Y. Liu and V. Vitart and M. Kirin and K. Petrovic and O. Polasek and L. Zgaga and C. Fawns-Ritchie and P. Hoffmann and J. Karjalainen and J. Lahti and Llewellyn, {D. J.} and Schmidt, {C. O.} and Mather, {K. A.} and V. Chouraki and Q. Sun and Resnick, {S. M.} and Rose, {L. M.} and C. Oldmeadow and M. Stewart and Smith, {B. H.} and V. Gudnason and Q. Yang and Mirza, {S. S.} and Jukema, {J. W.} and DeJager, {P. L.} and Harris, {T. B.} and Liewald, {D. C.} and N. Amin and Coker, {L. H.} and O. Stegle and Lopez, {O. L.} and R. Schmidt and A. Teumer and I. Ford and N. Karbalai and Becker, {J. T.} and Jonsdottir, {M. K.} and R. Au and Fehrmann, {R. S N} and S. Herms and M. Nalls and W. Zhao and Turner, {S. T.} and K. Yaffe and K. Lohman and {Van Swieten}, {J. C.} and Kardia, {S. L R} and Knopman, {D. S.} and Meeks, {W. M.} and G. Heiss and Holliday, {E. G.} and Schofield, {P. W.} and T. Tanaka and Stott, {D. J.} and J. Wang and P. Ridker and Gow, {A. J.} and A. Pattie and Starr, {J. M.} and Hocking, {L. J.} and Armstrong, {N. J.} and S. McLachlan and Shulman, {J. M.} and Pilling, {L. C.} and G. Eiriksdottir and Scott, {R. J.} and Kochan, {N. A.} and A. Palotie and Hsieh, {Y. C.} and Eriksson, {J. G.} and A. Penman and Gottesman, {R. F.} and Oostra, {B. A.} and L. Yu and DeStefano, {A. L.} and A. Beiser and M. Garcia and Rotter, {J. I.} and N{\"o}then, {M. M.} and A. Hofman and Slagboom, {P. E.} and Westendorp, {R. G J} and Buckley, {B. M.} and Wolf, {P. A.} and Uitterlinden, {A. G.} and Psaty, {B. M.} and Grabe, {H. J.} and S. Bandinelli and Chasman, {D. I.} and F. Grodstein and K. R{\"a}ikk{\"o}nen and Lambert, {J. C.} and Porteous, {D. J.} and Price, {J. F.} and Sachdev, {P. S.} and L. Ferrucci and Attia, {J. R.} and I. Rudan and C. Hayward and Wright, {A. F.} and Wilson, {J. F.} and S. Cichon and L. Franke and H. Schmidt and J. Ding and {De Craen}, {A. J M} and M. Fornage and Bennett, {D. A.} and Deary, {I. J.} and Ikram, {M. A.} and Launer, {L. J.} and Fitzpatrick, {A. L.} and S. Seshadri and {Van Duijn}, {C. M.} and Mosley, {T. H.}",

year = "2016",

month = feb,

day = "1",

doi = "10.1038/mp.2015.37",

language = "English",

volume = "21",

pages = "189--197",

journal = "Molecular Psychiatry",

issn = "1359-4184",

publisher = "Springer Nature",

number = "2",

}

TY - JOUR

T1 - GWAS for executive function and processing speed suggests involvement of the CADM2 gene

AU - Ibrahim-Verbaas, C. A.

AU - Bressler, J.

AU - Debette, S.

AU - Schuur, M.

AU - Smith, A. V.

AU - Bis, J. C.

AU - Davies, G.

AU - Trompet, S.

AU - Smith, J. A.

AU - Wolf, C.

AU - Chibnik, L. B.

AU - Liu, Y.

AU - Vitart, V.

AU - Kirin, M.

AU - Petrovic, K.

AU - Polasek, O.

AU - Zgaga, L.

AU - Fawns-Ritchie, C.

AU - Hoffmann, P.

AU - Karjalainen, J.

AU - Lahti, J.

AU - Llewellyn, D. J.

AU - Schmidt, C. O.

AU - Mather, K. A.

AU - Chouraki, V.

AU - Sun, Q.

AU - Resnick, S. M.

AU - Rose, L. M.

AU - Oldmeadow, C.

AU - Stewart, M.

AU - Smith, B. H.

AU - Gudnason, V.

AU - Yang, Q.

AU - Mirza, S. S.

AU - Jukema, J. W.

AU - DeJager, P. L.

AU - Harris, T. B.

AU - Liewald, D. C.

AU - Amin, N.

AU - Coker, L. H.

AU - Stegle, O.

AU - Lopez, O. L.

AU - Schmidt, R.

AU - Teumer, A.

AU - Ford, I.

AU - Karbalai, N.

AU - Becker, J. T.

AU - Jonsdottir, M. K.

AU - Au, R.

AU - Fehrmann, R. S N

AU - Herms, S.

AU - Nalls, M.

AU - Zhao, W.

AU - Turner, S. T.

AU - Yaffe, K.

AU - Lohman, K.

AU - Van Swieten, J. C.

AU - Kardia, S. L R

AU - Knopman, D. S.

AU - Meeks, W. M.

AU - Heiss, G.

AU - Holliday, E. G.

AU - Schofield, P. W.

AU - Tanaka, T.

AU - Stott, D. J.

AU - Wang, J.

AU - Ridker, P.

AU - Gow, A. J.

AU - Pattie, A.

AU - Starr, J. M.

AU - Hocking, L. J.

AU - Armstrong, N. J.

AU - McLachlan, S.

AU - Shulman, J. M.

AU - Pilling, L. C.

AU - Eiriksdottir, G.

AU - Scott, R. J.

AU - Kochan, N. A.

AU - Palotie, A.

AU - Hsieh, Y. C.

AU - Eriksson, J. G.

AU - Penman, A.

AU - Gottesman, R. F.

AU - Oostra, B. A.

AU - Yu, L.

AU - DeStefano, A. L.

AU - Beiser, A.

AU - Garcia, M.

AU - Rotter, J. I.

AU - Nöthen, M. M.

AU - Hofman, A.

AU - Slagboom, P. E.

AU - Westendorp, R. G J

AU - Buckley, B. M.

AU - Wolf, P. A.

AU - Uitterlinden, A. G.

AU - Psaty, B. M.

AU - Grabe, H. J.

AU - Bandinelli, S.

AU - Chasman, D. I.

AU - Grodstein, F.

AU - Räikkönen, K.

AU - Lambert, J. C.

AU - Porteous, D. J.

AU - Price, J. F.

AU - Sachdev, P. S.

AU - Ferrucci, L.

AU - Attia, J. R.

AU - Rudan, I.

AU - Hayward, C.

AU - Wright, A. F.

AU - Wilson, J. F.

AU - Cichon, S.

AU - Franke, L.

AU - Schmidt, H.

AU - Ding, J.

AU - De Craen, A. J M

AU - Fornage, M.

AU - Bennett, D. A.

AU - Deary, I. J.

AU - Ikram, M. A.

AU - Launer, L. J.

AU - Fitzpatrick, A. L.

AU - Seshadri, S.

AU - Van Duijn, C. M.

AU - Mosley, T. H.

PY - 2016/2/1

Y1 - 2016/2/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84956720004&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84956720004&partnerID=8YFLogxK

U2 - 10.1038/mp.2015.37

DO - 10.1038/mp.2015.37

M3 - Article

C2 - 25869804

AN - SCOPUS:84956720004

SN - 1359-4184

VL - 21

SP - 189

EP - 197

JO - Molecular Psychiatry

JF - Molecular Psychiatry

IS - 2

ER -

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

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