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

Carla Verbaas; J Bressler; S Debette; Maaike Schuur; AV Smith; JC Bis; G Davies; S Trompet; JA Smith; C Wolf; LB Chibnik; Y Liu; V Vitart; M Kirin; K Petrovic; O Polasek; L Zgaga; C Fawns-Ritchie; P Hoffmann; J Karjalainen; J Lahti; DJ Llewellyn; CO Schmidt; KA Mather; V Chouraki; Q Sun; SM Resnick; LM Rose; C Oldmeadow; M Stewart; BH Smith; V Gudnason; Q Yang; Saira Mirza; JW Jukema; PL DeJager; TB Harris; DC Liewald; Najaf Amin; LH Coker; O Stegle; OL Lopez; R Schmidt; A Teumer; I Ford; N Karbalai; JT Becker; MK Jonsdottir; R (Rhoda) Au; RSN Fehrmann; S Herms; M Nalls; W Zhao; ST Turner; K Yaffe; K Lohman; J.C. van Swieten; SLR Kardia; DS Knopman; WM Meeks; G Heiss; EG Holliday; PW Schofield; T Tanaka; DJ Stott; Johnny Wang; P Ridker; AJ Gow; A Pattie; JM Starr; LJ Hocking; NJ Armstrong; S McLachlan; JM Shulman; LC Pilling; G Eiriksdottir; RJ Scott; NA Kochan; A Palotie; YC (Yi-Chen) Hsieh; JG Eriksson; A Penman; RF Gottesman; Ben Oostra; L Yu; AL DeStefano; A Beiser; M Garcia; JI Rotter; MM Nothen; Bert Hofman; PE (Eline) Slagboom; RGJ Westendorp; BM Buckley; PA Wolf; André Uitterlinden; BM Psaty; HJ Grabe; S Bandinelli; DI Chasman; F Grodstein; K Roikkonen; JC Lambert; DJ Porteous; JF Price; PS Sachdev; L Ferrucci; JR Attia; I Rudan; C Hayward; AF Wright; JF Wilson; S Cichon; L Franke; Heléna Schmidt; J Ding; AJM de Craen; M Fornage; DA Bennett; IJ Deary; Arfan Ikram; LJ (Lenore) Launer; AL Fitzpatrick; S Seshadri; Cornelia Duijn; TH Mosley

doi:10.1038/mp.2015.37

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

Carla Verbaas, J Bressler, S Debette, Maaike Schuur, AV Smith, JC Bis, G Davies, S Trompet, JA Smith, C Wolf, LB Chibnik, Y Liu, V Vitart, M Kirin, K Petrovic, O Polasek, L Zgaga, C Fawns-Ritchie, P Hoffmann, J KarjalainenJ Lahti, DJ Llewellyn, CO Schmidt, KA Mather, V Chouraki, Q Sun, SM Resnick, LM Rose, C Oldmeadow, M Stewart, BH Smith, V Gudnason, Q Yang, Saira Mirza, JW Jukema, PL DeJager, TB Harris, DC Liewald, Najaf Amin, LH Coker, O Stegle, OL Lopez, R Schmidt, A Teumer, I Ford, N Karbalai, JT Becker, MK Jonsdottir, R (Rhoda) Au, RSN Fehrmann, S Herms, M Nalls, W Zhao, ST Turner, K Yaffe, K Lohman, J.C. van Swieten, SLR Kardia, DS Knopman, WM Meeks, G Heiss, EG Holliday, PW Schofield, T Tanaka, DJ Stott, Johnny Wang, P Ridker, AJ Gow, A Pattie, JM Starr, LJ Hocking, NJ Armstrong, S McLachlan, JM Shulman, LC Pilling, G Eiriksdottir, RJ Scott, NA Kochan, A Palotie, YC (Yi-Chen) Hsieh, JG Eriksson, A Penman, RF Gottesman, Ben Oostra, L Yu, AL DeStefano, A Beiser, M Garcia, JI Rotter, MM Nothen, Bert Hofman, PE (Eline) Slagboom, RGJ Westendorp, BM Buckley, PA Wolf, André Uitterlinden, BM Psaty, HJ Grabe, S Bandinelli, DI Chasman, F Grodstein, K Roikkonen, JC Lambert, DJ Porteous, JF Price, PS Sachdev, L Ferrucci, JR Attia, I Rudan, C Hayward, AF Wright, JF Wilson, S Cichon, L Franke, Heléna Schmidt, J Ding, AJM de Craen, M Fornage, DA Bennett, IJ Deary, Arfan Ikram, LJ (Lenore) Launer, AL Fitzpatrick, S Seshadri, Cornelia Duijn, TH Mosley

Research output: Contribution to journal › Article › Academic › peer-review

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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 x 10(-8)) and in the joint discovery and replication meta-analysis (P-value = 3.28 x 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= 4x10(-4)). The protein encoded by CADM2 is involved in glutamate signaling (P-value = 7.22 x 10(-15)), gamma-aminobutyric acid (GABA) transport (P-value = 1.36 x 10(-11)) and neuron cell-cell adhesion (P-value = 1.48 x 10(-13)). Our findings suggest that genetic variation in the CADM2 gene is associated with individual differences in information processing speed.

Original language	Undefined/Unknown
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 - 2016

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10.1038/mp.2015.37

http://hdl.handle.net/1765/81367

Cite this

Verbaas, C., 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., ... Mosley, TH. (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

@article{9982896480e0441da9eedc1df9ae2ccb,

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 x 10(-8)) and in the joint discovery and replication meta-analysis (P-value = 3.28 x 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= 4x10(-4)). The protein encoded by CADM2 is involved in glutamate signaling (P-value = 7.22 x 10(-15)), gamma-aminobutyric acid (GABA) transport (P-value = 1.36 x 10(-11)) and neuron cell-cell adhesion (P-value = 1.48 x 10(-13)). Our findings suggest that genetic variation in the CADM2 gene is associated with individual differences in information processing speed.",

author = "Carla Verbaas and J Bressler and S Debette and Maaike Schuur and AV Smith and JC Bis and G Davies and S Trompet and JA Smith and C Wolf and LB Chibnik 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 DJ Llewellyn and CO Schmidt and KA Mather and V Chouraki and Q Sun and SM Resnick and LM Rose and C Oldmeadow and M Stewart and BH Smith and V Gudnason and Q Yang and Saira Mirza and JW Jukema and PL DeJager and TB Harris and DC Liewald and Najaf Amin and LH Coker and O Stegle and OL Lopez and R Schmidt and A Teumer and I Ford and N Karbalai and JT Becker and MK Jonsdottir and Au, {R (Rhoda)} and RSN Fehrmann and S Herms and M Nalls and W Zhao and ST Turner and K Yaffe and K Lohman and {van Swieten}, J.C. and SLR Kardia and DS Knopman and WM Meeks and G Heiss and EG Holliday and PW Schofield and T Tanaka and DJ Stott and Johnny Wang and P Ridker and AJ Gow and A Pattie and JM Starr and LJ Hocking and NJ Armstrong and S McLachlan and JM Shulman and LC Pilling and G Eiriksdottir and RJ Scott and NA Kochan and A Palotie and Hsieh, {YC (Yi-Chen)} and JG Eriksson and A Penman and RF Gottesman and Ben Oostra and L Yu and AL DeStefano and A Beiser and M Garcia and JI Rotter and MM Nothen and Bert Hofman and Slagboom, {PE (Eline)} and RGJ Westendorp and BM Buckley and PA Wolf and Andr{\'e} Uitterlinden and BM Psaty and HJ Grabe and S Bandinelli and DI Chasman and F Grodstein and K Roikkonen and JC Lambert and DJ Porteous and JF Price and PS Sachdev and L Ferrucci and JR Attia and I Rudan and C Hayward and AF Wright and JF Wilson and S Cichon and L Franke and Hel{\'e}na Schmidt and J Ding and {de Craen}, AJM and M Fornage and DA Bennett and IJ Deary and Arfan Ikram and Launer, {LJ (Lenore)} and AL Fitzpatrick and S Seshadri and Cornelia Duijn and TH Mosley",

year = "2016",

doi = "10.1038/mp.2015.37",

language = "Undefined/Unknown",

volume = "21",

pages = "189--197",

journal = "Molecular Psychiatry",

issn = "1359-4184",

publisher = "Nature Publishing Group",

number = "2",

}

Verbaas, C, 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, S, 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, B, Yu, L, DeStefano, AL, Beiser, A, Garcia, M, Rotter, JI, Nothen, MM, Hofman, B, Slagboom, PE, Westendorp, RGJ, Buckley, BM, Wolf, PA, Uitterlinden, A, Psaty, BM, Grabe, HJ, Bandinelli, S, Chasman, DI, Grodstein, F, Roikkonen, 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, A, Launer, LJ, Fitzpatrick, AL, Seshadri, S, Duijn, C & 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

TY - JOUR

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

AU - Verbaas, Carla

AU - Bressler, J

AU - Debette, S

AU - Schuur, Maaike

AU - Smith, AV

AU - Bis, JC

AU - Davies, G

AU - Trompet, S

AU - Smith, JA

AU - Wolf, C

AU - Chibnik, LB

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, DJ

AU - Schmidt, CO

AU - Mather, KA

AU - Chouraki, V

AU - Sun, Q

AU - Resnick, SM

AU - Rose, LM

AU - Oldmeadow, C

AU - Stewart, M

AU - Smith, BH

AU - Gudnason, V

AU - Yang, Q

AU - Mirza, Saira

AU - Jukema, JW

AU - DeJager, PL

AU - Harris, TB

AU - Liewald, DC

AU - Amin, Najaf

AU - Coker, LH

AU - Stegle, O

AU - Lopez, OL

AU - Schmidt, R

AU - Teumer, A

AU - Ford, I

AU - Karbalai, N

AU - Becker, JT

AU - Jonsdottir, MK

AU - Au, R (Rhoda)

AU - Fehrmann, RSN

AU - Herms, S

AU - Nalls, M

AU - Zhao, W

AU - Turner, ST

AU - Yaffe, K

AU - Lohman, K

AU - van Swieten, J.C.

AU - Kardia, SLR

AU - Knopman, DS

AU - Meeks, WM

AU - Heiss, G

AU - Holliday, EG

AU - Schofield, PW

AU - Tanaka, T

AU - Stott, DJ

AU - Wang, Johnny

AU - Ridker, P

AU - Gow, AJ

AU - Pattie, A

AU - Starr, JM

AU - Hocking, LJ

AU - Armstrong, NJ

AU - McLachlan, S

AU - Shulman, JM

AU - Pilling, LC

AU - Eiriksdottir, G

AU - Scott, RJ

AU - Kochan, NA

AU - Palotie, A

AU - Hsieh, YC (Yi-Chen)

AU - Eriksson, JG

AU - Penman, A

AU - Gottesman, RF

AU - Oostra, Ben

AU - Yu, L

AU - DeStefano, AL

AU - Beiser, A

AU - Garcia, M

AU - Rotter, JI

AU - Nothen, MM

AU - Hofman, Bert

AU - Slagboom, PE (Eline)

AU - Westendorp, RGJ

AU - Buckley, BM

AU - Wolf, PA

AU - Uitterlinden, André

AU - Psaty, BM

AU - Grabe, HJ

AU - Bandinelli, S

AU - Chasman, DI

AU - Grodstein, F

AU - Roikkonen, K

AU - Lambert, JC

AU - Porteous, DJ

AU - Price, JF

AU - Sachdev, PS

AU - Ferrucci, L

AU - Attia, JR

AU - Rudan, I

AU - Hayward, C

AU - Wright, AF

AU - Wilson, JF

AU - Cichon, S

AU - Franke, L

AU - Schmidt, Heléna

AU - Ding, J

AU - de Craen, AJM

AU - Fornage, M

AU - Bennett, DA

AU - Deary, IJ

AU - Ikram, Arfan

AU - Launer, LJ (Lenore)

AU - Fitzpatrick, AL

AU - Seshadri, S

AU - Duijn, Cornelia

AU - Mosley, TH

PY - 2016

Y1 - 2016

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 x 10(-8)) and in the joint discovery and replication meta-analysis (P-value = 3.28 x 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= 4x10(-4)). The protein encoded by CADM2 is involved in glutamate signaling (P-value = 7.22 x 10(-15)), gamma-aminobutyric acid (GABA) transport (P-value = 1.36 x 10(-11)) and neuron cell-cell adhesion (P-value = 1.48 x 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 x 10(-8)) and in the joint discovery and replication meta-analysis (P-value = 3.28 x 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= 4x10(-4)). The protein encoded by CADM2 is involved in glutamate signaling (P-value = 7.22 x 10(-15)), gamma-aminobutyric acid (GABA) transport (P-value = 1.36 x 10(-11)) and neuron cell-cell adhesion (P-value = 1.48 x 10(-13)). Our findings suggest that genetic variation in the CADM2 gene is associated with individual differences in information processing speed.

U2 - 10.1038/mp.2015.37

DO - 10.1038/mp.2015.37

M3 - Article

SN - 1359-4184

VL - 21

SP - 189

EP - 197

JO - Molecular Psychiatry

JF - Molecular Psychiatry

IS - 2

ER -