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

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

96 Citations (Scopus)

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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This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/mp.2015.37

Cite this

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.}",

note = "Funding Information: 3CS: The work was made possible by the generous participation of the control subjects and their families. This work was supported by the National Foundation for Alzheimer''s disease and related disorders, the Institut Pasteur de Lille, the Centre National de G{\'e}notypage, Inserm, FRC (fondation pour la recherche sur le cerveau) and Rotary. This work has been developed and supported by the LABEX (laboratory of excellence program investment for the future) DISTALZ grant (Development of Innovative Strategies for a Transdisciplinary approach to ALZheimer''s disease). JCL was funded by the MEDIALZ Project (Grant 11001003) financed by ERDF (European Regional Development Fund) and Conseil R{\'e}gional Nord Pas de Calais. The Three-City Study was performed as part of a collaboration between the Institut National de la Sant{\'e} et de la Recherche M{\'e}dicale (Inserm), the Victor Segalen Bordeaux II University and Sanofi-Synth{\'e}labo. The Fondation pour la Recherche M{\'e}dicale funded the preparation and initiation of the study. The 3C Study was also funded by the Caisse Nationale Maladie des Travailleurs Salari{\'e}s, Direction G{\'e}n{\'e}rale de la Sant{\'e}, MGEN, Institut de la Long{\'e}vit{\'e}, Agence Fran{\c c}aise de S{\'e}curit{\'e} Sanitaire des Produits de Sant{\'e}, the Aquitaine and Bourgogne Regional Councils, Fondation de France and the joint French Ministry of Research/INSERM ''Cohortes et collections de donn{\'e}es biologiques'' program. Lille G{\'e}nop{\^o}le received an unconditional grant from Eisai. AAA: We thank the cohort participants and team members who contributed to this study. Phenotype collection and DNA extraction were supported by the Wellcome Trust, the British Heart Foundation and the Chief Scientist Office of the Scottish Executive. The AAA Trial was performed and the database is maintained by members of the University of Edinburgh Molecular Epidemiology Research Group in the Centre for Population Health Sciences. We also thank staff at the Wellcome Trust Clinical Research Facility in Edinburgh where some of the research clinics and genotyping were undertaken. AGES: Aging Gene-Environment Susceptibility-Reykjavik Study: The research has been funded by NIA Contract N01-AG-12100 with contributions from NEI, NIDCD and NHLBI, the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association) and the Althingi (the Icelandic Parliament). ARIC: The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung and Blood Institute Contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C and HHSN268201100012C), R01HL70825, R01HL087641, R01HL59367 and R01HL086694; National Human Genome Research Institute Contract U01HG004402; and National Institutes of Health Contract HHSN268200625226C. We thank the staff and participants of the ARIC study for their important contributions. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. ASPS: We thank Ing. Johann Semmler and Irmgard P{\"o}lzl for creating the DNA bank and for supervising the quality managementof the biobanking and DNA analyses. The ASPS is funded by the Austrian Science Fond (FWF) Grant Number P20545-P05 and P13180. BLSA: Baltimore Longitudinal Study of Aging (BLSA): The Baltimore Longitudinal Study of Aging is supported by the Intramural Research Program of the NIH, National Institute on Aging. Cardiovascular Health Study: This CHS research was supported by NHLBI contracts HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086; and NHLBI grants U01HL080295, R01HL087652, R01HL105756, R01HL103612, and R01HL120393 with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through R01AG023629, R01AG15928, R01AG20098, and R01AG027058 from the National Institute on Aging (NIA). A full list of principal CHS investigators and institutions can be found at CHSNHLBI. org. The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR000124, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. CROATIA-Korcula: The CROATIA-Korcula study was funded by grants from the Medical Research Council (UK), European Commission Framework 6 project EUROSPAN (Contract No. LSHG-CT-2006-018947) and Republic of Croatia Ministry of Science, Education and Sports research grants to IR (108-1080315-0302). We would like to acknowledge the invaluable contributions of the recruitment team in Korcula, the administrative teams in Croatia and Edinburgh and the people of Korcula. The SNP genotyping for the CROATIA-Korcula cohort was performed in Helmholtz Zentrum M{\"u}nchen, Neuherberg, Germany. CROATIA-Split: The CROATIA-Split study is funded by grants from the Medical Research Council (UK), European Commission Framework 6 project EUROSPAN (Contract No. LSHG-CT-2006-018947) and Republic of Croatia Ministry of Science, Education and Sports research grants to IR (108-1080315-0302). We would like to acknowledge the invaluable contributions of the recruitment team in Split, the administrative teams in Croatia and Edinburgh and the people of Split. The SNP genotyping for the CROATIA-Split cohort was performed by AROS Applied Biotechnology, Aarhus, Denmark. CROATIA-Vis: The CROATIA-Vis study was funded by grants from the Medical Research Council (UK) and Republic of Croatia Ministry of Science, Education and Sports research grants to IR (108-1080315-0302). We would like to acknowledge the staff of several institutions in Croatia that supported the field work, including but not limited to The University of Split and Zagreb Medical Schools, the Institute for Anthropological Research in Zagreb and Croatian Institute for Public Health. The SNP genotyping for the CROATIA-Vis cohort was performed in the core genotyping laboratory of the Wellcome Trust Clinical Research Facility at the Western General Hospital, Edinburgh, Scotland. ERF: This study was financially supported by the Netherlands Organization for Scientific Research (NWO), the Internationale Stichting Alzheimer Onderzoek (ISAO), the Hersenstichting Nederland (HSN) and the Centre for Medical Systems Biology (CMSB) in the framework of the Netherlands Genomics Initiative (NGI) and by the Russian Foundation for Basic Research (RFBR). We thank the participants from the Genetic Research in Isolated Populations, Erasmus Rucphen Family, who made this work possible. Also, we thank Petra Veraart for collecting all genealogical data. FHS: This work was supported by the National Heart, Lung and Blood Institute''s Framingham Heart Study (Contract No. N01-HC-25195) and its contract with Affymetrix, Inc for genotyping services (Contract No. N02-HL-6-4278) and Grants (U01 HL096917 and R01 HL093029). A portion of this research utilized the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. Analyses reflect intellectual input and resource development from the Framingham Heart Study investigators participating in the SNP Health Association Resource (SHARe) project. This study was also supported by grants from the National Institute of Neurological Disorders and Stroke (NS17950) and the National Institute of Aging (U01 AG049505, AG033193, AG008122, AG16495). The content is solely the responsibility of the authors and does not necessarily represent the official views of NINDS, NHLBI, NIA, NIH or AHA. Dr. Debette is a recipient of a Chaire d''Excellence grant from the Agence National de la Recherche and a grant from the Leducq Foundation. GENOA: Support for the Genetic Epidemiology Network of Arteriopathy (GENOA) was provided by the National Heart, Lung and Blood Institute (HL054464, HL054457, HL054481, HL071917 and HL87660) and the National Institute of Neurological Disorders and Stroke (NS041558) of the National Institutes of Health. Genotyping was performed at the Mayo Clinic (S.T.T., Mariza de Andrade, Julie Cunningham) and was made possible by the University of Texas Health Sciences Center (Eric Boerwinkle, Megan L Grove-Gaona). We would also like to thank the families that participated in the GENOA study. GS: We are grateful to the GS Executive Committee Professors Blair H. Smith, David J. Porteous, Sandosh Padmanabhan and Dr. Lynne J. Hocking, and all the families who took part, the general practitioners and the Scottish School of Primary Care for their help in recruiting them, and the whole Generation Scotland team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists, healthcare assistants and nurses. Generation Scotland received core support from the Chief Scientist Office of the Scottish Government Health Directorates [CZD/16/6] and the Scottish Funding Council [HR03006]. Funding Information: ASPS: We thank Ing. Johann Semmler and Irmgard P{\"o}lzl for creating the DNA bank and for supervising the quality managementof the biobanking and DNA analyses.The ASPS is funded by the Austrian Science Fond (FWF) Grant Number P20545-P05 and P13180. Funding Information: ARIC: The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung and Blood Institute Contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C and HHSN268201100012C), R01HL70825, R01HL087641, R01HL59367 and R01HL086694; National Human Genome Research Institute Contract U01HG004402; and National Institutes of Health Contract HHSN268200625226C. We thank the staff and participants of the ARIC study for their important contributions. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. Funding Information: CROATIA-Korcula: The CROATIA-Korcula study was funded by grants from the Medical Research Council (UK), European Commission Framework 6 project EUROSPAN (Contract No. LSHG-CT-2006-018947) and Republic of Croatia Ministry of Science, Education and Sports research grants to IR (108-1080315-0302). We would like to acknowledge the invaluable contributions of the recruitment team in Korcula, the administrative teams in Croatia and Edinburgh and the people of Korcula. The SNP genotyping for the CROATIA-Korcula cohort was performed in Helmholtz Zentrum M{\"u}nchen, Neuherberg, Germany. Funding Information: GS: We are grateful to the GS Executive Committee Professors Blair H. Smith, David J. Porteous, Sandosh Padmanabhan and Dr. Lynne J. Hocking, and all the families who took part, the general practitioners and the Scottish School of Primary Care for their help in recruiting them, and the whole Generation Scotland team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists, healthcare assistants and nurses. Generation Scotland received core support from the Chief Scientist Office of the Scottish Government Health Directorates [CZD/16/6] and the Scottish Funding Council [HR03006]. Funding Information: Cardiovascular Health Study: This CHS research was supported by NHLBI contracts HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086; and NHLBI grants U01HL080295, R01HL087652, R01HL105756, R01HL103612, and R01HL120393 with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through R01AG023629, R01AG15928, R01AG20098, and R01AG027058 from the National Institute on Aging (NIA). A full list of principal CHS investigators and institutions can be found at CHS-NHLBI.org. The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR000124, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Funding Information: PROSPER: The PROSPER study was supported by an investigator initiated grant obtained from Bristol-Myers Squibb. Prof. Dr JW Jukema is an Established Clinical Investigator of the Netherlands Heart Foundation (Grant 2001 D 032). Support for genotyping was provided by the seventh framework program of the European commission (Grant 223004) and by the Netherlands Genomics Initiative (Netherlands Consortium for Healthy Aging Grant 050-060-810). Funding Information: InCHIANTI: The Invechhiare in Chianti (InCHIANTI) Study was supported as a targeted project (ICS 110.1RS97.71) by the Italian Ministry of Health, by the US National Institute on Aging (Contracts N01[AG]916413, N01[AG] 821336, 263 MD 9164 13, and 263 MD 821336), and, in part, by the Intramural Research Program, National Institute on Aging, National Institutes of Health. Funding Information: MAS: We would like to acknowledge and thank the Sydney MAS participants and the Research Team for their contributions and assistance. We would like to specifically acknowledge the support and contributions of Professor Henry Brodaty (Chief Investigator), Dr Simone Reppermund (Study Co-ordinator), Professor Peter Schofield, Dr Arezoo Assareh and Dr John Kwok to this work. DNA was extracted by Genetic Repositories Australia, an Enabling Facility supported by NHMRC Grant 401184. DNA sample preparation was undertaken in the laboratory of Professor Peter Schofield and Dr John Kwok, Neuroscience Research Australia, with the assistance of Dr Arezoo Assareh. Genotyping was performed by the Ramaciotti Centre, University of New South Wales. Sydney MAS is supported by the Australian National Health & Medical Research Council Program Grants 350833 and 568969. Karen Mather is supported by the Capacity Building Grant 568940. Nicola Armstrong is supported by the NHMRC Project Grant 525453. Funding Information: HBCS: We thank all study participants as well as everybody involved in the Helsinki Birth Cohort Study. Helsinki Birth Cohort Study has been supported by grants from the Academy of Finland, the Finnish Diabetes Research Society, Folkh{\"a}lsan Research Foundation, Novo Nordisk Foundation, Finska L{\"a}kares{\"a}llskapet, Signe and Ane Gyllenberg Foundation, University of Helsinki, Ministry of Education, Ahokas Foundation, Emil Aaltonen Foundation, Juho Vainio Foundation and Wellcome Trust (Grant Number WT089062). Funding Information: NHS: This study was supported by research Grants CA87969, CA49449, HL34594, U01HG004399, DK058845, CA65725, CA67262, CA50385, 5UO1CA098233, EY09611, EY015473, HG004728, HL35464, CA55075, CA134958 and DK070756 from the National Institutes of Health. The genotyping was partly supported by an unrestricted grant from Merck Research Laboratories. Dr Sun is supported by career development award K99HL098459 from the National Heart, Lung and Blood Institute. Supported in part by NIH. Funding Information: Health ABC: This research was supported by NIA Contracts N01AG62101, N01AG62103 and N01AG62106. The genome-wide association study was funded by NIA Grant 1R01AG032098-01A1 to Wake Forest University Health Sciences and genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, Contract Number HHSN268200782096C. This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging. Funding Information: AGES: Aging Gene-Environment Susceptibility-Reykjavik Study: The research has been funded by NIA Contract N01-AG-12100 with contributions from NEI, NIDCD and NHLBI, the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association) and the Althingi (the Icelandic Parliament). Funding Information: SHIP: SHIP is part of the Community Medicine Research net of the University Medicine of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research (grants no. 01ZZ9603, 01ZZ0103, and 01ZZ0403), the Ministry of Cultural Affairs as well as the Social Ministry of the Federal State of Mecklenburg-West Pomerania. The SHIP authors are grateful to Holger Prokisch and Thomas Meitinger (Helmholtz Zentrum M{\"u}nchen) for the genotyping of the SHIP-TREND cohort. Funding Information: CROATIA-Vis: The CROATIA-Vis study was funded by grants from the Medical Research Council (UK) and Republic of Croatia Ministry of Science, Education and Sports research grants to IR (108-1080315-0302). We would like to acknowledge the staff of several institutions in Croatia that supported the field work, including but not limited to The University of Split and Zagreb Medical Schools, the Institute for Anthropological Research in Zagreb and Croatian Institute for Public Health. The SNP genotyping for the CROATIA-Vis cohort was performed in the core genotyping laboratory of the Wellcome Trust Clinical Research Facility at the Western General Hospital, Edinburgh, Scotland. Funding Information: AAA: We thank the cohort participants and team members who contributed to this study. Phenotype collection and DNA extraction were supported by the Wellcome Trust, the British Heart Foundation and the Chief Scientist Office of the Scottish Executive. The AAA Trial was performed and the database is maintained by members of the University of Edinburgh Molecular Epidemiology Research Group in the Centre for Population Health Sciences. We also thank staff at the Wellcome Trust Clinical Research Facility in Edinburgh where some of the research clinics and genotyping were undertaken. Funding Information: FHS: This work was supported by the National Heart, Lung and Blood Institute{\textquoteright}s Framingham Heart Study (Contract No. N01-HC-25195) and its contract with Affymetrix, Inc for genotyping services (Contract No. N02-HL-6-4278) and Grants (U01 HL096917 and R01 HL093029). A portion of this research utilized the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. Analyses reflect intellectual input and resource development from the Framingham Heart Study investigators participating in the SNP Health Association Resource (SHARe) project. This study was also supported by grants from the National Institute of Neurological Disorders and Stroke (NS17950) and the National Institute of Aging (U01 AG049505, AG033193, AG008122, AG16495). The content is solely the responsibility of the authors and does not necessarily represent the official views of NINDS, NHLBI, NIA, NIH or AHA. Dr. Debette is a recipient of a Chaire d'Excellence grant from the Agence National de la Recherche and a grant from the Leducq Foundation. Funding Information: RUSH: Supported in part by NIA Grants P30AG10161, R01AG15819, R01AG17917, R01AG30146, K08AG34290 and K25AG41906. Funding Information: WGHS: The WGHS is supported by HL043851 and HL080467 from the National Heart, Lung and Blood Institute and CA047988 from the National Cancer Institute, the Donald W Reynolds Foundation and the Fondation Leducq, with collaborative scientific support and funding for genotyping provided by Amgen. Funding Information: CROATIA-Split: The CROATIA-Split study is funded by grants from the Medical Research Council (UK), European Commission Framework 6 project EUROSPAN (Contract No. LSHG-CT-2006-018947) and Republic of Croatia Ministry of Science, Education and Sports research grants to IR (108-1080315-0302). We would like to acknowledge the invaluable contributions of the recruitment team in Split, the administrative teams in Croatia and Edinburgh and the people of Split. The SNP genotyping for the CROATIA-Split cohort was performed by AROS Applied Biotechnology, Aarhus, Denmark. Funding Information: ORCADES: ORCADES was supported by the Chief Scientist Office of the Scottish Government, the Royal Society, the MRC Human Genetics Unit, Arthritis Research UK and the European Union framework program 6 EUROSPAN project (Contract No. LSHG-CT-2006-018947). DNA extractions were performed at the Wellcome Trust Clinical Research Facility in Edinburgh. We would like to acknowledge the invaluable contributions of Lorraine Anderson and the research nurses in Orkney, the administrative team in Edinburgh and the people of Orkney. Funding Information: LBC1921/LBC1936: We thank the cohort participants and team members who contributed to these studies. Phenotype collection in the Lothian Birth Cohort 1921 was supported by the BBSRC, The Royal Society and The Chief Scientist Office of the Scottish Government. Phenotype collection in the Lothian Birth Cohort 1936 was supported by Research Into Ageing (continues as part of Age UK The Disconnected Mind project). Genotyping of the cohorts was funded by the UK Biotechnology and Biological Sciences Research Council (BBSRC). The work was undertaken by The University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology, part of the cross council Lifelong Health and Wellbeing Initiative (G0700704/84698). Funding from the BBSRC, Engineering and Physical Sciences Research Council (EPSRC), Economic and Social Research Council (ESRC) and MRC is gratefully acknowledged. Funding Information: 3CS: The work was made possible by the generous participation of the control subjects and their families. This work was supported by the National Foundation for Alzheimer{\textquoteright}s disease and related disorders, the Institut Pasteur de Lille, the Centre National de G{\'e}notypage, Inserm, FRC (fondation pour la recherche sur le cerveau) and Rotary. This work has been developed and supported by the LABEX (laboratory of excellence program investment for the future) DISTALZ grant (Development of Innovative Strategies for a Transdisciplinary approach to ALZheimer{\textquoteright}s disease). JCL was funded by the MEDIALZ Project (Grant 11001003) financed by ERDF (European Regional Development Fund) and Conseil R{\'e}gional Nord Pas de Calais. The Three-City Study was performed as part of a collaboration between the Institut National de la Sant{\'e} et de la Recherche M{\'e}dicale (Inserm), the Victor Segalen Bordeaux II University and Sanofi-Synth{\'e}labo. The Fondation pour la Recherche M{\'e}dicale funded the preparation and initiation of the study. The 3C Study was also funded by the Caisse Nationale Maladie des Travailleurs Salari{\'e}s, Direction G{\'e}n{\'e}rale de la Sant{\'e}, MGEN, Institut de la Long{\'e}vit{\'e}, Agence Fran{\c c}aise de S{\'e}curit{\'e} Sanitaire des Produits de Sant{\'e}, the Aquitaine and Bourgogne Regional Councils, Fondation de France and the joint French Ministry of Research/INSERM {\textquoteleft}Cohortes et collections de donn{\'e}es biologiques{\textquoteright} program. Lille G{\'e}nop{\^o}le received an unconditional grant from Eisai. Funding Information: ERF: This study was financially supported by the Netherlands Organization for Scientific Research (NWO), the Internationale Stichting Alzheimer Onderzoek (ISAO), the Hersenstichting Nederland (HSN) and the Centre for Medical Systems Biology (CMSB) in the framework of the Netherlands Genomics Initiative (NGI) and by the Russian Foundation for Basic Research (RFBR). We thank the participants from the Genetic Research in Isolated Populations, Erasmus Rucphen Family, who made this work possible. Also, we thank Petra Veraart for collecting all genealogical data. Funding Information: Hunter: The authors would like to thank the men and women participating in the HCS as well as all the staff, investigators and collaborators who have supported or been involved in the project to date. The cohort was made possible with support from the University of Newcastle's Strategic Initiative Fund, the Vincent Fairfax Family Foundation and the Hunter Medical Research Institute. Funding Information: GENOA: Support for the Genetic Epidemiology Network of Arteriopathy (GENOA) was provided by the National Heart, Lung and Blood Institute (HL054464, HL054457, HL054481, HL071917 and HL87660) and the National Institute of Neurological Disorders and Stroke (NS041558) of the National Institutes of Health. Genotyping was performed at the Mayo Clinic (S.T.T., Mariza de Andrade, Julie Cunningham) and was made possible by the University of Texas Health Sciences Center (Eric Boerwinkle, Megan L Grove-Gaona). We would also like to thank the families that participated in the GENOA study. Funding Information: RS: The generation and management of GWAS genotype data for the Rotterdam Study is supported by the Netherlands Organisation of Scientific Research NWO Investments (nr. 175.010.2005.011, 911-03-012). This study is funded by the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), the Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) project nr. 050-060-810. We thank Pascal Arp, Mila Jhamai, Marijn Verkerk, Lizbeth Herrera and Marjolein Peters for their help in creating the GWAS database, and Karol Estrada and Maksim V. Struchalin for their support in creation and analysis of imputed data. The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission 49 (DG XII), and the Municipality of Rotterdam. The authors are grateful to the study participants, the staff from the Rotterdam Study and the participating general practitioners and pharmacists. Dr Ikram was supported by a ZonMW Veni Grant: 916.13.054. Publisher Copyright: {\textcopyright} 2016 Macmillan Publishers Limited All rights reserved.",

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 = "Nature Publishing Group",

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.

N1 - Funding Information: 3CS: The work was made possible by the generous participation of the control subjects and their families. This work was supported by the National Foundation for Alzheimer''s disease and related disorders, the Institut Pasteur de Lille, the Centre National de Génotypage, Inserm, FRC (fondation pour la recherche sur le cerveau) and Rotary. This work has been developed and supported by the LABEX (laboratory of excellence program investment for the future) DISTALZ grant (Development of Innovative Strategies for a Transdisciplinary approach to ALZheimer''s disease). JCL was funded by the MEDIALZ Project (Grant 11001003) financed by ERDF (European Regional Development Fund) and Conseil Régional Nord Pas de Calais. The Three-City Study was performed as part of a collaboration between the Institut National de la Santé et de la Recherche Médicale (Inserm), the Victor Segalen Bordeaux II University and Sanofi-Synthélabo. The Fondation pour la Recherche Médicale funded the preparation and initiation of the study. The 3C Study was also funded by the Caisse Nationale Maladie des Travailleurs Salariés, Direction Générale de la Santé, MGEN, Institut de la Longévité, Agence Française de Sécurité Sanitaire des Produits de Santé, the Aquitaine and Bourgogne Regional Councils, Fondation de France and the joint French Ministry of Research/INSERM ''Cohortes et collections de données biologiques'' program. Lille Génopôle received an unconditional grant from Eisai. AAA: We thank the cohort participants and team members who contributed to this study. Phenotype collection and DNA extraction were supported by the Wellcome Trust, the British Heart Foundation and the Chief Scientist Office of the Scottish Executive. The AAA Trial was performed and the database is maintained by members of the University of Edinburgh Molecular Epidemiology Research Group in the Centre for Population Health Sciences. We also thank staff at the Wellcome Trust Clinical Research Facility in Edinburgh where some of the research clinics and genotyping were undertaken. AGES: Aging Gene-Environment Susceptibility-Reykjavik Study: The research has been funded by NIA Contract N01-AG-12100 with contributions from NEI, NIDCD and NHLBI, the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association) and the Althingi (the Icelandic Parliament). ARIC: The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung and Blood Institute Contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C and HHSN268201100012C), R01HL70825, R01HL087641, R01HL59367 and R01HL086694; National Human Genome Research Institute Contract U01HG004402; and National Institutes of Health Contract HHSN268200625226C. We thank the staff and participants of the ARIC study for their important contributions. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. ASPS: We thank Ing. Johann Semmler and Irmgard Pölzl for creating the DNA bank and for supervising the quality managementof the biobanking and DNA analyses. The ASPS is funded by the Austrian Science Fond (FWF) Grant Number P20545-P05 and P13180. BLSA: Baltimore Longitudinal Study of Aging (BLSA): The Baltimore Longitudinal Study of Aging is supported by the Intramural Research Program of the NIH, National Institute on Aging. Cardiovascular Health Study: This CHS research was supported by NHLBI contracts HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086; and NHLBI grants U01HL080295, R01HL087652, R01HL105756, R01HL103612, and R01HL120393 with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through R01AG023629, R01AG15928, R01AG20098, and R01AG027058 from the National Institute on Aging (NIA). A full list of principal CHS investigators and institutions can be found at CHSNHLBI. org. The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR000124, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. CROATIA-Korcula: The CROATIA-Korcula study was funded by grants from the Medical Research Council (UK), European Commission Framework 6 project EUROSPAN (Contract No. LSHG-CT-2006-018947) and Republic of Croatia Ministry of Science, Education and Sports research grants to IR (108-1080315-0302). We would like to acknowledge the invaluable contributions of the recruitment team in Korcula, the administrative teams in Croatia and Edinburgh and the people of Korcula. The SNP genotyping for the CROATIA-Korcula cohort was performed in Helmholtz Zentrum München, Neuherberg, Germany. CROATIA-Split: The CROATIA-Split study is funded by grants from the Medical Research Council (UK), European Commission Framework 6 project EUROSPAN (Contract No. LSHG-CT-2006-018947) and Republic of Croatia Ministry of Science, Education and Sports research grants to IR (108-1080315-0302). We would like to acknowledge the invaluable contributions of the recruitment team in Split, the administrative teams in Croatia and Edinburgh and the people of Split. The SNP genotyping for the CROATIA-Split cohort was performed by AROS Applied Biotechnology, Aarhus, Denmark. CROATIA-Vis: The CROATIA-Vis study was funded by grants from the Medical Research Council (UK) and Republic of Croatia Ministry of Science, Education and Sports research grants to IR (108-1080315-0302). We would like to acknowledge the staff of several institutions in Croatia that supported the field work, including but not limited to The University of Split and Zagreb Medical Schools, the Institute for Anthropological Research in Zagreb and Croatian Institute for Public Health. The SNP genotyping for the CROATIA-Vis cohort was performed in the core genotyping laboratory of the Wellcome Trust Clinical Research Facility at the Western General Hospital, Edinburgh, Scotland. ERF: This study was financially supported by the Netherlands Organization for Scientific Research (NWO), the Internationale Stichting Alzheimer Onderzoek (ISAO), the Hersenstichting Nederland (HSN) and the Centre for Medical Systems Biology (CMSB) in the framework of the Netherlands Genomics Initiative (NGI) and by the Russian Foundation for Basic Research (RFBR). We thank the participants from the Genetic Research in Isolated Populations, Erasmus Rucphen Family, who made this work possible. Also, we thank Petra Veraart for collecting all genealogical data. FHS: This work was supported by the National Heart, Lung and Blood Institute''s Framingham Heart Study (Contract No. N01-HC-25195) and its contract with Affymetrix, Inc for genotyping services (Contract No. N02-HL-6-4278) and Grants (U01 HL096917 and R01 HL093029). A portion of this research utilized the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. Analyses reflect intellectual input and resource development from the Framingham Heart Study investigators participating in the SNP Health Association Resource (SHARe) project. This study was also supported by grants from the National Institute of Neurological Disorders and Stroke (NS17950) and the National Institute of Aging (U01 AG049505, AG033193, AG008122, AG16495). The content is solely the responsibility of the authors and does not necessarily represent the official views of NINDS, NHLBI, NIA, NIH or AHA. Dr. Debette is a recipient of a Chaire d''Excellence grant from the Agence National de la Recherche and a grant from the Leducq Foundation. GENOA: Support for the Genetic Epidemiology Network of Arteriopathy (GENOA) was provided by the National Heart, Lung and Blood Institute (HL054464, HL054457, HL054481, HL071917 and HL87660) and the National Institute of Neurological Disorders and Stroke (NS041558) of the National Institutes of Health. Genotyping was performed at the Mayo Clinic (S.T.T., Mariza de Andrade, Julie Cunningham) and was made possible by the University of Texas Health Sciences Center (Eric Boerwinkle, Megan L Grove-Gaona). We would also like to thank the families that participated in the GENOA study. GS: We are grateful to the GS Executive Committee Professors Blair H. Smith, David J. Porteous, Sandosh Padmanabhan and Dr. Lynne J. Hocking, and all the families who took part, the general practitioners and the Scottish School of Primary Care for their help in recruiting them, and the whole Generation Scotland team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists, healthcare assistants and nurses. Generation Scotland received core support from the Chief Scientist Office of the Scottish Government Health Directorates [CZD/16/6] and the Scottish Funding Council [HR03006]. Funding Information: ASPS: We thank Ing. Johann Semmler and Irmgard Pölzl for creating the DNA bank and for supervising the quality managementof the biobanking and DNA analyses.The ASPS is funded by the Austrian Science Fond (FWF) Grant Number P20545-P05 and P13180. Funding Information: ARIC: The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung and Blood Institute Contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C and HHSN268201100012C), R01HL70825, R01HL087641, R01HL59367 and R01HL086694; National Human Genome Research Institute Contract U01HG004402; and National Institutes of Health Contract HHSN268200625226C. We thank the staff and participants of the ARIC study for their important contributions. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. Funding Information: CROATIA-Korcula: The CROATIA-Korcula study was funded by grants from the Medical Research Council (UK), European Commission Framework 6 project EUROSPAN (Contract No. LSHG-CT-2006-018947) and Republic of Croatia Ministry of Science, Education and Sports research grants to IR (108-1080315-0302). We would like to acknowledge the invaluable contributions of the recruitment team in Korcula, the administrative teams in Croatia and Edinburgh and the people of Korcula. The SNP genotyping for the CROATIA-Korcula cohort was performed in Helmholtz Zentrum München, Neuherberg, Germany. Funding Information: GS: We are grateful to the GS Executive Committee Professors Blair H. Smith, David J. Porteous, Sandosh Padmanabhan and Dr. Lynne J. Hocking, and all the families who took part, the general practitioners and the Scottish School of Primary Care for their help in recruiting them, and the whole Generation Scotland team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists, healthcare assistants and nurses. Generation Scotland received core support from the Chief Scientist Office of the Scottish Government Health Directorates [CZD/16/6] and the Scottish Funding Council [HR03006]. Funding Information: Cardiovascular Health Study: This CHS research was supported by NHLBI contracts HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086; and NHLBI grants U01HL080295, R01HL087652, R01HL105756, R01HL103612, and R01HL120393 with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through R01AG023629, R01AG15928, R01AG20098, and R01AG027058 from the National Institute on Aging (NIA). A full list of principal CHS investigators and institutions can be found at CHS-NHLBI.org. The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR000124, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Funding Information: PROSPER: The PROSPER study was supported by an investigator initiated grant obtained from Bristol-Myers Squibb. Prof. Dr JW Jukema is an Established Clinical Investigator of the Netherlands Heart Foundation (Grant 2001 D 032). Support for genotyping was provided by the seventh framework program of the European commission (Grant 223004) and by the Netherlands Genomics Initiative (Netherlands Consortium for Healthy Aging Grant 050-060-810). Funding Information: InCHIANTI: The Invechhiare in Chianti (InCHIANTI) Study was supported as a targeted project (ICS 110.1RS97.71) by the Italian Ministry of Health, by the US National Institute on Aging (Contracts N01[AG]916413, N01[AG] 821336, 263 MD 9164 13, and 263 MD 821336), and, in part, by the Intramural Research Program, National Institute on Aging, National Institutes of Health. Funding Information: MAS: We would like to acknowledge and thank the Sydney MAS participants and the Research Team for their contributions and assistance. We would like to specifically acknowledge the support and contributions of Professor Henry Brodaty (Chief Investigator), Dr Simone Reppermund (Study Co-ordinator), Professor Peter Schofield, Dr Arezoo Assareh and Dr John Kwok to this work. DNA was extracted by Genetic Repositories Australia, an Enabling Facility supported by NHMRC Grant 401184. DNA sample preparation was undertaken in the laboratory of Professor Peter Schofield and Dr John Kwok, Neuroscience Research Australia, with the assistance of Dr Arezoo Assareh. Genotyping was performed by the Ramaciotti Centre, University of New South Wales. Sydney MAS is supported by the Australian National Health & Medical Research Council Program Grants 350833 and 568969. Karen Mather is supported by the Capacity Building Grant 568940. Nicola Armstrong is supported by the NHMRC Project Grant 525453. Funding Information: HBCS: We thank all study participants as well as everybody involved in the Helsinki Birth Cohort Study. Helsinki Birth Cohort Study has been supported by grants from the Academy of Finland, the Finnish Diabetes Research Society, Folkhälsan Research Foundation, Novo Nordisk Foundation, Finska Läkaresällskapet, Signe and Ane Gyllenberg Foundation, University of Helsinki, Ministry of Education, Ahokas Foundation, Emil Aaltonen Foundation, Juho Vainio Foundation and Wellcome Trust (Grant Number WT089062). Funding Information: NHS: This study was supported by research Grants CA87969, CA49449, HL34594, U01HG004399, DK058845, CA65725, CA67262, CA50385, 5UO1CA098233, EY09611, EY015473, HG004728, HL35464, CA55075, CA134958 and DK070756 from the National Institutes of Health. The genotyping was partly supported by an unrestricted grant from Merck Research Laboratories. Dr Sun is supported by career development award K99HL098459 from the National Heart, Lung and Blood Institute. Supported in part by NIH. Funding Information: Health ABC: This research was supported by NIA Contracts N01AG62101, N01AG62103 and N01AG62106. The genome-wide association study was funded by NIA Grant 1R01AG032098-01A1 to Wake Forest University Health Sciences and genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, Contract Number HHSN268200782096C. This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging. Funding Information: AGES: Aging Gene-Environment Susceptibility-Reykjavik Study: The research has been funded by NIA Contract N01-AG-12100 with contributions from NEI, NIDCD and NHLBI, the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association) and the Althingi (the Icelandic Parliament). Funding Information: SHIP: SHIP is part of the Community Medicine Research net of the University Medicine of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research (grants no. 01ZZ9603, 01ZZ0103, and 01ZZ0403), the Ministry of Cultural Affairs as well as the Social Ministry of the Federal State of Mecklenburg-West Pomerania. The SHIP authors are grateful to Holger Prokisch and Thomas Meitinger (Helmholtz Zentrum München) for the genotyping of the SHIP-TREND cohort. Funding Information: CROATIA-Vis: The CROATIA-Vis study was funded by grants from the Medical Research Council (UK) and Republic of Croatia Ministry of Science, Education and Sports research grants to IR (108-1080315-0302). We would like to acknowledge the staff of several institutions in Croatia that supported the field work, including but not limited to The University of Split and Zagreb Medical Schools, the Institute for Anthropological Research in Zagreb and Croatian Institute for Public Health. The SNP genotyping for the CROATIA-Vis cohort was performed in the core genotyping laboratory of the Wellcome Trust Clinical Research Facility at the Western General Hospital, Edinburgh, Scotland. Funding Information: AAA: We thank the cohort participants and team members who contributed to this study. Phenotype collection and DNA extraction were supported by the Wellcome Trust, the British Heart Foundation and the Chief Scientist Office of the Scottish Executive. The AAA Trial was performed and the database is maintained by members of the University of Edinburgh Molecular Epidemiology Research Group in the Centre for Population Health Sciences. We also thank staff at the Wellcome Trust Clinical Research Facility in Edinburgh where some of the research clinics and genotyping were undertaken. Funding Information: FHS: This work was supported by the National Heart, Lung and Blood Institute’s Framingham Heart Study (Contract No. N01-HC-25195) and its contract with Affymetrix, Inc for genotyping services (Contract No. N02-HL-6-4278) and Grants (U01 HL096917 and R01 HL093029). A portion of this research utilized the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. Analyses reflect intellectual input and resource development from the Framingham Heart Study investigators participating in the SNP Health Association Resource (SHARe) project. This study was also supported by grants from the National Institute of Neurological Disorders and Stroke (NS17950) and the National Institute of Aging (U01 AG049505, AG033193, AG008122, AG16495). The content is solely the responsibility of the authors and does not necessarily represent the official views of NINDS, NHLBI, NIA, NIH or AHA. Dr. Debette is a recipient of a Chaire d'Excellence grant from the Agence National de la Recherche and a grant from the Leducq Foundation. Funding Information: RUSH: Supported in part by NIA Grants P30AG10161, R01AG15819, R01AG17917, R01AG30146, K08AG34290 and K25AG41906. Funding Information: WGHS: The WGHS is supported by HL043851 and HL080467 from the National Heart, Lung and Blood Institute and CA047988 from the National Cancer Institute, the Donald W Reynolds Foundation and the Fondation Leducq, with collaborative scientific support and funding for genotyping provided by Amgen. Funding Information: CROATIA-Split: The CROATIA-Split study is funded by grants from the Medical Research Council (UK), European Commission Framework 6 project EUROSPAN (Contract No. LSHG-CT-2006-018947) and Republic of Croatia Ministry of Science, Education and Sports research grants to IR (108-1080315-0302). We would like to acknowledge the invaluable contributions of the recruitment team in Split, the administrative teams in Croatia and Edinburgh and the people of Split. The SNP genotyping for the CROATIA-Split cohort was performed by AROS Applied Biotechnology, Aarhus, Denmark. Funding Information: ORCADES: ORCADES was supported by the Chief Scientist Office of the Scottish Government, the Royal Society, the MRC Human Genetics Unit, Arthritis Research UK and the European Union framework program 6 EUROSPAN project (Contract No. LSHG-CT-2006-018947). DNA extractions were performed at the Wellcome Trust Clinical Research Facility in Edinburgh. We would like to acknowledge the invaluable contributions of Lorraine Anderson and the research nurses in Orkney, the administrative team in Edinburgh and the people of Orkney. Funding Information: LBC1921/LBC1936: We thank the cohort participants and team members who contributed to these studies. Phenotype collection in the Lothian Birth Cohort 1921 was supported by the BBSRC, The Royal Society and The Chief Scientist Office of the Scottish Government. Phenotype collection in the Lothian Birth Cohort 1936 was supported by Research Into Ageing (continues as part of Age UK The Disconnected Mind project). Genotyping of the cohorts was funded by the UK Biotechnology and Biological Sciences Research Council (BBSRC). The work was undertaken by The University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology, part of the cross council Lifelong Health and Wellbeing Initiative (G0700704/84698). Funding from the BBSRC, Engineering and Physical Sciences Research Council (EPSRC), Economic and Social Research Council (ESRC) and MRC is gratefully acknowledged. Funding Information: 3CS: The work was made possible by the generous participation of the control subjects and their families. This work was supported by the National Foundation for Alzheimer’s disease and related disorders, the Institut Pasteur de Lille, the Centre National de Génotypage, Inserm, FRC (fondation pour la recherche sur le cerveau) and Rotary. This work has been developed and supported by the LABEX (laboratory of excellence program investment for the future) DISTALZ grant (Development of Innovative Strategies for a Transdisciplinary approach to ALZheimer’s disease). JCL was funded by the MEDIALZ Project (Grant 11001003) financed by ERDF (European Regional Development Fund) and Conseil Régional Nord Pas de Calais. The Three-City Study was performed as part of a collaboration between the Institut National de la Santé et de la Recherche Médicale (Inserm), the Victor Segalen Bordeaux II University and Sanofi-Synthélabo. The Fondation pour la Recherche Médicale funded the preparation and initiation of the study. The 3C Study was also funded by the Caisse Nationale Maladie des Travailleurs Salariés, Direction Générale de la Santé, MGEN, Institut de la Longévité, Agence Française de Sécurité Sanitaire des Produits de Santé, the Aquitaine and Bourgogne Regional Councils, Fondation de France and the joint French Ministry of Research/INSERM ‘Cohortes et collections de données biologiques’ program. Lille Génopôle received an unconditional grant from Eisai. Funding Information: ERF: This study was financially supported by the Netherlands Organization for Scientific Research (NWO), the Internationale Stichting Alzheimer Onderzoek (ISAO), the Hersenstichting Nederland (HSN) and the Centre for Medical Systems Biology (CMSB) in the framework of the Netherlands Genomics Initiative (NGI) and by the Russian Foundation for Basic Research (RFBR). We thank the participants from the Genetic Research in Isolated Populations, Erasmus Rucphen Family, who made this work possible. Also, we thank Petra Veraart for collecting all genealogical data. Funding Information: Hunter: The authors would like to thank the men and women participating in the HCS as well as all the staff, investigators and collaborators who have supported or been involved in the project to date. The cohort was made possible with support from the University of Newcastle's Strategic Initiative Fund, the Vincent Fairfax Family Foundation and the Hunter Medical Research Institute. Funding Information: GENOA: Support for the Genetic Epidemiology Network of Arteriopathy (GENOA) was provided by the National Heart, Lung and Blood Institute (HL054464, HL054457, HL054481, HL071917 and HL87660) and the National Institute of Neurological Disorders and Stroke (NS041558) of the National Institutes of Health. Genotyping was performed at the Mayo Clinic (S.T.T., Mariza de Andrade, Julie Cunningham) and was made possible by the University of Texas Health Sciences Center (Eric Boerwinkle, Megan L Grove-Gaona). We would also like to thank the families that participated in the GENOA study. Funding Information: RS: The generation and management of GWAS genotype data for the Rotterdam Study is supported by the Netherlands Organisation of Scientific Research NWO Investments (nr. 175.010.2005.011, 911-03-012). This study is funded by the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), the Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) project nr. 050-060-810. We thank Pascal Arp, Mila Jhamai, Marijn Verkerk, Lizbeth Herrera and Marjolein Peters for their help in creating the GWAS database, and Karol Estrada and Maksim V. Struchalin for their support in creation and analysis of imputed data. The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission 49 (DG XII), and the Municipality of Rotterdam. The authors are grateful to the study participants, the staff from the Rotterdam Study and the participating general practitioners and pharmacists. Dr Ikram was supported by a ZonMW Veni Grant: 916.13.054. Publisher Copyright: © 2016 Macmillan Publishers Limited All rights reserved.

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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