Genetic contributions to variation in general cognitive function: a meta-analysis of genome-wide association studies in the CHARGE consortium (N=53949)

Gail Davies; Nicola Armstrong; Joshua C Bis; Jan Bressler; Vincent Chouraki; Sudheer Giddaluru; Edith Hofer; Carla A Ibrahim-Verbaas; Mirna Kirin; Jari Marko Lahti; Sven J van der Lee; Stephanie Le Hellard; Tian Liu; Riccardo E Marioni; Christopher Oldmeadow; Iris Postmus; Albert Vernon Smith; Jennifer Ann Smith; Anbupalam Thalamuthu; Russell Thomson; Veronique Vitart; Jing Wang; Lei Yu; Lina Zgaga; Wei Zhao; Ruth Boxall; Sarah E Harris; William David Hill; David C Liewald; Michelle Luciano; Hieab H H Adams; David J Ames; Najaf Amin; Philippe Amouyel; Amelia A Assareh; Rhoda Au; James T Becker; Alexa Beiser; Claudine Berr; Lars Bertram; Eric Boerwinkle; Brendan M Buckley; Harry Campbell; Janie Corley; Philip Laurence De Jager; Carole Dufouil; Johan Gunnar Eriksson; Thomas Espeseth; Jessica D Faul; Ian Ford; Rebecca F Gottesman; Michael E Griswold; Vilmundur G Gudnason; Tamara B Harris; Gerardo Heiss; Albert Hofman; Elizabeth G Holliday; Jennifer Huffman; Sharon L R Kardia; Nicole Kochan; David S Knopman; John B J Kwok; Jean-Charles Lambert; Teresa Lee; Guo Li; Shu-Chen Li; Marisa Loitfelder; Oscar L Lopez; Astri Johansen Lundervold; Anders Lundqvist; Karen A Mather; Saira Saeed Mirza; Lars Nyberg; Ben A Oostra; Aarno Palotie; Goran Papenberg; Alison Pattie; Katja Elisabeth Petrovic; Ozren Polasek; Bruce M Psaty; Paul Redmond; Simone Reppermund; Jerome I Rotter; Helena Schmidt; Maaike Schuur; Peter W Schofield; Rodney J Scott; Vidar M Steen; David J Stott; John C van Swieten; Kent D Taylor; Julian Norman Trollor; Stella Trompet; Andre G Uitterlinden; Galit Weinstein; Elisabeth Widen; Beverly Gwen Windham; J Wouter Jukema; Alan F Wright; Margaret J Wright; Qiong Yang; Helene Amieva; John R Attia; David A Bennett; Henry Brodaty; Anton J M de Craen; Caroline Hayward; Mohammed Arfan Ikram; Lars-Goran Nilsson; Ulman Lindenberger; David J Porteous; Katri Raikkonen; Ivar Reinvang; Igor Rudan; Perminder Singh Sachdev; Reinhold Schmidt; Peter R Schofield; Velandai Srikanth; John M Starr; Stephen T Turner; David R Weir; Jim F Wilson; Cornelia M van Duijn; Lenore J Launer; Annette L Fitzpatrick; Sudha Seshadri; Thomas H Mosley; Ian J Deary

doi:10.1038/mp.2014.188

Genetic contributions to variation in general cognitive function: a meta-analysis of genome-wide association studies in the CHARGE consortium (N=53949)

Gail Davies, Nicola Armstrong, Joshua C Bis, Jan Bressler, Vincent Chouraki, Sudheer Giddaluru, Edith Hofer, Carla A Ibrahim-Verbaas, Mirna Kirin, Jari Marko Lahti, Sven J van der Lee, Stephanie Le Hellard, Tian Liu, Riccardo E Marioni, Christopher Oldmeadow, Iris Postmus, Albert Vernon Smith, Jennifer Ann Smith, Anbupalam Thalamuthu, Russell ThomsonVeronique Vitart, Jing Wang, Lei Yu, Lina Zgaga, Wei Zhao, Ruth Boxall, Sarah E Harris, William David Hill, David C Liewald, Michelle Luciano, Hieab H H Adams, David J Ames, Najaf Amin, Philippe Amouyel, Amelia A Assareh, Rhoda Au, James T Becker, Alexa Beiser, Claudine Berr, Lars Bertram, Eric Boerwinkle, Brendan M Buckley, Harry Campbell, Janie Corley, Philip Laurence De Jager, Carole Dufouil, Johan Gunnar Eriksson, Thomas Espeseth, Jessica D Faul, Ian Ford, Rebecca F Gottesman, Michael E Griswold, Vilmundur G Gudnason, Tamara B Harris, Gerardo Heiss, Albert Hofman, Elizabeth G Holliday, Jennifer Huffman, Sharon L R Kardia, Nicole Kochan, David S Knopman, John B J Kwok, Jean-Charles Lambert, Teresa Lee, Guo Li, Shu-Chen Li, Marisa Loitfelder, Oscar L Lopez, Astri Johansen Lundervold, Anders Lundqvist, Karen A Mather, Saira Saeed Mirza, Lars Nyberg, Ben A Oostra, Aarno Palotie, Goran Papenberg, Alison Pattie, Katja Elisabeth Petrovic, Ozren Polasek, Bruce M Psaty, Paul Redmond, Simone Reppermund, Jerome I Rotter, Helena Schmidt, Maaike Schuur, Peter W Schofield, Rodney J Scott, Vidar M Steen, David J Stott, John C van Swieten, Kent D Taylor, Julian Norman Trollor, Stella Trompet, Andre G Uitterlinden, Galit Weinstein, Elisabeth Widen, Beverly Gwen Windham, J Wouter Jukema, Alan F Wright, Margaret J Wright, Qiong Yang, Helene Amieva, John R Attia, David A Bennett, Henry Brodaty, Anton J M de Craen, Caroline Hayward, Mohammed Arfan Ikram, Lars-Goran Nilsson, Ulman Lindenberger, David J Porteous, Katri Raikkonen, Ivar Reinvang, Igor Rudan, Perminder Singh Sachdev, Reinhold Schmidt, Peter R Schofield, Velandai Srikanth, John M Starr, Stephen T Turner, David R Weir, Jim F Wilson, Cornelia M van Duijn, Lenore J Launer, Annette L Fitzpatrick, Sudha Seshadri, Thomas H Mosley, Ian J Deary

Medicine Monash Health

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

222 Citations (Scopus)

Abstract

General cognitive function is substantially heritable across the human life course from adolescence to old age. We investigated the genetic contribution to variation in this important, health- and well-being-related trait in middle-aged and older adults. We conducted a meta-analysis of genome-wide association studies of 31 cohorts (N=53 949) in which the participants had undertaken multiple, diverse cognitive tests. A general cognitive function phenotype was tested for, and created in each cohort by principal component analysis. We report 13 genome-wide significant single-nucleotide polymorphism (SNP) associations in three genomic regions, 6q16.1, 14q12 and 19q13.32 (best SNP and closest gene, respectively: rs10457441, P=3.93 x 10(-9), MIR2113; rs17522122, P=2.55 x 10(-8), AKAP6; rs10119, P=5.67 x 10(-9), APOE/TOMM40). We report one gene-based significant association with the HMGN1 gene located on chromosome 21 (P=1 x 10(-6)). These genes have previously been associated with neuropsychiatric phenotypes. Meta-analysis results are consistent with a polygenic model of inheritance. To estimate SNP-based heritability, the genome-wide complex trait analysis procedure was applied to two large cohorts, the Atherosclerosis Risk in Communities Study (N=6617) and the Health and Retirement Study (N=5976). The proportion of phenotypic variation accounted for by all genotyped common SNPs was 29 (s.e.=5 ) and 28 (s.e.=7 ), respectively. Using polygenic prediction analysis, 1.2 of the variance in general cognitive function was predicted in the Generation Scotland cohort (N=5487; P=1.5 x 10(-17)). In hypothesis-driven tests, there was significant association between general cognitive function and four genes previously associated with Alzheimer s disease: TOMM40, APOE, ABCG1 and MEF2C.

Original language	English
Pages (from-to)	183 - 192
Number of pages	10
Journal	Molecular Psychiatry
Volume	20
Issue number	2
DOIs	https://doi.org/10.1038/mp.2014.188
Publication status	Published - 2015

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Davies, G., Armstrong, N., Bis, J. C., Bressler, J., Chouraki, V., Giddaluru, S., Hofer, E., Ibrahim-Verbaas, C. A., Kirin, M., Lahti, J. M., van der Lee, S. J., Le Hellard, S., Liu, T., Marioni, R. E., Oldmeadow, C., Postmus, I., Smith, A. V., Smith, J. A., Thalamuthu, A., ... Deary, I. J. (2015). Genetic contributions to variation in general cognitive function: a meta-analysis of genome-wide association studies in the CHARGE consortium (N=53949). Molecular Psychiatry, 20(2), 183 - 192. https://doi.org/10.1038/mp.2014.188

Davies, Gail ; Armstrong, Nicola ; Bis, Joshua C ; Bressler, Jan ; Chouraki, Vincent ; Giddaluru, Sudheer ; Hofer, Edith ; Ibrahim-Verbaas, Carla A ; Kirin, Mirna ; Lahti, Jari Marko ; van der Lee, Sven J ; Le Hellard, Stephanie ; Liu, Tian ; Marioni, Riccardo E ; Oldmeadow, Christopher ; Postmus, Iris ; Smith, Albert Vernon ; Smith, Jennifer Ann ; Thalamuthu, Anbupalam ; Thomson, Russell ; Vitart, Veronique ; Wang, Jing ; Yu, Lei ; Zgaga, Lina ; Zhao, Wei ; Boxall, Ruth ; Harris, Sarah E ; Hill, William David ; Liewald, David C ; Luciano, Michelle ; Adams, Hieab H H ; Ames, David J ; Amin, Najaf ; Amouyel, Philippe ; Assareh, Amelia A ; Au, Rhoda ; Becker, James T ; Beiser, Alexa ; Berr, Claudine ; Bertram, Lars ; Boerwinkle, Eric ; Buckley, Brendan M ; Campbell, Harry ; Corley, Janie ; De Jager, Philip Laurence ; Dufouil, Carole ; Eriksson, Johan Gunnar ; Espeseth, Thomas ; Faul, Jessica D ; Ford, Ian ; Gottesman, Rebecca F ; Griswold, Michael E ; Gudnason, Vilmundur G ; Harris, Tamara B ; Heiss, Gerardo ; Hofman, Albert ; Holliday, Elizabeth G ; Huffman, Jennifer ; Kardia, Sharon L R ; Kochan, Nicole ; Knopman, David S ; Kwok, John B J ; Lambert, Jean-Charles ; Lee, Teresa ; Li, Guo ; Li, Shu-Chen ; Loitfelder, Marisa ; Lopez, Oscar L ; Lundervold, Astri Johansen ; Lundqvist, Anders ; Mather, Karen A ; Mirza, Saira Saeed ; Nyberg, Lars ; Oostra, Ben A ; Palotie, Aarno ; Papenberg, Goran ; Pattie, Alison ; Petrovic, Katja Elisabeth ; Polasek, Ozren ; Psaty, Bruce M ; Redmond, Paul ; Reppermund, Simone ; Rotter, Jerome I ; Schmidt, Helena ; Schuur, Maaike ; Schofield, Peter W ; Scott, Rodney J ; Steen, Vidar M ; Stott, David J ; van Swieten, John C ; Taylor, Kent D ; Trollor, Julian Norman ; Trompet, Stella ; Uitterlinden, Andre G ; Weinstein, Galit ; Widen, Elisabeth ; Windham, Beverly Gwen ; Jukema, J Wouter ; Wright, Alan F ; Wright, Margaret J ; Yang, Qiong ; Amieva, Helene ; Attia, John R ; Bennett, David A ; Brodaty, Henry ; de Craen, Anton J M ; Hayward, Caroline ; Ikram, Mohammed Arfan ; Nilsson, Lars-Goran ; Lindenberger, Ulman ; Porteous, David J ; Raikkonen, Katri ; Reinvang, Ivar ; Rudan, Igor ; Sachdev, Perminder Singh ; Schmidt, Reinhold ; Schofield, Peter R ; Srikanth, Velandai ; Starr, John M ; Turner, Stephen T ; Weir, David R ; Wilson, Jim F ; van Duijn, Cornelia M ; Launer, Lenore J ; Fitzpatrick, Annette L ; Seshadri, Sudha ; Mosley, Thomas H ; Deary, Ian J. / Genetic contributions to variation in general cognitive function: a meta-analysis of genome-wide association studies in the CHARGE consortium (N=53949). In: Molecular Psychiatry. 2015 ; Vol. 20, No. 2. pp. 183 - 192.

@article{daf7581f195246ed995915ff84958be7,

title = "Genetic contributions to variation in general cognitive function: a meta-analysis of genome-wide association studies in the CHARGE consortium (N=53949)",

abstract = "General cognitive function is substantially heritable across the human life course from adolescence to old age. We investigated the genetic contribution to variation in this important, health- and well-being-related trait in middle-aged and older adults. We conducted a meta-analysis of genome-wide association studies of 31 cohorts (N=53 949) in which the participants had undertaken multiple, diverse cognitive tests. A general cognitive function phenotype was tested for, and created in each cohort by principal component analysis. We report 13 genome-wide significant single-nucleotide polymorphism (SNP) associations in three genomic regions, 6q16.1, 14q12 and 19q13.32 (best SNP and closest gene, respectively: rs10457441, P=3.93 x 10(-9), MIR2113; rs17522122, P=2.55 x 10(-8), AKAP6; rs10119, P=5.67 x 10(-9), APOE/TOMM40). We report one gene-based significant association with the HMGN1 gene located on chromosome 21 (P=1 x 10(-6)). These genes have previously been associated with neuropsychiatric phenotypes. Meta-analysis results are consistent with a polygenic model of inheritance. To estimate SNP-based heritability, the genome-wide complex trait analysis procedure was applied to two large cohorts, the Atherosclerosis Risk in Communities Study (N=6617) and the Health and Retirement Study (N=5976). The proportion of phenotypic variation accounted for by all genotyped common SNPs was 29 (s.e.=5 ) and 28 (s.e.=7 ), respectively. Using polygenic prediction analysis, 1.2 of the variance in general cognitive function was predicted in the Generation Scotland cohort (N=5487; P=1.5 x 10(-17)). In hypothesis-driven tests, there was significant association between general cognitive function and four genes previously associated with Alzheimer s disease: TOMM40, APOE, ABCG1 and MEF2C.",

author = "Gail Davies and Nicola Armstrong and Bis, {Joshua C} and Jan Bressler and Vincent Chouraki and Sudheer Giddaluru and Edith Hofer and Ibrahim-Verbaas, {Carla A} and Mirna Kirin and Lahti, {Jari Marko} and {van der Lee}, {Sven J} and {Le Hellard}, Stephanie and Tian Liu and Marioni, {Riccardo E} and Christopher Oldmeadow and Iris Postmus and Smith, {Albert Vernon} and Smith, {Jennifer Ann} and Anbupalam Thalamuthu and Russell Thomson and Veronique Vitart and Jing Wang and Lei Yu and Lina Zgaga and Wei Zhao and Ruth Boxall and Harris, {Sarah E} and Hill, {William David} and Liewald, {David C} and Michelle Luciano and Adams, {Hieab H H} and Ames, {David J} and Najaf Amin and Philippe Amouyel and Assareh, {Amelia A} and Rhoda Au and Becker, {James T} and Alexa Beiser and Claudine Berr and Lars Bertram and Eric Boerwinkle and Buckley, {Brendan M} and Harry Campbell and Janie Corley and {De Jager}, {Philip Laurence} and Carole Dufouil and Eriksson, {Johan Gunnar} and Thomas Espeseth and Faul, {Jessica D} and Ian Ford and Gottesman, {Rebecca F} and Griswold, {Michael E} and Gudnason, {Vilmundur G} and Harris, {Tamara B} and Gerardo Heiss and Albert Hofman and Holliday, {Elizabeth G} and Jennifer Huffman and Kardia, {Sharon L R} and Nicole Kochan and Knopman, {David S} and Kwok, {John B J} and Jean-Charles Lambert and Teresa Lee and Guo Li and Shu-Chen Li and Marisa Loitfelder and Lopez, {Oscar L} and Lundervold, {Astri Johansen} and Anders Lundqvist and Mather, {Karen A} and Mirza, {Saira Saeed} and Lars Nyberg and Oostra, {Ben A} and Aarno Palotie and Goran Papenberg and Alison Pattie and Petrovic, {Katja Elisabeth} and Ozren Polasek and Psaty, {Bruce M} and Paul Redmond and Simone Reppermund and Rotter, {Jerome I} and Helena Schmidt and Maaike Schuur and Schofield, {Peter W} and Scott, {Rodney J} and Steen, {Vidar M} and Stott, {David J} and {van Swieten}, {John C} and Taylor, {Kent D} and Trollor, {Julian Norman} and Stella Trompet and Uitterlinden, {Andre G} and Galit Weinstein and Elisabeth Widen and Windham, {Beverly Gwen} and Jukema, {J Wouter} and Wright, {Alan F} and Wright, {Margaret J} and Qiong Yang and Helene Amieva and Attia, {John R} and Bennett, {David A} and Henry Brodaty and {de Craen}, {Anton J M} and Caroline Hayward and Ikram, {Mohammed Arfan} and Lars-Goran Nilsson and Ulman Lindenberger and Porteous, {David J} and Katri Raikkonen and Ivar Reinvang and Igor Rudan and Sachdev, {Perminder Singh} and Reinhold Schmidt and Schofield, {Peter R} and Velandai Srikanth and Starr, {John M} and Turner, {Stephen T} and Weir, {David R} and Wilson, {Jim F} and {van Duijn}, {Cornelia M} and Launer, {Lenore J} and Fitzpatrick, {Annette L} and Sudha Seshadri and Mosley, {Thomas H} and Deary, {Ian J}",

year = "2015",

doi = "10.1038/mp.2014.188",

language = "English",

volume = "20",

pages = "183 -- 192",

journal = "Molecular Psychiatry",

issn = "1359-4184",

publisher = "Nature Publishing Group",

number = "2",

}

Davies, G, Armstrong, N, Bis, JC, Bressler, J, Chouraki, V, Giddaluru, S, Hofer, E, Ibrahim-Verbaas, CA, Kirin, M, Lahti, JM, van der Lee, SJ, Le Hellard, S, Liu, T, Marioni, RE, Oldmeadow, C, Postmus, I, Smith, AV, Smith, JA, Thalamuthu, A, Thomson, R, Vitart, V, Wang, J, Yu, L, Zgaga, L, Zhao, W, Boxall, R, Harris, SE, Hill, WD, Liewald, DC, Luciano, M, Adams, HHH, Ames, DJ, Amin, N, Amouyel, P, Assareh, AA, Au, R, Becker, JT, Beiser, A, Berr, C, Bertram, L, Boerwinkle, E, Buckley, BM, Campbell, H, Corley, J, De Jager, PL, Dufouil, C, Eriksson, JG, Espeseth, T, Faul, JD, Ford, I, Gottesman, RF, Griswold, ME, Gudnason, VG, Harris, TB, Heiss, G, Hofman, A, Holliday, EG, Huffman, J, Kardia, SLR, Kochan, N, Knopman, DS, Kwok, JBJ, Lambert, J-C, Lee, T, Li, G, Li, S-C, Loitfelder, M, Lopez, OL, Lundervold, AJ, Lundqvist, A, Mather, KA, Mirza, SS, Nyberg, L, Oostra, BA, Palotie, A, Papenberg, G, Pattie, A, Petrovic, KE, Polasek, O, Psaty, BM, Redmond, P, Reppermund, S, Rotter, JI, Schmidt, H, Schuur, M, Schofield, PW, Scott, RJ, Steen, VM, Stott, DJ, van Swieten, JC, Taylor, KD, Trollor, JN, Trompet, S, Uitterlinden, AG, Weinstein, G, Widen, E, Windham, BG, Jukema, JW, Wright, AF, Wright, MJ, Yang, Q, Amieva, H, Attia, JR, Bennett, DA, Brodaty, H, de Craen, AJM, Hayward, C, Ikram, MA, Nilsson, L-G, Lindenberger, U, Porteous, DJ, Raikkonen, K, Reinvang, I, Rudan, I, Sachdev, PS, Schmidt, R, Schofield, PR, Srikanth, V, Starr, JM, Turner, ST, Weir, DR, Wilson, JF, van Duijn, CM, Launer, LJ, Fitzpatrick, AL, Seshadri, S, Mosley, TH & Deary, IJ 2015, 'Genetic contributions to variation in general cognitive function: a meta-analysis of genome-wide association studies in the CHARGE consortium (N=53949)', Molecular Psychiatry, vol. 20, no. 2, pp. 183 - 192. https://doi.org/10.1038/mp.2014.188

Genetic contributions to variation in general cognitive function: a meta-analysis of genome-wide association studies in the CHARGE consortium (N=53949). / Davies, Gail; Armstrong, Nicola; Bis, Joshua C; Bressler, Jan; Chouraki, Vincent; Giddaluru, Sudheer; Hofer, Edith; Ibrahim-Verbaas, Carla A; Kirin, Mirna; Lahti, Jari Marko; van der Lee, Sven J; Le Hellard, Stephanie; Liu, Tian; Marioni, Riccardo E; Oldmeadow, Christopher; Postmus, Iris; Smith, Albert Vernon; Smith, Jennifer Ann; Thalamuthu, Anbupalam; Thomson, Russell; Vitart, Veronique; Wang, Jing; Yu, Lei; Zgaga, Lina; Zhao, Wei; Boxall, Ruth; Harris, Sarah E; Hill, William David; Liewald, David C; Luciano, Michelle; Adams, Hieab H H; Ames, David J; Amin, Najaf; Amouyel, Philippe; Assareh, Amelia A; Au, Rhoda; Becker, James T; Beiser, Alexa; Berr, Claudine; Bertram, Lars; Boerwinkle, Eric; Buckley, Brendan M; Campbell, Harry; Corley, Janie; De Jager, Philip Laurence; Dufouil, Carole; Eriksson, Johan Gunnar; Espeseth, Thomas; Faul, Jessica D; Ford, Ian; Gottesman, Rebecca F; Griswold, Michael E; Gudnason, Vilmundur G; Harris, Tamara B; Heiss, Gerardo; Hofman, Albert; Holliday, Elizabeth G; Huffman, Jennifer; Kardia, Sharon L R; Kochan, Nicole; Knopman, David S; Kwok, John B J; Lambert, Jean-Charles; Lee, Teresa; Li, Guo; Li, Shu-Chen; Loitfelder, Marisa; Lopez, Oscar L; Lundervold, Astri Johansen; Lundqvist, Anders; Mather, Karen A; Mirza, Saira Saeed; Nyberg, Lars; Oostra, Ben A; Palotie, Aarno; Papenberg, Goran; Pattie, Alison; Petrovic, Katja Elisabeth; Polasek, Ozren; Psaty, Bruce M; Redmond, Paul; Reppermund, Simone; Rotter, Jerome I; Schmidt, Helena; Schuur, Maaike; Schofield, Peter W; Scott, Rodney J; Steen, Vidar M; Stott, David J; van Swieten, John C; Taylor, Kent D; Trollor, Julian Norman; Trompet, Stella; Uitterlinden, Andre G; Weinstein, Galit; Widen, Elisabeth; Windham, Beverly Gwen; Jukema, J Wouter; Wright, Alan F; Wright, Margaret J; Yang, Qiong; Amieva, Helene; Attia, John R; Bennett, David A; Brodaty, Henry; de Craen, Anton J M; Hayward, Caroline; Ikram, Mohammed Arfan; Nilsson, Lars-Goran; Lindenberger, Ulman; Porteous, David J; Raikkonen, Katri; Reinvang, Ivar; Rudan, Igor; Sachdev, Perminder Singh; Schmidt, Reinhold; Schofield, Peter R; Srikanth, Velandai; Starr, John M; Turner, Stephen T; Weir, David R; Wilson, Jim F; van Duijn, Cornelia M; Launer, Lenore J; Fitzpatrick, Annette L; Seshadri, Sudha; Mosley, Thomas H; Deary, Ian J.

In: Molecular Psychiatry, Vol. 20, No. 2, 2015, p. 183 - 192.

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

TY - JOUR

T1 - Genetic contributions to variation in general cognitive function: a meta-analysis of genome-wide association studies in the CHARGE consortium (N=53949)

AU - Davies, Gail

AU - Armstrong, Nicola

AU - Bis, Joshua C

AU - Bressler, Jan

AU - Chouraki, Vincent

AU - Giddaluru, Sudheer

AU - Hofer, Edith

AU - Ibrahim-Verbaas, Carla A

AU - Kirin, Mirna

AU - Lahti, Jari Marko

AU - van der Lee, Sven J

AU - Le Hellard, Stephanie

AU - Liu, Tian

AU - Marioni, Riccardo E

AU - Oldmeadow, Christopher

AU - Postmus, Iris

AU - Smith, Albert Vernon

AU - Smith, Jennifer Ann

AU - Thalamuthu, Anbupalam

AU - Thomson, Russell

AU - Vitart, Veronique

AU - Wang, Jing

AU - Yu, Lei

AU - Zgaga, Lina

AU - Zhao, Wei

AU - Boxall, Ruth

AU - Harris, Sarah E

AU - Hill, William David

AU - Liewald, David C

AU - Luciano, Michelle

AU - Adams, Hieab H H

AU - Ames, David J

AU - Amin, Najaf

AU - Amouyel, Philippe

AU - Assareh, Amelia A

AU - Au, Rhoda

AU - Becker, James T

AU - Beiser, Alexa

AU - Berr, Claudine

AU - Bertram, Lars

AU - Boerwinkle, Eric

AU - Buckley, Brendan M

AU - Campbell, Harry

AU - Corley, Janie

AU - De Jager, Philip Laurence

AU - Dufouil, Carole

AU - Eriksson, Johan Gunnar

AU - Espeseth, Thomas

AU - Faul, Jessica D

AU - Ford, Ian

AU - Gottesman, Rebecca F

AU - Griswold, Michael E

AU - Gudnason, Vilmundur G

AU - Harris, Tamara B

AU - Heiss, Gerardo

AU - Hofman, Albert

AU - Holliday, Elizabeth G

AU - Huffman, Jennifer

AU - Kardia, Sharon L R

AU - Kochan, Nicole

AU - Knopman, David S

AU - Kwok, John B J

AU - Lambert, Jean-Charles

AU - Lee, Teresa

AU - Li, Guo

AU - Li, Shu-Chen

AU - Loitfelder, Marisa

AU - Lopez, Oscar L

AU - Lundervold, Astri Johansen

AU - Lundqvist, Anders

AU - Mather, Karen A

AU - Mirza, Saira Saeed

AU - Nyberg, Lars

AU - Oostra, Ben A

AU - Palotie, Aarno

AU - Papenberg, Goran

AU - Pattie, Alison

AU - Petrovic, Katja Elisabeth

AU - Polasek, Ozren

AU - Psaty, Bruce M

AU - Redmond, Paul

AU - Reppermund, Simone

AU - Rotter, Jerome I

AU - Schmidt, Helena

AU - Schuur, Maaike

AU - Schofield, Peter W

AU - Scott, Rodney J

AU - Steen, Vidar M

AU - Stott, David J

AU - van Swieten, John C

AU - Taylor, Kent D

AU - Trollor, Julian Norman

AU - Trompet, Stella

AU - Uitterlinden, Andre G

AU - Weinstein, Galit

AU - Widen, Elisabeth

AU - Windham, Beverly Gwen

AU - Jukema, J Wouter

AU - Wright, Alan F

AU - Wright, Margaret J

AU - Yang, Qiong

AU - Amieva, Helene

AU - Attia, John R

AU - Bennett, David A

AU - Brodaty, Henry

AU - de Craen, Anton J M

AU - Hayward, Caroline

AU - Ikram, Mohammed Arfan

AU - Nilsson, Lars-Goran

AU - Lindenberger, Ulman

AU - Porteous, David J

AU - Raikkonen, Katri

AU - Reinvang, Ivar

AU - Rudan, Igor

AU - Sachdev, Perminder Singh

AU - Schmidt, Reinhold

AU - Schofield, Peter R

AU - Srikanth, Velandai

AU - Starr, John M

AU - Turner, Stephen T

AU - Weir, David R

AU - Wilson, Jim F

AU - van Duijn, Cornelia M

AU - Launer, Lenore J

AU - Fitzpatrick, Annette L

AU - Seshadri, Sudha

AU - Mosley, Thomas H

AU - Deary, Ian J

PY - 2015

Y1 - 2015

N2 - General cognitive function is substantially heritable across the human life course from adolescence to old age. We investigated the genetic contribution to variation in this important, health- and well-being-related trait in middle-aged and older adults. We conducted a meta-analysis of genome-wide association studies of 31 cohorts (N=53 949) in which the participants had undertaken multiple, diverse cognitive tests. A general cognitive function phenotype was tested for, and created in each cohort by principal component analysis. We report 13 genome-wide significant single-nucleotide polymorphism (SNP) associations in three genomic regions, 6q16.1, 14q12 and 19q13.32 (best SNP and closest gene, respectively: rs10457441, P=3.93 x 10(-9), MIR2113; rs17522122, P=2.55 x 10(-8), AKAP6; rs10119, P=5.67 x 10(-9), APOE/TOMM40). We report one gene-based significant association with the HMGN1 gene located on chromosome 21 (P=1 x 10(-6)). These genes have previously been associated with neuropsychiatric phenotypes. Meta-analysis results are consistent with a polygenic model of inheritance. To estimate SNP-based heritability, the genome-wide complex trait analysis procedure was applied to two large cohorts, the Atherosclerosis Risk in Communities Study (N=6617) and the Health and Retirement Study (N=5976). The proportion of phenotypic variation accounted for by all genotyped common SNPs was 29 (s.e.=5 ) and 28 (s.e.=7 ), respectively. Using polygenic prediction analysis, 1.2 of the variance in general cognitive function was predicted in the Generation Scotland cohort (N=5487; P=1.5 x 10(-17)). In hypothesis-driven tests, there was significant association between general cognitive function and four genes previously associated with Alzheimer s disease: TOMM40, APOE, ABCG1 and MEF2C.

AB - General cognitive function is substantially heritable across the human life course from adolescence to old age. We investigated the genetic contribution to variation in this important, health- and well-being-related trait in middle-aged and older adults. We conducted a meta-analysis of genome-wide association studies of 31 cohorts (N=53 949) in which the participants had undertaken multiple, diverse cognitive tests. A general cognitive function phenotype was tested for, and created in each cohort by principal component analysis. We report 13 genome-wide significant single-nucleotide polymorphism (SNP) associations in three genomic regions, 6q16.1, 14q12 and 19q13.32 (best SNP and closest gene, respectively: rs10457441, P=3.93 x 10(-9), MIR2113; rs17522122, P=2.55 x 10(-8), AKAP6; rs10119, P=5.67 x 10(-9), APOE/TOMM40). We report one gene-based significant association with the HMGN1 gene located on chromosome 21 (P=1 x 10(-6)). These genes have previously been associated with neuropsychiatric phenotypes. Meta-analysis results are consistent with a polygenic model of inheritance. To estimate SNP-based heritability, the genome-wide complex trait analysis procedure was applied to two large cohorts, the Atherosclerosis Risk in Communities Study (N=6617) and the Health and Retirement Study (N=5976). The proportion of phenotypic variation accounted for by all genotyped common SNPs was 29 (s.e.=5 ) and 28 (s.e.=7 ), respectively. Using polygenic prediction analysis, 1.2 of the variance in general cognitive function was predicted in the Generation Scotland cohort (N=5487; P=1.5 x 10(-17)). In hypothesis-driven tests, there was significant association between general cognitive function and four genes previously associated with Alzheimer s disease: TOMM40, APOE, ABCG1 and MEF2C.

UR - http://www.nature.com/mp/journal/v20/n2/pdf/mp2014188a.pdf

U2 - 10.1038/mp.2014.188

DO - 10.1038/mp.2014.188

M3 - Article

VL - 20

SP - 183

EP - 192

JO - Molecular Psychiatry

JF - Molecular Psychiatry

SN - 1359-4184

IS - 2

ER -

Genetic contributions to variation in general cognitive function: a meta-analysis of genome-wide association studies in the CHARGE consortium (N=53949)

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