Large-Scale Cognitive GWAS Meta-Analysis Reveals Tissue-Specific Neural Expression and Potential Nootropic Drug Targets

Max Lam; Joey W. Trampush; Jin Yu; Emma Knowles; Gail Davies; David C. Liewald; John M. Starr; Srdjan Djurovic; Ingrid Melle; Kjetil Sundet; Andrea Christoforou; Ivar Reinvang; Pamela DeRosse; Astri J. Lundervold; Vidar M. Steen; Thomas Espeseth; Katri Räikkönen; Elisabeth Widen; Aarno Palotie; Johan G. Eriksson; Ina Giegling; Bettina Konte; Panos Roussos; Stella Giakoumaki; Katherine E. Burdick; Antony Payton; William Ollier; Ornit Chiba-Falek; Deborah K. Attix; Anna C. Need; Elizabeth T. Cirulli; Aristotle N. Voineskos; Nikos C. Stefanis; Dimitrios Avramopoulos; Alex Hatzimanolis; Dan E. Arking; Nikolaos Smyrnis; Robert M. Bilder; Nelson A. Freimer; Tyrone D. Cannon; Edythe London; Russell A. Poldrack; Fred W. Sabb; Eliza Congdon; Emily Drabant Conley; Matthew A. Scult; Dwight Dickinson; Richard E. Straub; Gary Donohoe; Derek Morris; Aiden Corvin; Michael Gill; Ahmad R. Hariri; Daniel R. Weinberger; Neil Pendleton; Panos Bitsios; Dan Rujescu; Jari Lahti; Stephanie Le Hellard; Matthew C. Keller; Ole A. Andreassen; Ian J. Deary; David C. Glahn; Anil K. Malhotra; Todd Lencz

doi:10.1016/j.celrep.2017.11.028

Large-Scale Cognitive GWAS Meta-Analysis Reveals Tissue-Specific Neural Expression and Potential Nootropic Drug Targets

Max Lam, Joey W. Trampush, Jin Yu, Emma Knowles, Gail Davies, David C. Liewald, John M. Starr, Srdjan Djurovic, Ingrid Melle, Kjetil Sundet, Andrea Christoforou, Ivar Reinvang, Pamela DeRosse, Astri J. Lundervold, Vidar M. Steen, Thomas Espeseth, Katri Räikkönen, Elisabeth Widen, Aarno Palotie, Johan G. ErikssonIna Giegling, Bettina Konte, Panos Roussos, Stella Giakoumaki, Katherine E. Burdick, Antony Payton, William Ollier, Ornit Chiba-Falek, Deborah K. Attix, Anna C. Need, Elizabeth T. Cirulli, Aristotle N. Voineskos, Nikos C. Stefanis, Dimitrios Avramopoulos, Alex Hatzimanolis, Dan E. Arking, Nikolaos Smyrnis, Robert M. Bilder, Nelson A. Freimer, Tyrone D. Cannon, Edythe London, Russell A. Poldrack, Fred W. Sabb, Eliza Congdon, Emily Drabant Conley, Matthew A. Scult, Dwight Dickinson, Richard E. Straub, Gary Donohoe, Derek Morris, Aiden Corvin, Michael Gill, Ahmad R. Hariri, Daniel R. Weinberger, Neil Pendleton, Panos Bitsios, Dan Rujescu, Jari Lahti, Stephanie Le Hellard, Matthew C. Keller, Ole A. Andreassen, Ian J. Deary, David C. Glahn, Anil K. Malhotra, Todd Lencz

School of Medicine

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

49 Scopus citations

Abstract

Here, we present a large (n = 107,207) genome-wide association study (GWAS) of general cognitive ability (“g”), further enhanced by combining results with a large-scale GWAS of educational attainment. We identified 70 independent genomic loci associated with general cognitive ability. Results showed significant enrichment for genes causing Mendelian disorders with an intellectual disability phenotype. Competitive pathway analysis implicated the biological processes of neurogenesis and synaptic regulation, as well as the gene targets of two pharmacologic agents: cinnarizine, a T-type calcium channel blocker, and LY97241, a potassium channel inhibitor. Transcriptome-wide and epigenome-wide analysis revealed that the implicated loci were enriched for genes expressed across all brain regions (most strongly in the cerebellum). Enrichment was exclusive to genes expressed in neurons but not oligodendrocytes or astrocytes. Finally, we report genetic correlations between cognitive ability and disparate phenotypes including psychiatric disorders, several autoimmune disorders, longevity, and maternal age at first birth. Lam et al. conduct a large-scale genome-wide association study of cognitive ability, identifying 70 associated loci. Results provide biological insights into the molecular basis of individual differences in cognitive ability, as well as their relationship to psychiatric and other health-relevant phenotypes.

Original language	English (US)
Pages (from-to)	2597-2613
Number of pages	17
Journal	Cell Reports
Volume	21
Issue number	9
DOIs	https://doi.org/10.1016/j.celrep.2017.11.028
State	Published - Nov 28 2017

Keywords

GWAS
calcium channel
cerebellum
gene expression
general cognitive ability
neurodevelopment
nootropics
potassium channel
synapse

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)

Access to Document

10.1016/j.celrep.2017.11.028

Cite this

Lam, M., Trampush, J. W., Yu, J., Knowles, E., Davies, G., Liewald, D. C., Starr, J. M., Djurovic, S., Melle, I., Sundet, K., Christoforou, A., Reinvang, I., DeRosse, P., Lundervold, A. J., Steen, V. M., Espeseth, T., Räikkönen, K., Widen, E., Palotie, A., ... Lencz, T. (2017). Large-Scale Cognitive GWAS Meta-Analysis Reveals Tissue-Specific Neural Expression and Potential Nootropic Drug Targets. Cell Reports, 21(9), 2597-2613. https://doi.org/10.1016/j.celrep.2017.11.028

Lam, M, Trampush, JW, Yu, J, Knowles, E, Davies, G, Liewald, DC, Starr, JM, Djurovic, S, Melle, I, Sundet, K, Christoforou, A, Reinvang, I, DeRosse, P, Lundervold, AJ, Steen, VM, Espeseth, T, Räikkönen, K, Widen, E, Palotie, A, Eriksson, JG, Giegling, I, Konte, B, Roussos, P, Giakoumaki, S, Burdick, KE, Payton, A, Ollier, W, Chiba-Falek, O, Attix, DK, Need, AC, Cirulli, ET, Voineskos, AN, Stefanis, NC, Avramopoulos, D, Hatzimanolis, A, Arking, DE, Smyrnis, N, Bilder, RM, Freimer, NA, Cannon, TD, London, E, Poldrack, RA, Sabb, FW, Congdon, E, Conley, ED, Scult, MA, Dickinson, D, Straub, RE, Donohoe, G, Morris, D, Corvin, A, Gill, M, Hariri, AR, Weinberger, DR, Pendleton, N, Bitsios, P, Rujescu, D, Lahti, J, Le Hellard, S, Keller, MC, Andreassen, OA, Deary, IJ, Glahn, DC, Malhotra, AK & Lencz, T 2017, 'Large-Scale Cognitive GWAS Meta-Analysis Reveals Tissue-Specific Neural Expression and Potential Nootropic Drug Targets', Cell Reports, vol. 21, no. 9, pp. 2597-2613. https://doi.org/10.1016/j.celrep.2017.11.028

@article{c9530cb6824f47deb890b74d2c7e6c18,

title = "Large-Scale Cognitive GWAS Meta-Analysis Reveals Tissue-Specific Neural Expression and Potential Nootropic Drug Targets",

abstract = "Here, we present a large (n = 107,207) genome-wide association study (GWAS) of general cognitive ability (“g”), further enhanced by combining results with a large-scale GWAS of educational attainment. We identified 70 independent genomic loci associated with general cognitive ability. Results showed significant enrichment for genes causing Mendelian disorders with an intellectual disability phenotype. Competitive pathway analysis implicated the biological processes of neurogenesis and synaptic regulation, as well as the gene targets of two pharmacologic agents: cinnarizine, a T-type calcium channel blocker, and LY97241, a potassium channel inhibitor. Transcriptome-wide and epigenome-wide analysis revealed that the implicated loci were enriched for genes expressed across all brain regions (most strongly in the cerebellum). Enrichment was exclusive to genes expressed in neurons but not oligodendrocytes or astrocytes. Finally, we report genetic correlations between cognitive ability and disparate phenotypes including psychiatric disorders, several autoimmune disorders, longevity, and maternal age at first birth. Lam et al. conduct a large-scale genome-wide association study of cognitive ability, identifying 70 associated loci. Results provide biological insights into the molecular basis of individual differences in cognitive ability, as well as their relationship to psychiatric and other health-relevant phenotypes.",

keywords = "GWAS, calcium channel, cerebellum, gene expression, general cognitive ability, neurodevelopment, nootropics, potassium channel, synapse",

author = "Max Lam and Trampush, {Joey W.} and Jin Yu and Emma Knowles and Gail Davies and Liewald, {David C.} and Starr, {John M.} and Srdjan Djurovic and Ingrid Melle and Kjetil Sundet and Andrea Christoforou and Ivar Reinvang and Pamela DeRosse and Lundervold, {Astri J.} and Steen, {Vidar M.} and Thomas Espeseth and Katri R{\"a}ikk{\"o}nen and Elisabeth Widen and Aarno Palotie and Eriksson, {Johan G.} and Ina Giegling and Bettina Konte and Panos Roussos and Stella Giakoumaki and Burdick, {Katherine E.} and Antony Payton and William Ollier and Ornit Chiba-Falek and Attix, {Deborah K.} and Need, {Anna C.} and Cirulli, {Elizabeth T.} and Voineskos, {Aristotle N.} and Stefanis, {Nikos C.} and Dimitrios Avramopoulos and Alex Hatzimanolis and Arking, {Dan E.} and Nikolaos Smyrnis and Bilder, {Robert M.} and Freimer, {Nelson A.} and Cannon, {Tyrone D.} and Edythe London and Poldrack, {Russell A.} and Sabb, {Fred W.} and Eliza Congdon and Conley, {Emily Drabant} and Scult, {Matthew A.} and Dwight Dickinson and Straub, {Richard E.} and Gary Donohoe and Derek Morris and Aiden Corvin and Michael Gill and Hariri, {Ahmad R.} and Weinberger, {Daniel R.} and Neil Pendleton and Panos Bitsios and Dan Rujescu and Jari Lahti and {Le Hellard}, Stephanie and Keller, {Matthew C.} and Andreassen, {Ole A.} and Deary, {Ian J.} and Glahn, {David C.} and Malhotra, {Anil K.} and Todd Lencz",

note = "Funding Information: This work has been supported by grants from the NIH (R01 MH079800 and P50 MH080173 to A.K.M., R01 MH080912 to D.C.G., K23 MH077807 to K.E.B., and K01 MH085812 to M.C.K.). Data collection for the TOP cohort was supported by the Research Council of Norway, South-East Norway Health Authority, and KG Jebsen Foundation. The NCNG study was supported by Research Council of Norway Grants 154313/V50 and 177458/V50. The NCNG GWAS was financed by grants from the Bergen Research Foundation, the University of Bergen, the Research Council of Norway (FUGE, Psykisk Helse), Helse Vest RHF, and the Dr. Einar Martens Fund. The Helsinki Birth Cohort Study has been supported by grants from the Academy of Finland, the Finnish Diabetes Research Society, the Folkh{\"a}lsan Research Foundation, the Novo Nordisk Foundation, Finska L{\"a}kares{\"a}llskapet, Signe and the Ane Gyllenberg Foundation, University of Helsinki, Ministry of Education, the Ahokas Foundation, and the Emil Aaltonen Foundation. For the LBC1936 cohort, phenotype collection was supported by The Disconnected Mind project. Genotyping was funded by the UK Biotechnology and Biological Sciences Research Council (BBSRC grant No. BB/F019394/1). 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, which is funded by the Medical Research Council and the Biotechnology and Biological Sciences Research Council (MR/K026992/1). The CAMH work was supported by the CAMH Foundation and the Canadian Institutes of Health Research. The Duke Cognition Cohort (DCC) acknowledges K. Linney, J.M. McEvoy, P. Hunt, V. Dixon, T. Pennuto, K. Cornett, D. Swilling, L. Phillips, M. Silver, J. Covington, N. Walley, J. Dawson, H. Onabanjo, P. Nicoletti, A. Wagoner, J. Elmore, L. Bevan, J. Hunkin, and R. Wilson for recruitment and testing of subjects. DCC also acknowledges the Ellison Medical Foundation New Scholar award AG-NS-0441-08 for partial funding of this study as well as the National Institute of Mental Health of the NIH under award number K01MH098126. The UCLA Consortium for Neuropsychiatric Phenomics (CNP) study acknowledges the following sources of funding from the NIH: Grants UL1DE019580 and PL1MH083271 (R.M.B.), RL1MH083269 (T.D.C.), RL1DA024853 (E.L.), and PL1NS062410. The ASPIS study was supported by National Institute of Mental Health research grants R01MH085018 and R01MH092515 to D.A. Support for the Duke Neurogenetics Study was provided by the NIH (R01 DA033369 and R01 AG049789 to A.R.H.) and by a National Science Foundation Graduate Research Fellowship to M.A.S. Recruitment, genotyping and analysis of the TCD (Trinity College, Dublin) healthy control samples were supported by Science Foundation Ireland (grants 12/IP/1670, 12/IP/1359 and 08/IN.1/B1916). Funding Information: Cardiovascular Health Study: This research was supported by contracts HHSN268201200036C, HHSN268200800007C, N01-HC-85079, N01-HC-85080, N01-HC-85081, N01-HC-85082, N01-HC-85083, N01-HC-85084, N01-HC-85085, N01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, and N01-HC-85239 and grant numbers U01 HL080295 and U01 HL130014 from the National Heart, Lung, and Blood Institute and R01 AG-023629 from the National Institute on Aging, with additional contribution from the National Institute of Neurological Disorders and Stroke. A full list of principal CHS investigators and institutions can be found at https://chs-nhlbi.org/pi . This manuscript was not prepared in collaboration with CHS investigators and does not necessarily reflect the opinions or views of CHS or the NHLBI. Support for the genotyping through the CARE Study was provided by NHLBI Contract N01-HC-65226. Support for the Cardiovascular Health Study Whole Genome Study was provided by NHLBI grant HL087652. Additional support for infrastructure was provided by HL105756, and additional genotyping among the African-American cohort was supported in part by HL085251. DNA handling and genotyping at Cedars-Sinai Medical Center was supported in part by the National Center for Research Resources grant UL1RR033176, now at the National Center for Advancing Translational Technologies CTSI grant UL1TR000124, in addition to the National Institute of Diabetes and Digestive and Kidney Diseases grant DK063491 to the Southern California Diabetes Endocrinology Research Center. Funding Information: Long Life Family Study: Funding support for the Long Life Family Study was provided by the Division of Geriatrics and Clinical Gerontology, National Institute on Aging. The Long Life Family Study includes GWAS analyses for factors that contribute to long and healthy life. Assistance with phenotype harmonization and genotype cleaning, as well as with general study coordination, was provided by the Division of Geriatrics and Clinical Gerontology, National Institute on Aging. Support for the collection of datasets and samples were provided by Multicenter Cooperative Agreement support by the Division of Geriatrics and Clinical Gerontology, National Institute on Aging (UO1AG023746, UO1023755, UO1023749, UO1023744, and UO1023712). Funding support for the genotyping that was performed at the Johns Hopkins University Center for Inherited Disease Research was provided by the National Institute on Aging, NIH. Funding Information: Framingham Heart Study: The Framingham Heart Study is conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with Boston University (Contract No. N01-HC-25195 and HHSN268201500001I). This manuscript was not prepared in collaboration with investigators of the Framingham Heart Study and does not necessarily reflect the opinions or views of the Framingham Heart Study, Boston University, or NHLBI. Funding for SHARe Affymetrix genotyping was provided by NHLBI Contract N02-HL-64278. SHARe Illumina genotyping was provided under an agreement between Illumina and Boston University. Publisher Copyright: {\textcopyright} 2017 The Author(s)",

year = "2017",

month = nov,

day = "28",

doi = "10.1016/j.celrep.2017.11.028",

language = "English (US)",

volume = "21",

pages = "2597--2613",

journal = "Cell Reports",

issn = "2211-1247",

publisher = "Cell Press",

number = "9",

}

TY - JOUR

T1 - Large-Scale Cognitive GWAS Meta-Analysis Reveals Tissue-Specific Neural Expression and Potential Nootropic Drug Targets

AU - Lam, Max

AU - Trampush, Joey W.

AU - Yu, Jin

AU - Knowles, Emma

AU - Davies, Gail

AU - Liewald, David C.

AU - Starr, John M.

AU - Djurovic, Srdjan

AU - Melle, Ingrid

AU - Sundet, Kjetil

AU - Christoforou, Andrea

AU - Reinvang, Ivar

AU - DeRosse, Pamela

AU - Lundervold, Astri J.

AU - Steen, Vidar M.

AU - Espeseth, Thomas

AU - Räikkönen, Katri

AU - Widen, Elisabeth

AU - Palotie, Aarno

AU - Eriksson, Johan G.

AU - Giegling, Ina

AU - Konte, Bettina

AU - Roussos, Panos

AU - Giakoumaki, Stella

AU - Burdick, Katherine E.

AU - Payton, Antony

AU - Ollier, William

AU - Chiba-Falek, Ornit

AU - Attix, Deborah K.

AU - Need, Anna C.

AU - Cirulli, Elizabeth T.

AU - Voineskos, Aristotle N.

AU - Stefanis, Nikos C.

AU - Avramopoulos, Dimitrios

AU - Hatzimanolis, Alex

AU - Arking, Dan E.

AU - Smyrnis, Nikolaos

AU - Bilder, Robert M.

AU - Freimer, Nelson A.

AU - Cannon, Tyrone D.

AU - London, Edythe

AU - Poldrack, Russell A.

AU - Sabb, Fred W.

AU - Congdon, Eliza

AU - Conley, Emily Drabant

AU - Scult, Matthew A.

AU - Dickinson, Dwight

AU - Straub, Richard E.

AU - Donohoe, Gary

AU - Morris, Derek

AU - Corvin, Aiden

AU - Gill, Michael

AU - Hariri, Ahmad R.

AU - Weinberger, Daniel R.

AU - Pendleton, Neil

AU - Bitsios, Panos

AU - Rujescu, Dan

AU - Lahti, Jari

AU - Le Hellard, Stephanie

AU - Keller, Matthew C.

AU - Andreassen, Ole A.

AU - Deary, Ian J.

AU - Glahn, David C.

AU - Malhotra, Anil K.

AU - Lencz, Todd

N1 - Funding Information: This work has been supported by grants from the NIH (R01 MH079800 and P50 MH080173 to A.K.M., R01 MH080912 to D.C.G., K23 MH077807 to K.E.B., and K01 MH085812 to M.C.K.). Data collection for the TOP cohort was supported by the Research Council of Norway, South-East Norway Health Authority, and KG Jebsen Foundation. The NCNG study was supported by Research Council of Norway Grants 154313/V50 and 177458/V50. The NCNG GWAS was financed by grants from the Bergen Research Foundation, the University of Bergen, the Research Council of Norway (FUGE, Psykisk Helse), Helse Vest RHF, and the Dr. Einar Martens Fund. The Helsinki Birth Cohort Study has been supported by grants from the Academy of Finland, the Finnish Diabetes Research Society, the Folkhälsan Research Foundation, the Novo Nordisk Foundation, Finska Läkaresällskapet, Signe and the Ane Gyllenberg Foundation, University of Helsinki, Ministry of Education, the Ahokas Foundation, and the Emil Aaltonen Foundation. For the LBC1936 cohort, phenotype collection was supported by The Disconnected Mind project. Genotyping was funded by the UK Biotechnology and Biological Sciences Research Council (BBSRC grant No. BB/F019394/1). 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, which is funded by the Medical Research Council and the Biotechnology and Biological Sciences Research Council (MR/K026992/1). The CAMH work was supported by the CAMH Foundation and the Canadian Institutes of Health Research. The Duke Cognition Cohort (DCC) acknowledges K. Linney, J.M. McEvoy, P. Hunt, V. Dixon, T. Pennuto, K. Cornett, D. Swilling, L. Phillips, M. Silver, J. Covington, N. Walley, J. Dawson, H. Onabanjo, P. Nicoletti, A. Wagoner, J. Elmore, L. Bevan, J. Hunkin, and R. Wilson for recruitment and testing of subjects. DCC also acknowledges the Ellison Medical Foundation New Scholar award AG-NS-0441-08 for partial funding of this study as well as the National Institute of Mental Health of the NIH under award number K01MH098126. The UCLA Consortium for Neuropsychiatric Phenomics (CNP) study acknowledges the following sources of funding from the NIH: Grants UL1DE019580 and PL1MH083271 (R.M.B.), RL1MH083269 (T.D.C.), RL1DA024853 (E.L.), and PL1NS062410. The ASPIS study was supported by National Institute of Mental Health research grants R01MH085018 and R01MH092515 to D.A. Support for the Duke Neurogenetics Study was provided by the NIH (R01 DA033369 and R01 AG049789 to A.R.H.) and by a National Science Foundation Graduate Research Fellowship to M.A.S. Recruitment, genotyping and analysis of the TCD (Trinity College, Dublin) healthy control samples were supported by Science Foundation Ireland (grants 12/IP/1670, 12/IP/1359 and 08/IN.1/B1916). Funding Information: Cardiovascular Health Study: This research was supported by contracts HHSN268201200036C, HHSN268200800007C, N01-HC-85079, N01-HC-85080, N01-HC-85081, N01-HC-85082, N01-HC-85083, N01-HC-85084, N01-HC-85085, N01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, and N01-HC-85239 and grant numbers U01 HL080295 and U01 HL130014 from the National Heart, Lung, and Blood Institute and R01 AG-023629 from the National Institute on Aging, with additional contribution from the National Institute of Neurological Disorders and Stroke. A full list of principal CHS investigators and institutions can be found at https://chs-nhlbi.org/pi . This manuscript was not prepared in collaboration with CHS investigators and does not necessarily reflect the opinions or views of CHS or the NHLBI. Support for the genotyping through the CARE Study was provided by NHLBI Contract N01-HC-65226. Support for the Cardiovascular Health Study Whole Genome Study was provided by NHLBI grant HL087652. Additional support for infrastructure was provided by HL105756, and additional genotyping among the African-American cohort was supported in part by HL085251. DNA handling and genotyping at Cedars-Sinai Medical Center was supported in part by the National Center for Research Resources grant UL1RR033176, now at the National Center for Advancing Translational Technologies CTSI grant UL1TR000124, in addition to the National Institute of Diabetes and Digestive and Kidney Diseases grant DK063491 to the Southern California Diabetes Endocrinology Research Center. Funding Information: Long Life Family Study: Funding support for the Long Life Family Study was provided by the Division of Geriatrics and Clinical Gerontology, National Institute on Aging. The Long Life Family Study includes GWAS analyses for factors that contribute to long and healthy life. Assistance with phenotype harmonization and genotype cleaning, as well as with general study coordination, was provided by the Division of Geriatrics and Clinical Gerontology, National Institute on Aging. Support for the collection of datasets and samples were provided by Multicenter Cooperative Agreement support by the Division of Geriatrics and Clinical Gerontology, National Institute on Aging (UO1AG023746, UO1023755, UO1023749, UO1023744, and UO1023712). Funding support for the genotyping that was performed at the Johns Hopkins University Center for Inherited Disease Research was provided by the National Institute on Aging, NIH. Funding Information: Framingham Heart Study: The Framingham Heart Study is conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with Boston University (Contract No. N01-HC-25195 and HHSN268201500001I). This manuscript was not prepared in collaboration with investigators of the Framingham Heart Study and does not necessarily reflect the opinions or views of the Framingham Heart Study, Boston University, or NHLBI. Funding for SHARe Affymetrix genotyping was provided by NHLBI Contract N02-HL-64278. SHARe Illumina genotyping was provided under an agreement between Illumina and Boston University. Publisher Copyright: © 2017 The Author(s)

PY - 2017/11/28

Y1 - 2017/11/28

N2 - Here, we present a large (n = 107,207) genome-wide association study (GWAS) of general cognitive ability (“g”), further enhanced by combining results with a large-scale GWAS of educational attainment. We identified 70 independent genomic loci associated with general cognitive ability. Results showed significant enrichment for genes causing Mendelian disorders with an intellectual disability phenotype. Competitive pathway analysis implicated the biological processes of neurogenesis and synaptic regulation, as well as the gene targets of two pharmacologic agents: cinnarizine, a T-type calcium channel blocker, and LY97241, a potassium channel inhibitor. Transcriptome-wide and epigenome-wide analysis revealed that the implicated loci were enriched for genes expressed across all brain regions (most strongly in the cerebellum). Enrichment was exclusive to genes expressed in neurons but not oligodendrocytes or astrocytes. Finally, we report genetic correlations between cognitive ability and disparate phenotypes including psychiatric disorders, several autoimmune disorders, longevity, and maternal age at first birth. Lam et al. conduct a large-scale genome-wide association study of cognitive ability, identifying 70 associated loci. Results provide biological insights into the molecular basis of individual differences in cognitive ability, as well as their relationship to psychiatric and other health-relevant phenotypes.

AB - Here, we present a large (n = 107,207) genome-wide association study (GWAS) of general cognitive ability (“g”), further enhanced by combining results with a large-scale GWAS of educational attainment. We identified 70 independent genomic loci associated with general cognitive ability. Results showed significant enrichment for genes causing Mendelian disorders with an intellectual disability phenotype. Competitive pathway analysis implicated the biological processes of neurogenesis and synaptic regulation, as well as the gene targets of two pharmacologic agents: cinnarizine, a T-type calcium channel blocker, and LY97241, a potassium channel inhibitor. Transcriptome-wide and epigenome-wide analysis revealed that the implicated loci were enriched for genes expressed across all brain regions (most strongly in the cerebellum). Enrichment was exclusive to genes expressed in neurons but not oligodendrocytes or astrocytes. Finally, we report genetic correlations between cognitive ability and disparate phenotypes including psychiatric disorders, several autoimmune disorders, longevity, and maternal age at first birth. Lam et al. conduct a large-scale genome-wide association study of cognitive ability, identifying 70 associated loci. Results provide biological insights into the molecular basis of individual differences in cognitive ability, as well as their relationship to psychiatric and other health-relevant phenotypes.

KW - GWAS

KW - calcium channel

KW - cerebellum

KW - gene expression

KW - general cognitive ability

KW - neurodevelopment

KW - nootropics

KW - potassium channel

KW - synapse

UR - http://www.scopus.com/inward/record.url?scp=85035770040&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85035770040&partnerID=8YFLogxK

U2 - 10.1016/j.celrep.2017.11.028

DO - 10.1016/j.celrep.2017.11.028

M3 - Article

C2 - 29186694

AN - SCOPUS:85035770040

SN - 2211-1247

VL - 21

SP - 2597

EP - 2613

JO - Cell Reports

JF - Cell Reports

IS - 9

ER -

Large-Scale Cognitive GWAS Meta-Analysis Reveals Tissue-Specific Neural Expression and Potential Nootropic Drug Targets

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this