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

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

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.

Original language	English
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
Publication status	Published - 28 Nov 2017

Keywords / Materials (for Non-textual outputs)

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

Access to Document

10.1016/j.celrep.2017.11.028

LamEtal2017CRLargeScaleCognitiveGWASFinal published version, 4.28 MBLicence: CC BY-NC-ND

The Disconnected Mind Phase 3
Cox, S. & Deary, I.
1/04/16 → 31/03/23
Project: Research
RA2661 Centre for Cognitive Ageing and Cognitive Epidemiology Phase 2. Main Budget.
Deary, I., Gale, C., Holmes, M., Logie, P., Maclullich, A., Porteous, D., Seckl, J., Starr, J., Wardlaw, J. & Okely, J.
1/09/13 → 31/08/19
Project: Research
Brain White mater imaging and cognitive ageing in the Lothian Birth Cohort of 1936:II
Deary, I., Bastin, M., Penke, L., Starr, J. & Wardlaw, J.
MRC
8/06/11 → 7/03/15
Project: Research

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

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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.",

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

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",

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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

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

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.

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.

KW - GWAS

KW - general cognitive ability

KW - nootropics

KW - gene expression

KW - neurodevelopment

KW - synapse

KW - calcium channel

KW - potassium channel

KW - cerebellum

U2 - 10.1016/j.celrep.2017.11.028

DO - 10.1016/j.celrep.2017.11.028

M3 - Article

C2 - 29186694

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 / Materials (for Non-textual outputs)

Access to Document

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Projects

The Disconnected Mind Phase 3

RA2661 Centre for Cognitive Ageing and Cognitive Epidemiology Phase 2. Main Budget.

Brain White mater imaging and cognitive ageing in the Lothian Birth Cohort of 1936:II

Cite this