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

被引：80

作者：

Lam, Max ^{[1
]}

Trampush, Joey W. ^{[2
]}

Yu, Jin ^{[3
]}

Knowles, Emma ^{[4
]}

Davies, Gail ^{[5
,6
]}

Liewald, David C. ^{[6
]}

Starr, John M. ^{[5
,7
]}

Djurovic, Srdjan ^{[8
,9
]}

Melle, Ingrid ^{[9
,10
]}

Sundet, Kjetil ^{[10
,11
]}

Christoforou, Andrea ^{[12
]}

Reinvang, Ivar ^{[11
]}

DeRosse, Pamela ^{[3
]}

Lundervold, Astri J. ^{[13
]}

Steen, Vidar M. ^{[9
,12
]}

Espeseth, Thomas ^{[10
,11
]}

Raikkonen, Katri ^{[14
]}

Widen, Elisabeth ^{[15
]}

Palotie, Aarno ^{[15
,16
,17
,18
]}

Eriksson, Johan G. ^{[19
,20
,21
,22
]}

Giegling, Ina ^{[23
]}

Konte, Bettina ^{[23
]}

Roussos, Panos ^{[24
,25
,26
,27
]}

Giakoumaki, Stella ^{[28
]}

Burdick, Katherine E. ^{[24
,27
,29
]}

Payton, Antony ^{[30
]}

Ollier, William ^{[30
,31
]}

Chiba-Falek, Ornit ^{[32
,33
]}

Attix, Deborah K. ^{[32
,33
,34
]}

Need, Anna C. ^{[35
]}

Cirulli, Elizabeth T. ^{[36
]}

Voineskos, Aristotle N. ^{[37
]}

Stefanis, Nikos C. ^{[38
,39
]}

Avramopoulos, Dimitrios ^{[41
,42
]}

Hatzimanolis, Alex ^{[38
,39
,40
]}

Arking, Dan E. ^{[42
]}

Smyrnis, Nikolaos ^{[38
,39
]}

Bilder, Robert M. ^{[43
]}

Freimer, Nelson A. ^{[43
]}

Cannon, Tyrone D. ^{[44
,45
]}

London, Edythe ^{[43
]}

Poldrack, Russell A.

Sabb, Fred W. ^{[46
]}

Congdon, Eliza ^{[43
]}

Conley, Emily Drabant ^{[47
]}

Scult, Matthew A. ^{[48
]}

Dickinson, Dwight ^{[49
]}

Straub, Richard E. ^{[50
]}

Donohoe, Gary ^{[51
]}

Morris, Derek ^{[51
]}

机构：

[1] Inst Mental Hlth, Singapore, Singapore

[2] BrainWorkup LLC, Los Angeles, CA USA

[3] Zucker Hillside Hosp, Div Psychiat Res, Glen Oaks, NY 11004 USA

[4] Yale Univ, Sch Med, Dept Psychiat, New Haven, CT USA

[5] Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh, Midlothian, Scotland

[6] Univ Edinburgh, Dept Psychol, Edinburgh, Midlothian, Scotland

[7] Univ Edinburgh, Alzheimer Scotland Dementia Res Ctr, Edinburgh, Midlothian, Scotland

[8] Univ Bergen, Oslo Univ Hosp, Dept Med Genet, Oslo, Norway

[9] Univ Bergen, KG Jebsen Ctr Psychosis Res, NORMENT, Bergen, Norway

[10] Oslo Univ Hosp, Div Mental Hlth & Addict, Oslo, Norway

[11] Univ Oslo, Dept Psychol, Oslo, Norway

[12] Haukeland Hosp, Ctr Med Genet & Mol Med, Dr Einar Martens Res Grp Biol Psychiat, Bergen, Norway

[13] Univ Bergen, Dept Biol & Med Psychol, Bergen, Norway

[14] Univ Helsinki, Inst Behav Sci, Helsinki, Finland

[15] Univ Helsinki, Inst Mol Med Finland FIMM, Helsinki, Finland

[16] Wellcome Trust Sanger Inst, Wellcome Trust Genome Campus, Cambridge, England

[17] Univ Helsinki, Dept Med Genet, Helsinki, Finland

[18] Univ Cent Hosp, Helsinki, Finland

[19] Univ Helsinki, Dept Gen Practice, Helsinki, Finland

[20] Helsinki Univ Hosp, Helsinki, Finland

[21] Natl Inst Hlth & Welf, Helsinki, Finland

[22] Folkhalsan Res Ctr, Helsinki, Finland

[23] Martin Luther Univ Halle Wittenberg, Dept Psychiat, Halle, Germany

[24] Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA

[25] Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA

[26] Icahn Sch Med Mt Sinai, Inst Multiscale Biol, New York, NY 10029 USA

[27] James J Peters VA Med Ctr, Mental Illness Res Educ & Clin Ctr VISN 2, Bronx, NY USA

[28] Univ Crete, Dept Psychol, Iraklion, Greece

[29] Harvard Med Sch, Brigham & Womens Hosp, Dept Psychiat, Boston, MA USA

[30] Univ Manchester, Ctr Epidemiol, Div Populat Hlth Hlth Serv Res & Primary Care, Manchester, Lancs, England

[31] Univ Manchester, Inst Populat Hlth, Ctr Integrated Genom Med Res, Manchester, Lancs, England

[32] Duke Univ, Med Ctr, Bryan Alzheimers Dis Res Ctr, Dept Neurol, Durham, NC USA

[33] Duke Univ, Med Ctr, Ctr Genom & Computat Biol, Durham, NC USA

[34] Duke Univ, Med Ctr, Dept Psychiat & Behav Sci, Div Med Psychol, Durham, NC USA

[35] Imperial Coll, Dept Med, Div Brain Sci, London, England

[36] Human Longev Inc, Durham, NC USA

[37] Univ Toronto, Ctr Addict & Mental Hlth, Campbell Family Mental Hlth Inst, Toronto, ON, Canada

[38] Natl & Kapodistrian Univ Athens, Eginit Hosp, Med Sch, Dept Psychiat, Athens, Greece

[39] Univ Mental Hlth Res Inst, Athens, Greece

[40] Theodor Theohari Cozzika Fdn, Neurobiol Res Inst, Athens, Greece

[41] Johns Hopkins Univ, Sch Med, Dept Psychiat, Baltimore, MD 21205 USA

[42] Johns Hopkins Univ, McKusick Nathans Inst Genet Med, Sch Med, Baltimore, MD USA

[43] UCLA Semel Inst Neurosci & Human Behav Ange, Los Angeles, CA USA

[44] Yale Univ, Dept Psychol, New Haven, CT USA

[45] Stanford Univ, Dept Psychol, Palo Alto, CA 94304 USA

[46] Univ Oregon, Robert & Beverly Lewis Ctr Neuroimaging, Eugene, OR 97403 USA

[47] 23andMe Inc, Mountain View, CA USA

[48] Duke Univ, Dept Psychol & Neurosci, Lab NeuroGenet, Durham, NC USA

[49] NIMH, Clin & Translat Neurosc Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA

[50] Johns Hopkins Univ, Lieber Inst Brain Dev, Med Campus, Baltimore, MD USA

来源：

CELL REPORTS | 2017年 / 21卷 / 09期

基金：

英国生物技术与生命科学研究理事会;

关键词：

GENOME-WIDE ASSOCIATION; SINGLE-NUCLEOTIDE POLYMORPHISMS; LD SCORE REGRESSION; EDUCATIONAL-ATTAINMENT; GENETIC-EVIDENCE; LOCI; VARIANTS; SCHIZOPHRENIA; RISK; IDENTIFICATION;

D O I：

10.1016/j.celrep.2017.11.028

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页码：2597 / 2613

页数：17

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