Large-scale cognitive gwas meta-analysis reveals tissue-specific neural expression and potential nootropic drug targets
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2017-11-01Author
Lam, Max
Trampush, Joey W.
Yu, Jin
Knowles, Emma
Davies, Gail
Liewald, David C.
Starr, John M.
Djurovic, Srdjan
Melle, Ingrid
Sundet, Kjetil
Christoforou, Andrea
Reinvang, Ivar
DeRosse, Pamela
Lundervold, Astri J.
Steen, Vidar M.
Espeseth, Thomas
Räikkönen, Katri
Widen, Elisabeth
Palotie, Aarno
Eriksson, Johan G.
Giegling, Ina
Konte, Bettina
Roussos, Panos
Giakoumaki, Stella
Burdick, Katherine E.
Payton, Antony
Ollier, William
Chiba-Falek, Ornit
Attix, Deborah K.
Need, Anna C.
Cirulli, Elizabeth T.
Voineskos, Aristotle N.
Stefanis, Nikos C.
Avramopoulos, Dimitrios
Hatzimanolis, Alex
Arking, Dan E.
Smyrnis, Nikolaos
Bilder, Robert M.
Freimer, Nelson A.
Cannon, Tyrone D.
London, Edythe
Poldrack, Russell A.
Sabb, Fred W.
Congdon, Eliza
Conley, Emily Drabant
Scult, Matthew A.
Dickinson, Dwight
Straub, Richard E.
Donohoe, Gary
Morris, Derek
Corvin, Aiden
Gill, Michael
Hariri, Ahmad R.
Weinberger, Daniel R.
Pendleton, Neil
Bitsios, Panos
Rujescu, Dan
Lahti, Jari
Le Hellard, Stephanie
Keller, Matthew C.
Andreassen, Ole A.
Deary, Ian J.
Glahn, David C.
Malhotra, Anil K.
Lencz, Todd
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Lam, Max; Trampush, Joey W. Yu, Jin; Knowles, Emma; Davies, Gail; Liewald, David C.; Starr, John M.; Djurovic, Srdjan; Melle, Ingrid; Sundet, Kjetil; Christoforou, Andrea; Reinvang, Ivar; DeRosse, Pamela; Lundervold, Astri J.; Steen, Vidar M.; Espeseth, Thomas; Räikkönen, Katri; Widen, Elisabeth; Palotie, Aarno; Eriksson, Johan G.; Giegling, Ina; Konte, Bettina; Roussos, Panos; Giakoumaki, Stella; Burdick, Katherine E.; Payton, Antony; Ollier, William; Chiba-Falek, Ornit; Attix, Deborah K.; Need, Anna C.; Cirulli, Elizabeth T.; Voineskos, Aristotle N.; Stefanis, Nikos C.; Avramopoulos, Dimitrios; Hatzimanolis, Alex; Arking, Dan E.; Smyrnis, Nikolaos; Bilder, Robert M.; Freimer, Nelson A.; Cannon, Tyrone D.; London, Edythe; Poldrack, Russell A.; Sabb, Fred W.; Congdon, Eliza; Conley, Emily Drabant; Scult, Matthew A.; Dickinson, Dwight; Straub, Richard E.; Donohoe, Gary; Morris, Derek; Corvin, Aiden; Gill, Michael; Hariri, Ahmad R.; Weinberger, Daniel R.; Pendleton, Neil; Bitsios, Panos; Rujescu, Dan; Lahti, Jari; Le Hellard, Stephanie; Keller, Matthew C.; Andreassen, Ole A.; Deary, Ian J.; Glahn, David C.; Malhotra, Anil K.; Lencz, Todd (2017). Large-scale cognitive gwas meta-analysis reveals tissue-specific neural expression and potential nootropic drug targets. Cell Reports 21 (9), 2597-2613
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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.