Large-Scale cognitive GWAS Meta-analysis Reveals Tissue-Specific Neural Expression and Potential Nootopic Drug Targets
By
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 Cirulli,
Aristotle N. Voineskos,
Nikos C. Stefanis,
Dimitrios G. Avramopoulos,
Alex Hatzimanolis,
Dan E. Arking,
Nikolaos Smyrnis,
Robert M. Bilder,
Nelson A. Freimer,
Tyrone D. Cannon,
Edythe London,
Russell Poldrack,
Fred W. Sabb,
Eliza Congdon,
Emily Drabant Conley,
Matthew A. Scult,
Dwight Dickinson,
Richard E Straub,
Gary Donohoe,
Derek W 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 Andreassen,
Ian J Deary,
David C Glahn,
Anil K. Malhotra,
Todd Lencz
Posted 16 Aug 2017
bioRxiv DOI: 10.1101/176842
(published DOI: 10.1016/j.celrep.2017.11.028)
Neurocognitive ability is a fundamental readout of brain function, and cognitive deficits are a critical component of neuropsychiatric disorders, yet neurocognition is poorly understood at the molecular level. In the present report, we present the largest genome-wide association studies (GWAS) of cognitive ability to date (N=107,207), and further enhance signal by combining results with a large-scale GWAS of educational attainment. We identified 70 independent genomic loci associated with cognitive ability, 34 of which were novel. A total of 350 genes were implicated, and this list showed significant enrichment for genes associated with Mendelian disorders with an intellectual disability phenotype. Competitive pathway analysis of gene results implicated the biological process of neurogenesis, 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 analysis revealed that the implicated genes were strongly expressed in neurons, but not astrocytes or oligodendrocytes, and were more strongly associated with fetal brain expression than adult brain expression. Several tissue-specific gene expression relationships to cognitive ability were observed (for example, DAG1 levels in the hippocampus). Finally, we report novel genetic correlations between cognitive ability and disparate phenotypes such as maternal age at first birth and number of children, as well as several autoimmune disorders.
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