Author:
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,Hellard Stephanie Le,Keller Matthew C.,Andreassen Ole A.,Deary Ian J.,Glahn David C.,Malhotra Anil K.,Lencz Todd
Abstract
AbstractNeurocognitive 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.
Publisher
Cold Spring Harbor Laboratory