Large-scale cognitive GWAS Meta-Analysis Reveals Tissue-Specific Neural Expression and Potential Nootropic Drug Targets

Abstract

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.

Comment on “Large-Scale cognitive GWAS Meta-analysis Reveals Tissue-Specific Neural Expression and Potential Nootropic Drug Targets” by Lam et al.

“…The downstream consequences of combining two very differently powered traits can be seen in Supplementary Table 14 of Lam et al's paper (2017), and are presented in Table 1 (Sniekers et al, 2017;Trampush et al, 2017) and MTAG (Okbay et al, 2016;Sniekers et al, 2017;Trampush et al, 2017)). Also provided by Lam et al (2017) are the genetic correlations between years of education (labeled in Lam et al as Education (Okbay et al, 2016)) with the same four measures of education. This makes it possible to determine whether the polygenic signal in the MTAG data set of Lam et al more closely resembles cognitive ability or education.…”

“…The purpose of this commentary is to examine whether the use of MTAG, in this case , has resulted in genetic information about a phenotype that is more similar to education than to cognitive ability. Lam et al (2017) correctly state that MTAG (Turley et al, 2018) can generate trait-specific associations from a metaanalysis of different, genetically correlated traits. However, this is not the case when the statistical power for the different GWASs of the meta-analyzed traits are highly dissimilar, as seen below.…”

“…Such sample sizes are typically attained by metaanalyzing multiple Genome-wide Association Studies (GWAS) on intelligence (Davies et al, 2015. However, a recently published method, Multi-Trait Analysis of GWAS (MTAG) (Turley et al, 2018), enables a metaanalysis to be conducted on genetically correlated traits; crucially, and unlike similar methods that test against a null hypothesis that each SNP is associated with none of the traits (Bolormaa et al, 2014;Zhu et al, 2015), MTAG Supplementary Table 14 of Lam et al (2017). As can be seen, following the application of MTAG, the genetic correlation between Cognitive ability and Education approaches unity (middle row of Table 1).…”

International Society of Psychiatric Genetics Ethics Committee: Issues facing us

“…Finally, very recent studies encompassing 100,000 to more than 1 million individuals have identified more than 1,000 genome‐wide significant loci associated with cognitive ability and/or educational attainment (Davies et al, ; Lam et al, ; Lee et al, ; Savage et al, ). The potential use of cognitive polygenic testing in educational settings (Selzam et al, ) and prenatal screening (Seidel, ) requires the psychiatric genetics community to take the utmost care in the conduct and communication of such research (Callier & Bonham, ; Sabatello, ).…”

Epigenetic mechanisms in cognitive development

“…The main goal of this paper is to analyze the factors determining the development of cognitive skills and to assess the relative contribution of inheritance in a person's perception and comprehension. An intensive research, conducted during the last three decades has revealed numerous gene loci, controlling cognitive development [1]. At the same time, the application of the typical genetic methods, including the use of modeled mutant lines for studying of the functioning of the normal cognitive development genes, does not provide straightforward information due to the complicated nature of the behavioral, on the whole, and cognitive, in particular, phenotypes [2].…”