Genome-wide association meta-analysis in 269,867 individuals identifies new genetic and functional links to intelligence

Intelligence is highly heritable(1) and a major determinant of human health and well-being(2). Recent genome-wide meta-analyses have identified 24 genomic loci linked to variation in intelligence3-7, but much about its genetic underpinnings remains to be discovered. Here, we present a large-scale genetic association study of intelligence (n = 269,867), identifying 205 associated genomic loci (190 new) and 1,016 genes (939 new) via positional mapping, expression quantitative trait locus (eQTL) mapping, chromatin interaction mapping, and gene-based association analysis. We find enrichment of genetic effects in conserved and coding regions and associations with 146 nonsynonymous exonic variants. Associated genes are strongly expressed in the brain, specifically in striatal medium spiny neurons and hippocampal pyramidal neurons. Gene set analyses implicate pathways related to nervous system development and synaptic structure. We confirm previous strong genetic correlations with multiple health-related outcomes, and Mendelian randomization analysis results suggest protective effects of intelligence for Alzheimer's disease and ADHD and bidirectional causation with pleiotropic effects for schizophrenia. These results are a major step forward in understanding the neurobiology of cognitive function as well as genetically related neurological and psychiatric disorders.Peer reviewe

A periodic pattern generator for dental diversity

© 2008 Fraser et al; licensee BioMed Central Ltd. The electronic version of this article is the complete one and can be found online at: http://www.biomedcentral.com/1741-7007/6/32DOI:10.1186/1741-7007-6-22Background: Periodic patterning of iterative structures is a fundamental process during embryonic organization and development. Studies have shown how gene networks are employed to pattern butterfly eyespots, fly bristles and vertebrate epithelial appendages such as teeth, feathers, hair and mammary glands. Despite knowledge of how these features are organized, little is known about how diversity in periodic patterning is generated in nature. We address this problem through the molecular analysis of oral jaw dental diversity in Lake Malawi cichlids, where closely related species exhibit from 1 to 20 rows of teeth, with total teeth counts ranging from around 10 to 700. Results: We investigate the expression of conserved gene networks (involving bmp2, bmp4, eda, edar, fgf8, pax9, pitx2, runx2, shh and wnt7b) known to pattern iterative structures and teeth in other vertebrates. We show that spatiotemporal variation in expression pattern reflects adult morphological diversity among three closely related Malawi cichlid species. Combinatorial epithelial expression of pitx2 and shh appears to govern the competence both of initial tooth sites and future tooth rows. Epithelial wnt7b and mesenchymal eda are expressed in the inter-germ and inter-row regions, and likely regulate the spacing of these shh-positive units. Finally, we used chemical knockdown to demonstrate the fundamental role of hedgehog signalling and initial placode formation in the organization of the periodically patterned cichlid dental programme. Conclusion: Coordinated patterns of gene expression differ among Malawi species and prefigure the future-ordered distribution of functional teeth of specific size and spacing. This variation in gene expression among species occurs early in the developmental programme for dental patterning. These data show how a complex multi-rowed vertebrate dentition is organized and how developmental tinkering of conserved gene networks during iterative pattern formation can impact upon the evolution of trophic novelty