title: Early developmental gene enhancers affect subcortical volumes in the adult human brain.
abstract: Genome-wide association screens aim to identify common genetic variants contributing to the phenotypic variability of complex traits, such as human height or brain morphology. The identified genetic variants are mostly within noncoding genomic regions and the biology of the genotype-phenotype association typically remains unclear. In this article, we propose a complementary targeted strategy to reveal the genetic underpinnings of variability in subcortical brain volumes, by specifically selecting genomic loci that are experimentally validated forebrain enhancers, active in early embryonic development. We hypothesized that genetic variation within these enhancers may affect the development and ultimately the structure of subcortical brain regions in adults. We tested whether variants in forebrain enhancer regions showed an overall enrichment of association with volumetric variation in subcortical structures of >13,000 healthy adults. We observed significant enrichment of genomic loci that affect the volume of the hippocampus within forebrain enhancers (empirical P = 0.0015), a finding which robustly passed the adjusted threshold for testing of multiple brain phenotypes (cutoff of P < 0.0083 at an alpha of 0.05). In analyses of individual single nucleotide polymorphisms (SNPs), we identified an association upstream of the ID2 gene with rs7588305 and variation in hippocampal volume. This SNP-based association survived multiple-testing correction for the number of SNPs analyzed but not for the number of subcortical structures. Targeting known regulatory regions offers a way to understand the underlying biology that connects genotypes to phenotypes, particularly in the context of neuroimaging genetics. This biology-driven approach generates testable hypotheses regarding the functional biology of identified associations. Hum Brain Mapp 37:1788-1800, 2016. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Max Planck Institute for Psycholinguistics, Nijmegen, the Netherlands.
authors.forename: Martin
authors.initials: M
authors.lastname: Becker
authors.affiliation: Max Planck Institute for Psycholinguistics, Nijmegen, the Netherlands.
authors.forename: Tulio
authors.initials: T
authors.lastname: Guadalupe
authors.affiliation: Donders Institute for Brain, Cognition and Behaviour, Nijmegen, the Netherlands.|Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands.|Department of Psychiatry, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Barbara
authors.initials: B
authors.lastname: Franke
authors.affiliation: Imaging Genetics Center, Keck School of Medicine, University of Southern California, Marina Del Rey, California.
authors.forename: Derrek P
authors.initials: DP
authors.lastname: Hibar
authors.affiliation: Genetic Epidemiology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
authors.forename: Miguel E
authors.initials: ME
authors.lastname: Renteria
authors.affiliation: Imaging Genetics Center, Keck School of Medicine, University of Southern California, Marina Del Rey, California.|Department of Neurology, Neurogenetics Program, UCLA School of Medicine, Los Angeles, California.
authors.forename: Jason L
authors.initials: JL
authors.lastname: Stein
authors.affiliation: Imaging Genetics Center, Keck School of Medicine, University of Southern California, Marina Del Rey, California.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Thompson
authors.affiliation: Max Planck Institute for Psycholinguistics, Nijmegen, the Netherlands.|Donders Institute for Brain, Cognition and Behaviour, Nijmegen, the Netherlands.
authors.forename: Clyde
authors.initials: C
authors.lastname: Francks
authors.affiliation: Max Planck Institute for Psycholinguistics, Nijmegen, the Netherlands.|Donders Institute for Brain, Cognition and Behaviour, Nijmegen, the Netherlands.
authors.forename: Sonja C
authors.initials: SC
authors.lastname: Vernes
authors.affiliation: Max Planck Institute for Psycholinguistics, Nijmegen, the Netherlands.|Donders Institute for Brain, Cognition and Behaviour, Nijmegen, the Netherlands.
authors.forename: Simon E
authors.initials: SE
authors.lastname: Fisher
mesh_terms: D060887:B7 Antigens / Q000235:genetics*; D001921:Brain / Q000033:anatomy & histology* / Q000000981:diagnostic imaging / Q000254:growth & development*; D004742:Enhancer Elements, Genetic / Q000235:genetics*; D055106:Genome-Wide Association Study; D006801:Humans; D059906:Neuroimaging; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*
chemical_list: D060887:B7 Antigens; C000588758:VSIR protein, human
keywords: GWAS; functional genomics; gene enhancer; hippocampus; neurodevelopment; subcortical volume