title: G-protein genomic association with normal variation in gray matter density.
abstract: While detecting genetic variations underlying brain structures helps reveal mechanisms of neural disorders, high data dimensionality poses a major challenge for imaging genomic association studies. In this work, we present the application of a recently proposed approach, parallel independent component analysis with reference (pICA-R), to investigate genomic factors potentially regulating gray matter variation in a healthy population. This approach simultaneously assesses many variables for an aggregate effect and helps to elicit particular features in the data. We applied pICA-R to analyze gray matter density (GMD) images (274,131 voxels) in conjunction with single nucleotide polymorphism (SNP) data (666,019 markers) collected from 1,256 healthy individuals of the Brain Imaging Genetics (BIG) study. Guided by a genetic reference derived from the gene GNA14, pICA-R identified a significant SNP-GMD association (r=-0.16, P=2.34×10(-8)), implying that subjects with specific genotypes have lower localized GMD. The identified components were then projected to an independent dataset from the Mind Clinical Imaging Consortium (MCIC) including 89 healthy individuals, and the obtained loadings again yielded a significant SNP-GMD association (r=-0.25, P=0.02). The imaging component reflected GMD variations in frontal, precuneus, and cingulate regions. The SNP component was enriched in genes with neuronal functions, including synaptic plasticity, axon guidance, molecular signal transduction via PKA and CREB, highlighting the GRM1, PRKCH, GNA12, and CAMK2B genes. Collectively, our findings suggest that GNA12 and GNA14 play a key role in the genetic architecture underlying normal GMD variation in frontal and parietal regions.
authors.affiliation: The Mind Research Network, Albuquerque, New Mexico.
authors.forename: Jiayu
authors.initials: J
authors.lastname: Chen
authors.affiliation: The Mind Research Network, Albuquerque, New Mexico.|Department of Electrical and Computer Engineering, University of New Mexico, Albuquerque, New Mexico.
authors.forename: Vince D
authors.initials: VD
authors.lastname: Calhoun
authors.affiliation: Department of Human Genetics, Radboud University Medical Centre, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, The Netherlands.|Department of Cognitive Neuroscience, Radboud University Medical Centre, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, The Netherlands.|Department of Psychiatry, Radboud University Nijmegen Medical Centre, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, The Netherlands.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Arias-Vasquez
authors.affiliation: Centre for Cognitive Neuroimaging, Radboud University Nijmegen, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, The Netherlands.
authors.forename: Marcel P
authors.initials: MP
authors.lastname: Zwiers
authors.affiliation: Department of Human Genetics, Radboud University Medical Centre, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, The Netherlands.
authors.forename: Kimm
authors.initials: K
authors.lastname: van Hulzen
authors.affiliation: Department of Cognitive Neuroscience, Radboud University Medical Centre, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, The Netherlands.
authors.forename: Guillén
authors.initials: G
authors.lastname: Fernández
authors.affiliation: Language and Genetics Department, Max Planck Institute for Psycholinguistics, Nijmegen, The Netherlands.|Centre for Neuroscience, Radboud University Nijmegen, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, The Netherlands.
authors.forename: Simon E
authors.initials: SE
authors.lastname: Fisher
authors.affiliation: Department of Human Genetics, Radboud University Medical Centre, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, The Netherlands.|Department of Psychiatry, Radboud University Nijmegen Medical Centre, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, The Netherlands.
authors.forename: Barbara
authors.initials: B
authors.lastname: Franke
authors.affiliation: The Mind Research Network, Albuquerque, New Mexico.|Psychology Department, Georgia State University, Atlanta, Georgia.|Neuroscience Institute, Georgia State University, Atlanta, Georgia.
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Turner
authors.affiliation: The Mind Research Network, Albuquerque, New Mexico.|Department of Electrical and Computer Engineering, University of New Mexico, Albuquerque, New Mexico.
authors.forename: Jingyu
authors.initials: J
authors.lastname: Liu
mesh_terms: D000328:Adult; D002540:Cerebral Cortex / Q000033:anatomy & histology*; D005260:Female; D019204:GTP-Binding Proteins / Q000235:genetics*; D056726:Genetic Association Studies / Q000379:methods*; D066128:Gray Matter / Q000033:anatomy & histology*; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide; D055815:Young Adult
chemical_list: D019204:GTP-Binding Proteins
keywords: G-protein; SNP; multivariate; sMRI; semi-blind