title: Genetic markers of white matter integrity in schizophrenia revealed by parallel ICA.
abstract: It is becoming a consensus that white matter integrity is compromised in schizophrenia (SZ), however the underlying genetics remains elusive. Evidence suggests a polygenic basis of the disorder, which involves various genetic variants with modest individual effect sizes. In this work, we used a multivariate approach, parallel independent component analysis (P-ICA), to explore the genetic underpinnings of white matter abnormalities in SZ. A pre-filtering step was first applied to locate 6527 single nucleotide polymorphisms (SNPs) discriminating patients from controls with a nominal uncorrected p-value of 0.01. These potential susceptibility loci were then investigated for associations with fractional anisotropy (FA) images in a cohort consisting of 73 SZ patients and 87 healthy controls (HC). A significant correlation (r = -0.37, p = 1.25 × 10(-6)) was identified between one genetic factor and one FA component after controlling for scanning site, ethnicity, age, and sex. The identified FA-SNP association remained stable in a 10-fold validation. A 5000-run permutation test yielded a p-value of 2.00 × 10(-4). The FA component reflected decreased white matter integrity in the forceps major for SZ patients. The SNP component was overrepresented in genes whose products are involved in corpus callosum morphology (e.g., CNTNAP2, NPAS3, and NFIB) as well as canonical pathways of synaptic long term depression and protein kinase A signaling. Taken together, our finding delineates a part of genetic architecture underlying SZ-related FA reduction, emphasizing the important role of genetic variants involved in neural development.
authors.affiliation: The Mind Research Network Albuquerque, NM, USA.
authors.forename: Cota Navin
authors.initials: CN
authors.lastname: Gupta
authors.affiliation: The Mind Research Network Albuquerque, NM, USA.
authors.forename: Jiayu
authors.initials: J
authors.lastname: Chen
authors.affiliation: The Mind Research Network Albuquerque, NM, USA ; Department of Electrical and Computer Engineering, University of New Mexico Albuquerque, NM, USA.
authors.forename: Jingyu
authors.initials: J
authors.lastname: Liu
authors.affiliation: The Mind Research Network Albuquerque, NM, USA.
authors.forename: Eswar
authors.initials: E
authors.lastname: Damaraju
authors.affiliation: The Mind Research Network Albuquerque, NM, USA ; Department of Neurosciences, School of Medicine, University of New Mexico Albuquerque, NM, USA.
authors.forename: Carrie
authors.initials: C
authors.lastname: Wright
authors.affiliation: Department of Neurosciences, School of Medicine, University of New Mexico Albuquerque, NM, USA.
authors.forename: Nora I
authors.initials: NI
authors.lastname: Perrone-Bizzozero
authors.affiliation: Departments of Psychiatry, Yale University School of Medicine New Haven, CT, USA ; Olin Neuropsychiatry Research Center, Institute of Living Hartford, CT, USA.
authors.forename: Godfrey
authors.initials: G
authors.lastname: Pearlson
authors.affiliation: Department of Internal Medicine, University of New Mexico Albuquerque, NM, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Luo
authors.affiliation: The Mind Research Network Albuquerque, NM, USA.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Michael
authors.affiliation: The Mind Research Network Albuquerque, NM, USA ; Department of Psychology and Neuroscience Institute, Georgia State University Atlanta, GA, USA.
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Turner
authors.affiliation: The Mind Research Network Albuquerque, NM, USA ; Department of Electrical and Computer Engineering, University of New Mexico Albuquerque, NM, USA ; Department of Neurosciences, School of Medicine, University of New Mexico Albuquerque, NM, USA ; Departments of Psychiatry, Yale University School of Medicine New Haven, CT, USA.
authors.forename: Vince D
authors.initials: VD
authors.lastname: Calhoun
keywords: diffusion tension imaging (DTI); fractional anisotropy (FA); parallel independent component analysis (P-ICA); schizophrenia; single nucleotide polymorphisms (SNPs)