title: Guided exploration of genomic risk for gray matter abnormalities in schizophrenia using parallel independent component analysis with reference.
abstract: One application of imaging genomics is to explore genetic variants associated with brain structure and function, presenting a new means of mapping genetic influences on mental disorders. While there is growing interest in performing genome-wide searches for determinants, it remains challenging to identify genetic factors of small effect size, especially in limited sample sizes. In an attempt to address this issue, we propose to take advantage of a priori knowledge, specifically to extend parallel independent component analysis (pICA) to incorporate a reference (pICA-R), aiming to better reveal relationships between hidden factors of a particular attribute. The new approach was first evaluated on simulated data for its performance under different configurations of effect size and dimensionality. Then pICA-R was applied to a 300-participant (140 schizophrenia (SZ) patients versus 160 healthy controls) dataset consisting of structural magnetic resonance imaging (sMRI) and single nucleotide polymorphism (SNP) data. Guided by a reference SNP set derived from ANK3, a gene implicated by the Psychiatric Genomic Consortium SZ study, pICA-R identified one pair of SNP and sMRI components with a significant loading correlation of 0.27 (p=1.64×10(-6)). The sMRI component showed a significant group difference in loading parameters between patients and controls (p=1.33×10(-15)), indicating SZ-related reduction in gray matter concentration in prefrontal and temporal regions. The linked SNP component also showed a group difference (p=0.04) and was predominantly contributed to by 1030 SNPs. The effect of these top contributing SNPs was verified using association test results of the Psychiatric Genomic Consortium SZ study, where the 1030 SNPs exhibited significant SZ enrichment compared to the whole genome. In addition, pathway analyses indicated the genetic component majorly relating to neurotransmitter and nervous system signaling pathways. Given the simulation and experiment results, pICA-R may prove a promising multivariate approach for use in imaging genomics to discover reliable genetic risk factors under a scenario of relatively high dimensionality and small effect size.
authors.affiliation: Department of Electrical and Computer Engineering, University of New Mexico, Albuquerque, NM 87131, USA; The Mind Research Network, Albuquerque, NM 87106, USA.
authors.forename: Jiayu
authors.initials: J
authors.lastname: Chen
authors.forename: Vince D
authors.initials: VD
authors.lastname: Calhoun
authors.forename: Godfrey D
authors.initials: GD
authors.lastname: Pearlson
authors.forename: Nora
authors.initials: N
authors.lastname: Perrone-Bizzozero
authors.forename: Jing
authors.initials: J
authors.lastname: Sui
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Turner
authors.forename: Juan R
authors.initials: JR
authors.lastname: Bustillo
authors.forename: Stefan
authors.initials: S
authors.lastname: Ehrlich
authors.forename: Scott R
authors.initials: SR
authors.lastname: Sponheim
authors.forename: José M
authors.initials: JM
authors.lastname: Cañive
authors.forename: Beng-Choon
authors.initials: BC
authors.lastname: Ho
authors.forename: Jingyu
authors.initials: J
authors.lastname: Liu
mesh_terms: D000293:Adolescent; D000328:Adult; D001921:Brain / Q000473:pathology* / Q000503:physiopathology*; D002874:Chromosome Mapping / Q000379:methods*; D003627:Data Interpretation, Statistical; D005240:Feasibility Studies; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005820:Genetic Testing / Q000379:methods; D055106:Genome-Wide Association Study / Q000379:methods; D023281:Genomics / Q000379:methods; D066128:Gray Matter / Q000473:pathology* / Q000503:physiopathology*; D006801:Humans; D008297:Male; D015999:Multivariate Analysis; D025341:Principal Component Analysis; D012016:Reference Values; D015203:Reproducibility of Results; D012307:Risk Factors; D012559:Schizophrenia / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology*; D012680:Sensitivity and Specificity; D055815:Young Adult
keywords: Multivariate; Parallel ICA with reference; SNP; Schizophrenia; Semi-blind; sMRI