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Front Hum Neurosci. 2015 Mar 3;9:100. doi: 10.3389/fnhum.2015.00100. eCollection 2015.

Genetic markers of white matter integrity in schizophrenia revealed by parallel ICA.

Author information

1
The Mind Research Network Albuquerque, NM, USA.
2
The Mind Research Network Albuquerque, NM, USA ; Department of Electrical and Computer Engineering, University of New Mexico Albuquerque, NM, USA.
3
The Mind Research Network Albuquerque, NM, USA ; Department of Neurosciences, School of Medicine, University of New Mexico Albuquerque, NM, USA.
4
Department of Neurosciences, School of Medicine, University of New Mexico Albuquerque, NM, USA.
5
Departments of Psychiatry, Yale University School of Medicine New Haven, CT, USA ; Olin Neuropsychiatry Research Center, Institute of Living Hartford, CT, USA.
6
Department of Internal Medicine, University of New Mexico Albuquerque, NM, USA.
7
The Mind Research Network Albuquerque, NM, USA ; Department of Psychology and Neuroscience Institute, Georgia State University Atlanta, GA, USA.
8
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.

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.

KEYWORDS:

diffusion tension imaging (DTI); fractional anisotropy (FA); parallel independent component analysis (P-ICA); schizophrenia; single nucleotide polymorphisms (SNPs)

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