TY - JOUR
T1 - Genetic markers of white matter integrity in schizophrenia revealed by parallel ICA
AU - Gupta, Cota Navin
AU - Chen, Jiayu
AU - Liu, Jingyu
AU - Damaraju, Eswar
AU - Wright, Carrie
AU - Perrone-Bizzozero, Nora I.
AU - Pearlson, Godfrey
AU - Luo, Li
AU - Michael, Andrew M.
AU - Turner, Jessica A.
AU - Calhoun, Vince D.
N1 - Publisher Copyright:
© 2015 Gupta, Chen, Liu, Damaraju, Wright, Perrone-Bizzozero, Pearlson, Luo, Michael, Turner and Calhoun.
PY - 2015/3/3
Y1 - 2015/3/3
N2 - 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.
AB - 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.
KW - Diffusion tension imaging (DTI)
KW - Fractional anisotropy (FA)
KW - Parallel independent component analysis (P-ICA)
KW - Schizophrenia
KW - Single nucleotide polymorphisms (SNPs)
UR - http://www.scopus.com/inward/record.url?scp=84933679502&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84933679502&partnerID=8YFLogxK
U2 - 10.3389/fnhum.2015.00100
DO - 10.3389/fnhum.2015.00100
M3 - Article
C2 - 25784871
AN - SCOPUS:84933679502
SN - 1662-5161
VL - 9
JO - Frontiers in Human Neuroscience
JF - Frontiers in Human Neuroscience
IS - MAR
M1 - 100
ER -