TY - JOUR
T1 - A Pilot Study on Collective Effects of 22q13.31 Deletions on Gray Matter Concentration in Schizophrenia
AU - Liu, Jingyu
AU - Ulloa, Alvaro
AU - Perrone-Bizzozero, Nora
AU - Yeo, Ronald
AU - Chen, Jiayu
AU - Calhoun, Vince D.
PY - 2012/12/28
Y1 - 2012/12/28
N2 - The association of copy number variation (CNV) with schizophrenia has been reported with evidence of increased frequency of both rare and large CNVs. Yet, little is known about the impact of CNVs in brain structure. In this pilot study, we explored collective effects of all CNVs in each cytogenetic band on the risk of schizophrenia and gray matter variation measured in structural magnetic resonance imaging. With 324 participants' CNV profiles (151 schizophrenia patients and 173 healthy controls), we first extracted specific CNV features that differ between patients and controls using a two sample t-test, and then tested their associations with gray matter concentration using a linear regression model in a subset of 301 participants. Our data first provided evidence of population structure in CNV features where elevated rare CNV burden in schizophrenia patients was confounded by the levels associated with African American subjects. We considered this ethnic group difference in the following cytoband analyses. Deletions in one cytoband 22q13.31 were observed significantly (p<0.05) more in patients than controls from all samples after controlling ethnicity, and the deletion load was also significantly (p = 1.44×10-4) associated with reduced gray matter concentration of a brain network mainly comprised of the cingulate gyrus and insula. Since 80% deletion carriers were patients, patients with deletions also showed reduced gray matter concentration compared with patients without deletions (p = 3.36×10-4). Our findings indicate that regional CNVs at 22q13.31, no matter the size, may influence the risk of schizophrenia with a remarkably increased mutation rate and with reduced gray matter concentration in the peri-limbic cortex. This proof-of-concept study suggests that the CNVs occurring at some 'hotspots' may in fact cause biological downstream effects and larger studies are important for confirming our initial results.
AB - The association of copy number variation (CNV) with schizophrenia has been reported with evidence of increased frequency of both rare and large CNVs. Yet, little is known about the impact of CNVs in brain structure. In this pilot study, we explored collective effects of all CNVs in each cytogenetic band on the risk of schizophrenia and gray matter variation measured in structural magnetic resonance imaging. With 324 participants' CNV profiles (151 schizophrenia patients and 173 healthy controls), we first extracted specific CNV features that differ between patients and controls using a two sample t-test, and then tested their associations with gray matter concentration using a linear regression model in a subset of 301 participants. Our data first provided evidence of population structure in CNV features where elevated rare CNV burden in schizophrenia patients was confounded by the levels associated with African American subjects. We considered this ethnic group difference in the following cytoband analyses. Deletions in one cytoband 22q13.31 were observed significantly (p<0.05) more in patients than controls from all samples after controlling ethnicity, and the deletion load was also significantly (p = 1.44×10-4) associated with reduced gray matter concentration of a brain network mainly comprised of the cingulate gyrus and insula. Since 80% deletion carriers were patients, patients with deletions also showed reduced gray matter concentration compared with patients without deletions (p = 3.36×10-4). Our findings indicate that regional CNVs at 22q13.31, no matter the size, may influence the risk of schizophrenia with a remarkably increased mutation rate and with reduced gray matter concentration in the peri-limbic cortex. This proof-of-concept study suggests that the CNVs occurring at some 'hotspots' may in fact cause biological downstream effects and larger studies are important for confirming our initial results.
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U2 - 10.1371/journal.pone.0052865
DO - 10.1371/journal.pone.0052865
M3 - Article
C2 - 23285208
AN - SCOPUS:84871690396
VL - 7
JO - PLoS One
JF - PLoS One
SN - 1932-6203
IS - 12
M1 - e52865
ER -