The schizophrenia brain exhibits low-level aneuploidy involving chromosome 1.
OBJECTIVE
Genetic instability manifested as loss or gain of whole chromosomes (aneuploidy) is a newly described feature of the human brain. Aneuploidy in the brain was hypothesized to be involved in schizophrenia pathogenesis. To gain further insights into the relationship between aneuploidy in the brain and schizophrenia pathogenesis, a molecular-cytogenetic study of chromosome 1 aneuploidy was performed.


METHODS
Interphase multiprobe fluorescence in situ hybridization (FISH) with quantitative FISH (QFISH) and interphase chromosome-specific multicolor banding (ICS-MCB) were used to define aneuploidy rate in 12 unaffected and 12 schizophrenia brains.


RESULTS
In the unaffected brain (n=12; 22,794 cells analyzed), average frequencies of stochastic chromosome 1 loss and gain were 0.3% (95%CI 0.2-0.4%) and 0.3% (95%CI 0.2-0.4%), respectively. The threshold level for stochastic chromosome gain and loss (the mean+3SD) in the normal brain was 0.7%. Average rate of aneuploidy in the schizophrenia brain (n=12; 28,482 cells analyzed) was 0.9% (95%CI 0.3-1.5%) for chromosome 1 loss and 0.9% (95%CI 0.2-1.7%) for chromosome 1 gain. Significantly increased level of mosaic aneuploidy involving chromosome 1 was revealed in two schizophrenia brains (3.6% and 4.7% of cells with chromosome 1 loss and gain, respectively). Stochastic aneuploidy rate for chromosome 1 in the schizophrenia brain without two outliers (n=10) reached 0.6% (95%CI 0.3-0.9%) for loss and 0.5% (0.2-0.9%) for gain and was higher than in controls (P=0.005 and P=0.001, respectively).


CONCLUSIONS
Our findings support the hypothesis suggesting that subtle genomic imbalances manifesting as low-level mosaic aneuploidy may contribute to schizophrenia pathogenesis.
Yurov
Yuri B
YB
National Research Center of Mental Health, Russian Academy of Medical Sciences, Moscow 119152, Russian Federation. y_yurov@yahoo.com
Iourov
Ivan Y
IY
Vorsanova
Svetlana G
SG
Demidova
Irina A
IA
Kravetz
Viktor S
VS
Beresheva
Alphia K
AK
Kolotii
Alexei D
AD
Monakchov
Viktor V
VV
Uranova
Natalia A
NA
Vostrikov
Viktor M
VM
Soloviev
Ilia V
IV
Liehr
Thomas
T
D017668:Age of Onset; D000782:Aneuploidy; D001921:Brain / Q000378:metabolism*; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics* / Q000378:metabolism; D035061:Control Groups; D005260:Female; D042822:Genomic Instability / Q000235:genetics; D006801:Humans; D017404:In Situ Hybridization, Fluorescence / Q000379:methods; D008297:Male; D008875:Middle Aged; D009030:Mosaicism; D012559:Schizophrenia / Q000235:genetics* / Q000378:metabolism*; D013269:Stochastic Processes