A genome-wide scan for linkage to chromosomal regions in 382 sibling pairs with schizophrenia or schizoaffective disorder.
OBJECTIVE
Some genome-wide scans and association studies for schizophrenia susceptibility genes have yielded significant positive findings, but there is disagreement between studies on their locations, and no mutation has yet been found in any gene. Since schizophrenia is a complex disorder, a study with sufficient power to detect a locus with a small or moderate gene effect is necessary.


METHODS
In a genome-wide scan of 382 sibling pairs with a diagnosis of schizophrenia or schizoaffective disorder, 396 highly polymorphic markers spaced approximately 10 centimorgans apart throughout the genome were genotyped in all individuals. Multipoint nonparametric linkage analysis was performed to evaluate regions of the genome demonstrating increased allele sharing, as measured by a lod score.


RESULTS
Two regions with multipoint maximum lod scores suggesting linkage were found. The highest lod scores occurred on chromosome 10p15-p13 (peak lod score of 3.60 at marker D10S189) and the centromeric region of chromosome 2 (peak lod score of 2.99 at marker D2S139). In addition, a maximum lod score of 2.00 was observed with marker D22S283 on chromosome 22q12, which showed evidence of an imprinting effect, whereby an excess sharing of maternal, but not paternal, alleles was present. No evidence of linkage was obtained at several locations identified in previous studies, including chromosomes 1q, 4p, 5p-q, 6p, 8p, 13q, 15p, and 18p.


CONCLUSIONS
The findings of this large genome-wide scan emphasize the weakness and fragility of linkage reports on schizophrenia. No linkage appears to be consistently replicable across large studies. Thus, it has to be questioned whether the genetic contribution to this disorder is detectable by these strategies and the possibility raised that it may be epigenetic, i.e., related to gene expression rather than sequence variation. Nevertheless, the positive findings on chromosome 2, 10, and 22 should be pursued further.
DeLisi
Lynn E
LE
Department of Psychiatry, New York University, New York, NY 10016, USA. DeLisi76@aol.com
Shaw
Sarah H
SH
Crow
Timothy J
TJ
Shields
Gail
G
Smith
Angela B
AB
Larach
Veronica W
VW
Wellman
Nigel
N
Loftus
Josephine
J
Nanthakumar
Betsy
B
Razi
Kamran
K
Stewart
John
J
Comazzi
Margherita
M
Vita
Antonio
A
Heffner
Thomas
T
Sherrington
Robin
R
D002874:Chromosome Mapping / Q000379:methods / Q000706:statistics & numerical data*; D002877:Chromosomes, Human / Q000235:genetics; D005190:Family; D005260:Female; D015870:Gene Expression / Q000235:genetics; D005787:Gene Frequency; D005819:Genetic Markers; D014644:Genetic Variation; D015894:Genome, Human; D018392:Genomic Imprinting / Q000235:genetics; D005838:Genotype; D006801:Humans; D008126:Lod Score; D008297:Male; D018895:Microsatellite Repeats; D010375:Pedigree; D011110:Polymorphism, Genetic; D011618:Psychotic Disorders / Q000235:genetics*; D012559:Schizophrenia / Q000235:genetics*; D017421:Sequence Analysis
D005819:Genetic Markers