The genetics of symptom-based phenotypes: toward a molecular classification of schizophrenia.
OBJECTIVE
Genetic linkage studies in schizophrenia (SZ) have primarily focused on the phenotype of disease susceptibility. A limited number of studies, however, have reported suggestive linkage to specific SZ symptom domains including regions on chromosomes 6, 8, and 20. We examined these chromosomal regions for association to positive, negative, and disorganized symptom clusters, using a dense set of single-nucleotide polymorphisms (SNPs).


METHODS
We ascertained 178 Caucasian patients with SZ for lifetime severity of clinical symptomatology using a structured diagnostic interview. The cohort was genotyped with the Affymetrix 500K microarray, from which we selected, a priori, 4833 intragenic SNPs located within chromosomal regions previously linked to specific SZ symptom clusters. Parametric tests, corrected for multiple testing, were used to compare the effects of allelic variation within these SNPs to the lifetime severity of the specific symptom domain that had been implicated by prior linkage studies.


RESULTS
We were able to extend previous reports of linkage between chromosome 6q and both positive and disorganized symptoms. Lifetime severity of positive symptoms was significantly (P = 2.50 x 10(-5)) associated with a SNP within the origin recognition complex subunit 3-like (ORC3L) gene, a gene implicated in synaptic plasticity. Level of disorganized symptoms was significantly (P < 6.00 x 10(-5)) associated 2 SNPs within the brain-specific angiogenesis inhibitor 3 (BAI3) gene, which is highly expressed in brain during development.


CONCLUSIONS
These data point toward specific candidate genes located within previously implicated linkage peaks for clinical symptomatology. Identification of functional variants within these regions and a characterization of the effect of these risk genotypes on the treatment of specific clinical symptoms are needed.
DeRosse
Pamela
P
Center for Translational Psychiatry, The Feinstein Institute for Medical Research, Manhasset, NY, USA. pderosse@lij.edu
Lencz
Todd
T
Burdick
Katherine E
KE
Siris
Samuel G
SG
Kane
John M
JM
Malhotra
Anil K
AK
D000483:Alleles; D002890:Chromosomes, Human, Pair 20 / Q000235:genetics*; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics*; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics*; D015331:Cohort Studies; D008040:Genetic Linkage; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D006801:Humans; D008126:Lod Score; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009473:Neuronal Plasticity / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D051738:Origin Recognition Complex / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011569:Psychiatric Status Rating Scales; D011618:Psychotic Disorders / Q000145:classification* / Q000235:genetics* / Q000523:psychology; D012559:Schizophrenia / Q000145:classification* / Q000235:genetics*; D012565:Schizophrenic Psychology
C111500:ADGRB3 protein, human; D005819:Genetic Markers; D009419:Nerve Tissue Proteins; C497225:ORC3 protein, human; D051738:Origin Recognition Complex