Implication of SSAT by gene expression and genetic variation in suicide and major depression.
BACKGROUND
A large body of evidence suggests that predisposition to suicide, an important public health problem, is mediated to a certain extent by neurobiological factors.


OBJECTIVE
To investigate patterns of expression in suicide with and without major depression and to identify new molecular targets that may play a role in the neurobiology of these conditions.


METHODS
Brain gene expression analysis was performed using the Affymetrix HG-U133 chipset in the orbital cortex (Brodmann area [BA] 11), the dorsolateral prefrontal cortex (BA8/9), and motor cortex (BA4). Subsequent studies were carried out in independent samples from adjacent areas to validate positive findings, confirm their relevance at the protein level, and investigate possible effects of genetic variation.


METHODS
We investigated 12 psychiatrically normal control subjects and 24 suicide victims, including 16 with and 8 without major depression, in the brain gene expression analysis, validation, and protein studies. The genetic studies included 181 suicide completers and 80 psychiatrically normal controls. All subjects investigated were male and of French Canadian origin.


METHODS
Gene expression measures from microarray, semiquantitative reverse transcription-polymerase chain reaction, immunohistochemistry, and Western blot analyses.


RESULTS
Twenty-six genes were selected because of the consistency of their expression pattern (fold change, >1.3 in either direction [P<or=.01] in at least 2 regions). The spermine/spermidine N(1)-acetyltransferase gene (SSAT) was successfully validated by reverse transcription-polymerase chain reaction, immunohistochemistry, and Western blot analyses. A variant located in the SSAT polyamine-responsive element regulatory region (SSAT342A/C) demonstrated a significant effect of genotype on SSAT brain expression levels (F(1) = 5.34; P = .02). Further investigation of this variant in an independent sample of 181 male suicide completers and 80 male controls showed a higher frequency of the SSAT342C allele among suicide cases (odds ratio, 2.7; 95% confidence interval, 1.4-5.3; P = .005), suggesting that this allele may increase predisposition to suicide.


CONCLUSIONS
These data suggest a role for SSAT, the rate-limiting enzyme in the catabolism of polyamines, in suicide and depression and a role for the SSAT342 locus in the regulation of SSAT gene expression.
Sequeira
Adolfo
A
McGill Group for Suicide Studies, Douglas Hospital, McGill University, Montreal, Quebec, Canada.
Gwadry
Fuad G
FG
Ffrench-Mullen
Jarlath M H
JM
Canetti
Lilian
L
Gingras
Yves
Y
Casero
Robert A
RA
Rouleau
Guy
G
Benkelfat
Chawki
C
Turecki
Gustavo
G
D000123:Acetyltransferases / Q000235:genetics* / Q000378:metabolism; D000328:Adult; D015153:Blotting, Western; D002540:Cerebral Cortex / Q000378:metabolism; D002874:Chromosome Mapping; D016000:Cluster Analysis; D003865:Major Depressive Disorder / Q000175:diagnosis / Q000235:genetics*; D020869:Gene Expression Profiling / Q000706:statistics & numerical data; D020022:Genetic Predisposition to Disease / Q000235:genetics* / Q000523:psychology; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009044:Motor Cortex / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis / Q000706:statistics & numerical data*; D015345:Oligonucleotide Probes; D017397:Prefrontal Cortex / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013405:Suicide / Q000523:psychology / Q000706:statistics & numerical data*; D000099228:Diamine N-Acetyltransferase
D000123:Acetyltransferases; D015345:Oligonucleotide Probes; D000099228:Diamine N-Acetyltransferase